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1.  Genome-Wide Testing of Putative Functional Exonic Variants in Relationship with Breast and Prostate Cancer Risk in a Multiethnic Population 
PLoS Genetics  2013;9(3):e1003419.
Rare variation in protein coding sequence is poorly captured by GWAS arrays and has been hypothesized to contribute to disease heritability. Using the Illumina HumanExome SNP array, we successfully genotyped 191,032 common and rare non-synonymous, splice site, or nonsense variants in a multiethnic sample of 2,984 breast cancer cases, 4,376 prostate cancer cases, and 7,545 controls. In breast cancer, the strongest associations included either SNPs in or gene burden scores for genes LDLRAD1, SLC19A1, FGFBP3, CASP5, MMAB, SLC16A6, and INS-IGF2. In prostate cancer, one of the most associated SNPs was in the gene GPRC6A (rs2274911, Pro91Ser, OR = 0.88, P = 1.3×10−5) near to a known risk locus for prostate cancer; other suggestive associations were noted in genes such as F13A1, ANXA4, MANSC1, and GP6. For both breast and prostate cancer, several of the most significant associations involving SNPs or gene burden scores (sum of minor alleles) were noted in genes previously reported to be associated with a cancer-related phenotype. However, only one of the associations (rs145889899 in LDLRAD1, p = 2.5×10−7 only seen in African Americans) for overall breast or prostate cancer risk was statistically significant after correcting for multiple comparisons. In addition to breast and prostate cancer, other cancer-related traits were examined (body mass index, PSA level, and alcohol drinking) with a number of known and potentially novel associations described. In general, these findings do not support there being many protein coding variants of moderate to high risk for breast and prostate cancer with odds ratios over a range that is probably required for protein coding variation to play a truly outstanding role in risk heritability. Very large sample sizes will be required to better define the role of rare and less penetrant coding variation in prostate and breast cancer disease genetics.
Author Summary
For breast and prostate cancer, GWAS have revealed many risk variants (>70 for each cancer as of this report). All together the common variants in these regions explain only a minority of familial risk of these cancers. Using the Illumina HumanExome SNP array, we explored the hypothesis of rare coding variation contributing to breast and prostate cancer risk in a sample of African American, Latino, Japanese, Native Hawaiian, and European American breast and prostate cancer cases and controls from the Multiethnic Cohort study. While only one association exceeded significance thresholds after correcting for multiple comparisons, a number of suggestive associations involving genes previously reported to be associated with a cancer-related phenotype were noted. Our results do not generally support a major role of protein-coding variants with odds ratios over a range that is probably required for protein coding variation to play a truly outstanding role in risk heritability. If very rare and/or less penetrant coding variants underlie disease heritability of these cancers, then very large sample sizes (i.e. consortia) will be required for their discovery.
doi:10.1371/journal.pgen.1003419
PMCID: PMC3610631  PMID: 23555315
2.  Genetic Variation in the HSD17B1 Gene and Risk of Prostate Cancer 
PLoS Genetics  2005;1(5):e68.
Steroid hormones are believed to play an important role in prostate carcinogenesis, but epidemiological evidence linking prostate cancer and steroid hormone genes has been inconclusive, in part due to small sample sizes or incomplete characterization of genetic variation at the locus of interest. Here we report on the results of a comprehensive study of the association between HSD17B1 and prostate cancer by the Breast and Prostate Cancer Cohort Consortium, a large collaborative study. HSD17B1 encodes 17β-hydroxysteroid dehydrogenase 1, an enzyme that converts dihydroepiandrosterone to the testosterone precursor Δ5-androsterone-3β,17β-diol and converts estrone to estradiol. The Breast and Prostate Cancer Cohort Consortium researchers systematically characterized variation in HSD17B1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNPs) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,290 prostate cancer cases and 9,367 study-, age-, and ethnicity-matched controls. We found no evidence that HSD17B1 htSNPs (including the nonsynonymous coding SNP S312G) or htSNP haplotypes were associated with risk of prostate cancer or tumor stage in the pooled multiethnic sample or in U.S. and European whites. Analyses stratified by age, body mass index, and family history of disease found no subgroup-specific associations between these HSD17B1 htSNPs and prostate cancer. We found significant evidence of heterogeneity in associations between HSD17B1 haplotypes and prostate cancer across ethnicity: one haplotype had a significant (p < 0.002) inverse association with risk of prostate cancer in Latinos and Japanese Americans but showed no evidence of association in African Americans, Native Hawaiians, or whites. However, the smaller numbers of Latinos and Japanese Americans in this study makes these subgroup analyses less reliable. These results suggest that the germline variants in HSD17B1 characterized by these htSNPs do not substantially influence the risk of prostate cancer in U.S. and European whites.
Synopsis
Steroid hormones such as estrogen and testosterone are hypothesized to play a role in the development of cancer. This is the first substantive paper from the Breast and Prostate Cancer Cohort Consortium, a large, international study designed to assess the effect of variation in genes that influence hormone production and activity on the risk of breast and prostate cancer. The investigators first constructed a detailed map of genetic variation spanning HSD17B1, a gene involved in the production of estrogen and testosterone. This enabled them to efficiently measure common variation across the whole gene, capturing information about both known variants with a plausible function and unknown variants with an unknown function. Because of the results with a large number of study participants, the investigators could rule out strong associations between common HSD17B1 variants and risk of prostate cancer among U.S. and European whites. While this sheds some light on the carcinogenic effects of one enzyme involved in the complex process of steroid hormone production, it remains to be determined whether variants in other genes play a more important role or if the combined effects of several genes within these pathways have a larger impact.
doi:10.1371/journal.pgen.0010068
PMCID: PMC1287955  PMID: 16311626
3.  A Prospective Study of Plasma Vitamin D Metabolites, Vitamin D Receptor Polymorphisms, and Prostate Cancer 
PLoS Medicine  2007;4(3):e103.
Background
Vitamin D insufficiency is a common public health problem nationwide. Circulating 25-hydroxyvitamin D3 (25[OH]D), the most commonly used index of vitamin D status, is converted to the active hormone 1,25 dihydroxyvitamin D3 (1,25[OH]2D), which, operating through the vitamin D receptor (VDR), inhibits in vitro cell proliferation, induces differentiation and apoptosis, and may protect against prostate cancer. Despite intriguing results from laboratory studies, previous epidemiological studies showed inconsistent associations of circulating levels of 25(OH)D, 1,25(OH)2D, and several VDR polymorphisms with prostate cancer risk. Few studies have explored the joint association of circulating vitamin D levels with VDR polymorphisms.
Methods and Findings
During 18 y of follow-up of 14,916 men initially free of diagnosed cancer, we identified 1,066 men with incident prostate cancer (including 496 with aggressive disease, defined as stage C or D, Gleason 7–10, metastatic, and fatal prostate cancer) and 1,618 cancer-free, age- and smoking-matched control participants in the Physicians' Health Study. We examined the associations of prediagnostic plasma levels of 25(OH)D and 1,25(OH)2D, individually and jointly, with total and aggressive disease, and explored whether relations between vitamin D metabolites and prostate cancer were modified by the functional VDR FokI polymorphism, using conditional logistic regression. Among these US physicians, the median plasma 25(OH)D levels were 25 ng/ml in the blood samples collected during the winter or spring and 32 ng/ml in samples collected during the summer or fall. Nearly 13% (summer/fall) to 36% (winter/spring) of the control participants were deficient in 25(OH)D (<20 ng/ml) and 51% (summer/fall) and 77% (winter/spring) had insufficient plasma 25(OH)D levels (<32 ng/ml). Plasma levels of 1,25(OH)2D did not vary by season. Men whose levels for both 25(OH)D and 1,25(OH)2D were below (versus above) the median had a significantly increased risk of aggressive prostate cancer (odds ratio [OR] = 2.1, 95% confidence interval [CI] 1.2–3.4), although the interaction between the two vitamin D metabolites was not statistically significant (pinteraction = 0.23). We observed a significant interaction between circulating 25(OH)D levels and the VDR FokI genotype (pinteraction < 0.05). Compared with those with plasma 25(OH)D levels above the median and with the FokI FF or Ff genotype, men who had low 25(OH)D levels and the less functional FokI ff genotype had increased risks of total (OR = 1.9, 95% CI 1.1–3.3) and aggressive prostate cancer (OR = 2.5, 95% CI 1.1–5.8). Among men with plasma 25(OH)D levels above the median, the ff genotype was no longer associated with risk. Conversely, among men with the ff genotype, high plasma 25(OH)D level (above versus below the median) was related to significant 60%∼70% lower risks of total and aggressive prostate cancer.
Conclusions
Our data suggest that a large proportion of the US men had suboptimal vitamin D status (especially during the winter/spring season), and both 25(OH)D and 1,25(OH)2D may play an important role in preventing prostate cancer progression. Moreover, vitamin D status, measured by 25(OH)D in plasma, interacts with the VDR FokI polymorphism and modifies prostate cancer risk. Men with the less functional FokI ff genotype (14% in the European-descent population of this cohort) are more susceptible to this cancer in the presence of low 25(OH)D status.
Results of this study by Haojie Li and colleagues suggest that vitamin D deficiency is common among men in the US, and that vitamin D status and genetic variation in theVDR gene affect prostate cancer risk.
Editors' Summary
Background.
Prostate cancer occurs when cells in the prostate gland (part of the male reproductive system) accumulate genetic changes that allow them to grow into a disorganized mass of cells. Patients whose disease is diagnosed when these cells are still relatively normal can survive for many years, but for patients with aggressive cancers—ones containing fast-growing cells that can migrate around the body—the outlook is poor. Factors that increase prostate cancer risk include increasing age, having a family history of prostate cancer, and being African American. Also, there are hints that some environmental or dietary factors affect prostate cancer risk. One of these factors is vitamin D, of which high levels are found in seafood and dairy products, but which can also be made naturally by the body—more specifically, by sunlight-exposed skin. One reason researchers think vitamin D might protect against prostate cancer is that this cancer is more common in sun-starved northern countries (where people often have a vitamin D deficiency) than in sunny regions. Prostate cancer is also more common in African American men than in those of European descent (when exposed to the same amount of sunlight, individuals with darker skin make less vitamin D than those with lighter skin). Once in the human body, vitamin D is converted into the vitamin D metabolite 25-hydroxyvitamin D3 (25[OH]D) and then into the active hormone 1,25 dihydroxyvitamin D3 (1,25[OH]2D). This binds to vitamin D receptors (VDRs) and inhibits cell proliferation and migration.
Why Was This Study Done?
The effect of 1,25(OH)2D on cells and the observation that related chemicals slow prostate cancer growth in rodents suggest that vitamin D protects against prostate cancer. But circulating levels of vitamin D metabolites in human male populations do not always reflect how many men develop prostate cancer. This lack of correlation may partly be because different forms of the VDR gene exist. One area of variation in the VDR gene is called the FokI polymorphism. Because everyone carries two copies of the VDR gene, individuals may have a FokI FF, FokI Ff, or FokI ff genotype. The f variant (or allele) codes for a receptor that is less responsive to 1,25(OH)2D than the receptor encoded by the FokI F allele. So levels of vitamin D sufficient to prevent cancer in one person may be insufficient in someone with a different FokI genotype. In this study, the researchers have investigated how levels of 25(OH)D and 1,25(OH)2D in combination with different VDR FokI alleles are influencing prostate cancer risk.
What Did the Researchers Do and Find?
The researchers identified 1,066 men who developed prostate cancer between enrollment into the US Physicians' Health Study in 1982 and 2000, and 1,618 cancer-free men of the same ages and smoking levels as “controls.” They measured vitamin D metabolite levels in many of the blood samples taken from these men in 1982 and determined their FokI genotype. Two-thirds of the men had insufficient blood levels of vitamin D metabolites in the winter/spring; almost one-third had a vitamin D deficiency. Men whose blood levels of both metabolites were below average were twice as likely to develop aggressive prostate cancer as those in whom both levels were above average. Compared with men with high blood levels of 25(OH)D and the FokI FF or Ff genotype, men with low 25(OH)D levels and the FokI ff genotype were 2.5 times as likely to develop aggressive prostate cancer. However, men with the ff genotype were not at higher risk if they had sufficient 25(OH)D levels. Among men with the ff genotype, sufficient 25(OH)D levels might therefore protect against prostate cancer, especially against the clinically aggressive form.
What Do These Findings Mean?
These findings confirm that many US men have suboptimal levels of circulating vitamin D. This vitamin is essential for healthy bones, so irrespective of its effects on prostate cancer, vitamin D supplements might improve overall health. In addition, this large and lengthy study reveals an association between low levels of the two vitamin D metabolites and aggressive prostate cancer that is consistent with vitamin D helping to prevent the progression of prostate cancer. It also indicates that the VDR FokI genotype modifies the prostate cancer risk associated with different blood levels of vitamin D. Together, these results suggest that improving vitamin D status through increased exposure to sun and vitamin D supplements might reduce prostate cancer risk, particularly in men with the FokI ff genotype. Because the study participants were mainly of European descent, the researchers caution that these results may not apply to other ethnic groups and note that further detailed studies are needed to understand fully how vitamin D affects prostate cancer risk across the population.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040103.
MedlinePlus encyclopedia has pages on prostate cancer and on vitamin D
Information for patients and physicians is available from the US National Cancer Institute on prostate cancer and on cancer prevention
The Prostate Cancer Foundation's information on prostate cancer discusses the effects of nutrition on the disease
Patient information on prostate cancer is available from Cancer Research UK
Cancerbackup also has patient information on prostate cancer
doi:10.1371/journal.pmed.0040103
PMCID: PMC1831738  PMID: 17388667
4.  The BARD1 Cys557Ser Variant and Breast Cancer Risk in Iceland 
PLoS Medicine  2006;3(7):e217.
Background
Most, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer.
Methods and Findings
The Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.11–3.01, p = 0.014). The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22–4.75, p = 0.015). Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16–8.40, p = 0.046) in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors of contemporary carriers lived in a single county in the southeast of Iceland and that all carriers shared a SNP haplotype, which is suggestive of a founder event. Cys557Ser was found on the same SNP haplotype background in the HapMap Project CEPH sample of Utah residents.
Conclusions
Our findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation.
Editors' Summary
Background.
About 13% of women (one in eight women) will develop breast cancer during their lifetime, but many factors affect the likelihood of any individual woman developing this disease, for example, whether she has had children and at what age, when she started and stopped her periods, and her exposure to certain chemicals or radiation. She may also have inherited a defective gene that affects her risk of developing breast cancer. Some 5%–10% of all breast cancers are familial, or inherited. In 20% of these cases, the gene that is defective is BRCA1 or BRCA2. Inheriting a defective copy of one of these genes greatly increases a woman's risk of developing breast cancer, while researchers think that the other inherited genes that predispose to breast cancer—most of which have not been identified yet—have a much weaker effect. These are described as low-penetrance genes. Inheriting one such gene only slightly increases breast cancer risk; a woman has to inherit several to increase her lifetime risk of cancer significantly.
Why Was This Study Done?
It is important to identify these additional predisposing gene variants because they might provide insights into why breast cancer develops, how to prevent it, and how to treat it. To find low-penetrance genes, researchers do case–control association studies. They find a large group of women with breast cancer (cases) and a similar group of women without cancer (controls), and examine how often a specific gene variant occurs in the two groups. If the variant is found more often in the cases than in the controls, it might be a variant that increases a woman's risk of developing breast cancer.
What Did the Researchers Do and Find?
The researchers involved in this study recruited Icelandic women who had had breast cancer and unaffected women, and looked for a specific variant—the Cys557Ser allele—of a gene called BARD1. They chose BARD1 because the protein it encodes interacts with the protein encoded by BRCA1. Because defects in BRCA1 increase the risk of breast cancer, defects in an interacting protein might have a similar effect. In addition, the Cys557Ser allele has been implicated in breast cancer in other studies. The researchers found that the Cys557Ser allele was nearly twice as common in women with breast cancer as in control women. It was also more common (but not by much) in women who had a family history of breast cancer or who had developed breast cancer more than once. And having the Cys557Ser allele seemed to increase the already high risk of breast cancer in women who had a BRCA2 variant (known as BRCA2 999del5) that accounts for 40% of inherited breast cancer risk in Iceland.
What Do These Findings Mean?
These results indicate that inheriting the BARD1 Cys557Ser allele increases a woman's breast cancer risk but that she is unlikely to have a family history of the disease. Because carrying the Cys557Ser allele only slightly increases a woman's risk of breast cancer, for most women there is no clinical reason to test for this variant. Eventually, when all the low-penetrance genes that contribute to breast cancer risk have been identified, it might be helpful to screen women for the full set to determine whether they are at high risk of developing breast cancer. This will not happen for many years, however, since there might be tens or hundreds of these genes. For women who carry BRCA2 999del5, the situation might be different. It might be worth testing these women for the BARD1 Cys557Ser allele, the researchers explain, because the lifetime probability of developing breast cancer in women carrying both variants might approach 100%. This finding has clinical implications in terms of counseling and monitoring, as does the observation that Cys557Ser carriers have an increased risk of a second, independent breast cancer compared to non-carriers. However, all these findings need to be confirmed in other groups of patients before anyone is routinely tested for the BARD1 Cys557Ser allele.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030217.
• MedlinePlus pages about breast cancer
• Information on breast cancer from the United States National Cancer Institute
• Information on inherited breast cancer from the United States National Human Genome Research Institute
• United States National Cancer Institute information on genetic testing for BRCA1 and BRCA2 variants
• GeneTests pages on the involvement of BRCA1 and BRCA2 in hereditary breast and ovarian cancer
• Cancer Research UK's page on breast cancer statistics
In a population-based cohort of 1090 Icelandic patients, a Cys557Ser missense variant of the BARD1 gene, which interacts with BRCA1, increased the risk of single and multiple primary breast cancers.
doi:10.1371/journal.pmed.0030217
PMCID: PMC1479388  PMID: 16768547
5.  Analysis of the 10q11 Cancer Risk Locus Implicates MSMB and NCOA4 in Human Prostate Tumorigenesis 
PLoS Genetics  2010;6(11):e1001204.
Genome-wide association studies (GWAS) have established a variant, rs10993994, on chromosome 10q11 as being associated with prostate cancer risk. Since the variant is located outside of a protein-coding region, the target genes driving tumorigenesis are not readily apparent. Two genes nearest to this variant, MSMB and NCOA4, are strong candidates for mediating the effects of rs109939934. In a cohort of 180 individuals, we demonstrate that the rs10993994 risk allele is associated with decreased expression of two MSMB isoforms in histologically normal and malignant prostate tissue. In addition, the risk allele is associated with increased expression of five NCOA4 isoforms in histologically normal prostate tissue only. No consistent association with either gene is observed in breast or colon tissue. In conjunction with these findings, suppression of MSMB expression or NCOA4 overexpression promotes anchorage-independent growth of prostate epithelial cells, but not growth of breast epithelial cells. These data suggest that germline variation at chromosome 10q11 contributes to prostate cancer risk by influencing expression of at least two genes. More broadly, the findings demonstrate that disease risk alleles may influence multiple genes, and associations between genotype and expression may only be observed in the context of specific tissue and disease states.
Author Summary
Family history has long been recognized as an important risk factor for prostate cancer. Beginning in 2006, researchers have identified several genetic variants that are associated with prostate cancer risk. Intriguingly, the majority of prostate cancer risk variants do not reside in genes. Determining the genes involved in the development of disease, therefore, has proved challenging. In this study we interrogate a known prostate cancer risk polymorphism on chromosome 10—rs10993994. We report that this variant is significantly associated with the RNA expression levels of two genes—MSMB and NCOA4. When these expression changes are modeled in a cell line, prostate cells that were previously non-tumorigenic acquire a property known as anchorage independence, a characteristic of cancer cells. Notably, the prostate risk variant is not associated with expression or functional changes in breast or colon cells. In addition, the effects are most pronounced in normal rather than tumor prostate tissue. Overall, these findings help define the genes driving prostate cancer risk at chromosome 10. More generally, the discoveries demonstrate the importance of considering several target genes, as well as the importance of cellular context (tissue type and histological state), in future analyses of other genetic risk regions.
doi:10.1371/journal.pgen.1001204
PMCID: PMC2978684  PMID: 21085629
6.  DEAR1 Is a Dominant Regulator of Acinar Morphogenesis and an Independent Predictor of Local Recurrence-Free Survival in Early-Onset Breast Cancer 
PLoS Medicine  2009;6(5):e1000068.
Ann Killary and colleagues describe a new gene that is genetically altered in breast tumors, and that may provide a new breast cancer prognostic marker.
Background
Breast cancer in young women tends to have a natural history of aggressive disease for which rates of recurrence are higher than in breast cancers detected later in life. Little is known about the genetic pathways that underlie early-onset breast cancer. Here we report the discovery of DEAR1 (ductal epithelium–associated RING Chromosome 1), a novel gene encoding a member of the TRIM (tripartite motif) subfamily of RING finger proteins, and provide evidence for its role as a dominant regulator of acinar morphogenesis in the mammary gland and as an independent predictor of local recurrence-free survival in early-onset breast cancer.
Methods and Findings
Suppression subtractive hybridization identified DEAR1 as a novel gene mapping to a region of high-frequency loss of heterozygosity (LOH) in a number of histologically diverse human cancers within Chromosome 1p35.1. In the breast epithelium, DEAR1 expression is limited to the ductal and glandular epithelium and is down-regulated in transition to ductal carcinoma in situ (DCIS), an early histologic stage in breast tumorigenesis. DEAR1 missense mutations and homozygous deletion (HD) were discovered in breast cancer cell lines and tumor samples. Introduction of the DEAR1 wild type and not the missense mutant alleles to complement a mutation in a breast cancer cell line, derived from a 36-year-old female with invasive breast cancer, initiated acinar morphogenesis in three-dimensional (3D) basement membrane culture and restored tissue architecture reminiscent of normal acinar structures in the mammary gland in vivo. Stable knockdown of DEAR1 in immortalized human mammary epithelial cells (HMECs) recapitulated the growth in 3D culture of breast cancer cell lines containing mutated DEAR1, in that shDEAR1 clones demonstrated disruption of tissue architecture, loss of apical basal polarity, diffuse apoptosis, and failure of lumen formation. Furthermore, immunohistochemical staining of a tissue microarray from a cohort of 123 young female breast cancer patients with a 20-year follow-up indicated that in early-onset breast cancer, DEAR1 expression serves as an independent predictor of local recurrence-free survival and correlates significantly with strong family history of breast cancer and the triple-negative phenotype (ER−, PR−, HER-2−) of breast cancers with poor prognosis.
Conclusions
Our data provide compelling evidence for the genetic alteration and loss of expression of DEAR1 in breast cancer, for the functional role of DEAR1 in the dominant regulation of acinar morphogenesis in 3D culture, and for the potential utility of an immunohistochemical assay for DEAR1 expression as an independent prognostic marker for stratification of early-onset disease.
Editors' Summary
Background
Each year, more than one million women discover that they have breast cancer. This type of cancer begins when cells in the breast that line the milk-producing glands or the tubes that take the milk to the nipples (glandular and ductal epithelial cells, respectively) acquire genetic changes that allow them to grow uncontrollably and to move around the body (metastasize). The uncontrolled division leads to the formation of a lump that can be detected by mammography (a breast X-ray) or by manual breast examination. Breast cancer is treated by surgical removal of the lump or, if the cancer has started to spread, by removal of the whole breast (mastectomy). Surgery is usually followed by radiotherapy or chemotherapy. These “adjuvant” therapies are designed to kill any remaining cancer cells but can make patients very ill. Generally speaking, the outlook for women with breast cancer is good. In the US, for example, nearly 90% of affected women are still alive five years after their diagnosis.
Why Was This Study Done?
Although breast cancer is usually diagnosed in women in their 50s or 60s, some women develop breast cancer much earlier. In these women, the disease is often very aggressive. Compared to older women, young women with breast cancer have a lower overall survival rate and their cancer is more likely to recur locally or to metastasize. It would be useful to be able to recognize those younger women at the greatest risk of cancer recurrence so that they could be offered intensive surveillance and adjuvant therapy; those women at a lower risk could have gentler treatments. To achieve this type of “stratification,” the genetic changes that underlie breast cancer in young women need to be identified. In this study, the researchers discover a gene that is genetically altered (by mutations or deletion) in early-onset breast cancer and then investigate whether its expression can predict outcomes in women with this disease.
What Did the Researchers Do and Find?
The researchers used “suppression subtractive hybridization” to identify a new gene in a region of human Chromosome 1 where loss of heterozygosity (LOH; a genetic alteration associated with cancer development) frequently occurs. They called the gene DEAR1 (ductal epithelium-associated RING Chromosome 1) to indicate that it is expressed in ductal and glandular epithelial cells and encodes a “RING finger” protein (specifically, a subtype called a TRIM protein; RING finger proteins such as BRCA1 and BRCA2 have been implicated in early cancer development and in a large fraction of inherited breast cancers). DEAR1 expression was reduced or lost in several ductal carcinomas in situ (a local abnormality that can develop into breast cancer) and advanced breast cancers, the researchers report. Furthermore, many breast tumors carried DEAR1 missense mutations (genetic changes that interfere with the normal function of the DEAR1 protein) or had lost both copies of DEAR1 (the human genome contains two copies of most genes). To determine the function of DEAR1, the researchers replaced a normal copy of DEAR1 into a breast cancer cell that had a mutation in DEAR1. They then examined the growth of these genetically manipulated cells in special three-dimensional cultures. The breast cancer cells without DEAR1 grew rapidly without an organized structure while the breast cancer cells containing the introduced copy of DEAR1 formed structures that resembled normal breast acini (sac-like structures that secrete milk). In normal human mammary epithelial cells, the researchers silenced DEAR1 expression and also showed that without DEAR1, the normal mammary cells lost their ability to form proper acini. Finally, the researchers report that DEAR1 expression (detected “immunohistochemically”) was frequently lost in women who had had early-onset breast cancer and that the loss of DEAR1 expression correlated with reduced local recurrence-free survival, a strong family history of breast cancer and with a breast cancer subtype that has a poor outcome.
What Do These Findings Mean?
These findings indicate that genetic alteration and loss of expression of DEAR1 are common in breast cancer. Although laboratory experiments may not necessarily reflect what happens in people, the results from the three-dimensional culture of breast epithelial cells suggest that DEAR1 may regulate the normal acinar structure of the breast. Consequently, loss of DEAR1 expression could be an early event in breast cancer development. Most importantly, the correlation between DEAR1 expression and both local recurrence in early-onset breast cancer and a breast cancer subtype with a poor outcome suggests that it might be possible to use DEAR1 expression to identify women with early-onset breast cancer who have an increased risk of local recurrence so that they get the most appropriate treatment for their cancer.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000068.
This study is further discussed in a PLoS Medicine Perspective by Senthil Muthuswamy
The US National Cancer Institute provides detailed information for patients and health professionals on all aspects of breast cancer, including information on genetic alterations in breast cancer (in English and Spanish)
The MedlinePlus Encyclopedia provides information for patients about breast cancer; MedlinePlus also provides links to many other breast cancer resources (in English and Spanish)
The UK charities Cancerbackup (now merged with MacMillan Cancer Support) and Cancer Research UK also provide detailed information about breast cancer
doi:10.1371/journal.pmed.1000068
PMCID: PMC2673042  PMID: 19536326
7.  A comprehensive analysis of the androgen receptor gene and risk of breast cancer: results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3) 
Breast Cancer Research  2006;8(5):R54.
Introduction
Androgens have been hypothesised to influence risk of breast cancer through several possible mechanisms, including their conversion to estradiol or their binding to the oestrogen receptor and/or androgen receptor (AR) in the breast. Here, we report on the results of a large and comprehensive study of the association between genetic variation in the AR gene and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3).
Methods
The underlying genetic variation was determined by first sequencing the coding regions of the AR gene in a panel of 95 advanced breast cancer cases. Second, a dense set of markers from the public database was genotyped in a panel of 349 healthy women. The linkage disequilibrium relationships (blocks) across the gene were then identified, and haplotype-tagging single nucleotide polymorphisms (htSNPs) were selected to capture the common genetic variation across the locus. The htSNPs were then genotyped in the nested breast cancer cases and controls from the Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study, and Women's Health Study cohorts (5,603 breast cancer cases and 7,480 controls).
Results
We found no association between any genetic variation (SNP, haplotype, or the exon 1 CAG repeat) in the AR gene and risk of breast cancer, nor were any statistical interactions with known breast cancer risk factors observed.
Conclusion
Among postmenopausal Caucasian women, common variants of the AR gene are not associated with risk of breast cancer.
doi:10.1186/bcr1602
PMCID: PMC1779488  PMID: 16987421
8.  Immediate Risk for Cardiovascular Events and Suicide Following a Prostate Cancer Diagnosis: Prospective Cohort Study 
PLoS Medicine  2009;6(12):e1000197.
Katja Fall and Fang Fang and colleagues find that men newly diagnosed with prostate cancer are at increased risk of cardiovascular events and suicide.
Background
Stressful life events have been shown to be associated with altered risk of various health consequences. The aim of the present study was to investigate whether the emotional stress evoked by a prostate cancer diagnosis increases the immediate risks of cardiovascular events and suicide.
Methods and Findings
We conducted a prospective cohort study by following all men in Sweden who were 30 y or older (n = 4,305,358) for a diagnosis of prostate cancer (n = 168,584) and their subsequent occurrence of cardiovascular events and suicide between January 1, 1961 and December 31, 2004. We used Poisson regression models to calculate relative risks (RRs) and 95% confidence intervals (CIs) of cardiovascular events and suicide among men who had prostate cancer diagnosed within 1 y to men without any cancer diagnosis. The risks of cardiovascular events and suicide were elevated during the first year after prostate cancer diagnosis, particularly during the first week. Before 1987, the RR of fatal cardiovascular events was 11.2 (95% CI 10.4–12.1) during the first week and 1.9 (95% CI 1.9–2.0) during the first year after diagnosis. From 1987, the RR for cardiovascular events, nonfatal and fatal combined, was 2.8 (95% CI 2.5–3.2) during the first week and 1.3 (95% CI 1.3–1.3) during the first year after diagnosis. While the RR of cardiovascular events declined, the RR of suicide was stable over the entire study period: 8.4 (95% CI 1.9–22.7) during the first week and 2.6 (95% CI 2.1–3.0) during the first year after diagnosis. Men 54 y or younger at cancer diagnosis demonstrated the highest RRs of both cardiovascular events and suicide. A limitation of the present study is the lack of tumor stage data, which precluded possibilities of investigating the potential impact of the disease severity on the relationship between a recent diagnosis of prostate cancer and the risks of cardiovascular events and suicide. In addition, we cannot exclude residual confounding as a possible explanation.
Conclusions
Men newly diagnosed with prostate cancer are at increased risks for cardiovascular events and suicide. Future studies with detailed disease characteristic data are warranted.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Prostate cancer—a type of tumor that develops in a walnut-sized structure in the male reproductive system—is the commonest cancer (excluding skin cancer) among men in developed countries. In the USA and the UK, for example, one in six men will develop prostate cancer during their lifetime. Most prostate cancers develop in elderly men and, because these tumors usually grow relatively slowly, many men die with prostate cancer rather than as a result of it. Nevertheless, some prostate cancers are fast-growing and aggressive and prostate cancer is the second leading cause of cancer-related death among men. The symptoms of prostate cancer include problems urinating and excessive urination during the night. Nowadays, however, most prostate cancers are detected before they produce any symptoms by measuring the amount of a protein called the prostate-specific antigen (PSA) in the blood.
Why Was This Study Done?
Widespread PSA screening was introduced 20 years ago in the hope that early detection of prostate cancer would save lives. But, although many more prostate cancers are detected nowadays, the number of prostate cancer deaths has not changed significantly. Experts are divided, therefore, about whether the potential benefits of PSA screening outweigh its risks. Treatments for prostate cancer (for example, surgical removal of the prostate) may be more effective if they are started early but they can cause impotence and urinary incontinence, so should men be treated whose cancer might otherwise never affect their health? In addition, receiving a diagnosis of prostate cancer is stressful and there is growing evidence that stressful life events can increase an individual's risk of becoming ill or dying from a heart attack, stroke, or other “cardiovascular” events and of becoming mentally ill. In this study, therefore, the researchers investigate whether men diagnosed with prostate cancer in Sweden have increased risks of cardiovascular events and suicide during the first week and first year after their diagnosis.
What Did the Researchers Do and Find?
The researchers identified nearly 170, 000 men diagnosed with prostate cancer between 1961 and 2004 among Swedish men aged 30 years or older by searching the Swedish Cancer Register. They obtained information on subsequent fatal and nonfatal cardiovascular events and suicides from the Causes of Death Register and the Inpatient Register (in Sweden, everyone has a unique national registration number that facilitates searches of different health-related Registers). Before 1987, men with prostate cancer were about 11 times as likely to have a fatal cardiovascular event during the first week after their diagnosis as men without prostate cancer; during the first year after their diagnosis, men with prostate cancer were nearly twice as likely to have a cardiovascular event as men without prostate cancer (a relative risk of 1.9). From 1987, the relative risk of combined fatal and nonfatal cardiovascular events associated with a diagnosis of prostate cancer was 2.8 during the first week and 1.3 during the first year after diagnosis. The relative risk of suicide associated with a diagnosis of prostate cancer was 8.4 during the first week and 2.6 during the first year after diagnosis throughout the study period. Finally, men younger than 54 years at diagnosis had higher relative risks of both cardiovascular events and suicide.
What Do These Findings Mean?
These findings suggest that men newly diagnosed with prostate cancer have an increased risk of cardiovascular events and suicide. Because there is no information on tumor size or aggressiveness in the Cancer Register, the researchers could not look at the relationship between disease severity and the likelihood of a cardiovascular event or suicide. Furthermore, because of the study design, men who received a diagnosis of prostate cancer may have had additional characteristics in common that contributed to their increased risk of cardiovascular events and suicide. Nevertheless, these findings strongly suggest that the stress of the diagnosis itself rather than any subsequent treatment has deleterious effects on the health of men receiving a diagnosis of prostate cancer. Thus, strategies should be developed to reduce the risks of cardiovascular events and suicide—increased clinical and psychological monitoring—after a diagnosis of prostate cancer, particularly among young men, and this new information should be considered in the ongoing debate about the risks and benefits of PSA screening.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000197.
The US National Cancer Institute provides information on all aspects of prostate cancer, (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on prostate cancer, including Prostate Cancer Screening, A Decision Guide (some information in multiple languages)
The UK National Health Service Choices Web site provides detailed information on prostate cancer
The UK-based Samaritans charity provides confidential nonjudgmental emotional support, 24 hours a day, for people who are experiencing feelings of distress or despair, including those which could lead to suicide
Outside the UK, Befrienders provides information on help lines for those experiencing distress
doi:10.1371/journal.pmed.1000197
PMCID: PMC2784954  PMID: 20016838
9.  PTGS2 and IL6 genetic variation and risk of breast and prostate cancer: results from the Breast and Prostate Cancer Cohort Consortium (BPC3) 
Carcinogenesis  2009;31(3):455-461.
Genes involved in the inflammation pathway have been associated with cancer risk. Genetic variants in the interleukin-6 (IL6) and prostaglandin-endoperoxide synthase-2 (PTGS2, encoding for the COX-2 enzyme) genes, in particular, have been related to several cancer types, including breast and prostate cancers. We conducted a study within the Breast and Prostate Cancer Cohort Consortium to examine the association between IL6 and PTGS2 polymorphisms and breast and prostate cancer risk. Twenty-seven polymorphisms, selected by pairwise tagging, were genotyped on 6292 breast cancer cases and 8135 matched controls and 8008 prostate cancer cases and 8604 matched controls. The large sample sizes and comprehensive single nucleotide polymorphism tagging in this study gave us excellent power to detect modest effects for common variants. After adjustment for multiple testing, none of the associations examined remained statistically significant at P = 0.01. In analyses not adjusted for multiple testing, one IL6 polymorphism (rs6949149) was marginally associated with breast cancer risk (TT versus GG, odds ratios (OR): 1.32; 99% confidence intervals (CI): 1.00–1.74, Ptrend = 0.003) and two were marginally associated with prostate cancer risk (rs6969502-AA versus rs6969502-GG, OR: 0.87, 99% CI: 0.75–1.02; Ptrend = 0.002 and rs7805828-AA versus rs7805828-GG, OR: 1.11, 99% CI: 0.99–1.26; Ptrend = 0.007). An increase in breast cancer risk was observed for the PTGS2 polymorphism rs7550380 (TT versus GG, OR: 1.38, 99% CI: 1.04–1.83). No association was observed between PTGS2 polymorphisms and prostate cancer risk. In conclusion, common genetic variation in these two genes might play at best a limited role in breast and prostate cancers.
doi:10.1093/carcin/bgp307
PMCID: PMC2832545  PMID: 19965896
10.  Smoking and high-risk mammographic parenchymal patterns: a case-control study 
Breast Cancer Research  1999;2(1):59-63.
Current smoking was strongly and inversely associated with high-risk patterns, after adjustment for concomitant risk factors. Relative to never smokers, current smokers were significantly less likely to have a high-risk pattern. Similar results were obtained when the analysis was confined to postmenopausal women. Past smoking was not related to the mammographic parenchymal patterns. The overall effect in postmenopausal women lost its significance when adjusted for other risk factors for P2/DY patterns that were found to be significant in the present study, although the results are still strongly suggestive. The present data indicate that adjustment for current smoking status is important when evaluating the relationship between mammographic parenchymal pattern and breast cancer risk. They also indicate that smoking is a prominent potential confounder when analyzing effects of other risk factors such as obesity-related variables. It appears that parenchymal patterns may act as an informative biomarker of the effect of cigarette smoking on breast cancer risk.
Introduction:
Overall, epidemiological studies [1,2,3,4] have reported no substantial association between cigarette smoking and the risk of breast cancer. Some studies [5,6,7] reported a significant increase of breast cancer risk among smokers. In recent studies that addressed the association between breast cancer and cigarette smoking, however, there was some suggestion of a decreased risk [8,9,10], especially among current smokers, ranging from approximately 10 to 30% [9,10]. Brunet et al [11] reported that smoking might reduce the risk of breast cancer by 44% in carriers of BRCA1 or BRCA2 gene mutations. Wolfe [12] described four different mammographic patterns created by variations in the relative amounts of fat, epithelial and connective tissue in the breast, designated N1, P1, P2 and DY. Women with either P2 or DY pattern are considered at greater risk for breast cancer than those with N1 or P1 pattern [12,13,14,15]. There are no published studies that assessed the relationship between smoking and mammographic parenchymal patterns.
Aims:
To evaluate whether mammographic parenchymal patterns as classified by Wolfe, which have been positively associated with breast cancer risk, are affected by smoking. In this case-control study, nested within the European Prospective Investigation on Cancer in Norfolk (EPIC-Norfolk) cohort [16], the association between smoking habits and mammographic parenchymal patterns are examined. The full results will be published elsewhere.
Methods:
Study subjects were members of the EPIC cohort in Norwich who also attended the prevalence screening round at the Norwich Breast Screening Centre between November 1989 and December 1997, and were free of breast cancer at that screening. Cases were defined as women with a P2/DY Wolfe's mammographic parenchymal pattern on the prevalence screen mammograms. A total of 203 women with P2/DY patterns were identified as cases and were individually matched by date of birth (within 1 year) and date of prevalence screening (within 3 months) with 203 women with N1/P1 patterns who served as control individuals.
Two views, the mediolateral and craniocaudal mammograms, of both breasts were independently reviewed by two of the authors (ES and RW) to determine the Wolfe mammographic parenchymal pattern.
Considerable information on health and lifestyle factors was available from the EPIC Health and Lifestyle Questionnaire [16]. In the present study we examined the subjects' personal history of benign breast diseases, menstrual and reproductive factors, oral contraception and hormone replacement therapy, smoking, and anthropometric information such as body mass index and waist:hip ratio.
Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated by conditional logistic regression [17], and were adjusted for possible confounding factors.
Results:
The characteristics of the cases and controls are presented in Table 1. Cases were leaner than controls. A larger percentage of cases were nulliparous, premenopausal, current hormone replacement therapy users, had a personal history of benign breast diseases, and had had a hysterectomy. A larger proportion of controls had more than three births and were current smokers.
Table 2 shows the unadjusted and adjusted OR estimates for Wolfe's high-risk mammographic parenchymal patterns and smoking in the total study population and in postmenopausal women separately. Current smoking was strongly and inversely associated with high-risk patterns, after adjustment for concomitant risk factors. Relative to never smokers, current smokers were significantly less likely to have a high-risk pattern (OR 0.37, 95% CI 0.14-0.94). Similar results were obtained when the analysis was confined to postmenopausal women. Past smoking was not related to mammographic parenchymal patterns. The overall effect in postmenopausal women lost its significance when adjusted for other risk factors for P2/DY patterns that were found to be significant in the present study, although the results were still strongly suggestive. There was no interaction between cigarette smoking and body mass index.
Discussion:
In the present study we found a strong inverse relationship between current smoking and high-risk mammographic parenchymal patterns of breast tissue as classified by Wolfe [12]. These findings are not completely unprecedented; Greendale et al [18] found a reduced risk of breast density in association with smoking, although the magnitude of the reduction was unclear. The present findings suggest that this reduction is large.
Recent studies [9,10] have suggested that breast cancer risk may be reduced among current smokers. In a multicentre Italian case-control study, Braga et al [10] found that, relative to nonsmokers, current smokers had a reduced risk of breast cancer (OR 0.84, 95% CI 0.7-1.0). These findings were recently supported by Gammon et al [9], who reported that breast cancer risk in younger women (younger than 45 years) may be reduced among current smokers who began smoking at an early age (OR 0.59, 95% CI 0.41-0.85 for age 15 years or younger) and among long-term smokers (OR 0.70, 95% CI 0.52-0.94 for those who had smoked for 21 years or more).
The possible protective effect of smoking might be due to its anti-oestrogenic effect [1,2,19]. Recently there has been renewed interest in the potential effect of smoking on breast cancer risk, and whether individuals may respond differently on the basis of differences in metabolism of bioproducts of smoking [20,21]. Different relationships between smoking and breast cancer risk have been suggested that are dependent on the rapid or slow status of acetylators of aromatic amines [20,21]. More recent studies [22,23], however, do not support these findings.
The present study design minimized the opportunity for bias to influence the findings. Because subjects were unaware of their own case-control status, the possibility of recall bias in reporting smoking status was minimized. Systematic error in the assessment of mammograms was avoided because reading was done without knowledge of the risk factor data. Furthermore, the associations observed are unlikely to be explained by the confounding effect of other known breast cancer risk factors, because we adjusted for these in the analysis. We did not have information on passive smoking status, however, which has recently been reported to be a possible confounder [5,6,21,24].
The present data indicate that adjustment for current smoking status is important when evaluating the relationship between mammographic parenchymal pattern and breast cancer risk. They also indicate smoking as a prominent potential confounder when analyzing effects of other risk factors such as obesity-related variables. It seems that parenchymal patterns may act as an informative biomarker of the effect of cigarette smoking on breast cancer risk.
PMCID: PMC13911  PMID: 11056684
mammography; screening; smoking; Wolfe's parenchymal patterns
11.  Risk Prediction for Breast, Endometrial, and Ovarian Cancer in White Women Aged 50 y or Older: Derivation and Validation from Population-Based Cohort Studies 
PLoS Medicine  2013;10(7):e1001492.
Ruth Pfeiffer and colleagues describe models to calculate absolute risks for breast, endometrial, and ovarian cancers for white, non-Hispanic women over 50 years old using easily obtainable risk factors.
Please see later in the article for the Editors' Summary
Background
Breast, endometrial, and ovarian cancers share some hormonal and epidemiologic risk factors. While several models predict absolute risk of breast cancer, there are few models for ovarian cancer in the general population, and none for endometrial cancer.
Methods and Findings
Using data on white, non-Hispanic women aged 50+ y from two large population-based cohorts (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [PLCO] and the National Institutes of Health–AARP Diet and Health Study [NIH-AARP]), we estimated relative and attributable risks and combined them with age-specific US-population incidence and competing mortality rates. All models included parity. The breast cancer model additionally included estrogen and progestin menopausal hormone therapy (MHT) use, other MHT use, age at first live birth, menopausal status, age at menopause, family history of breast or ovarian cancer, benign breast disease/biopsies, alcohol consumption, and body mass index (BMI); the endometrial model included menopausal status, age at menopause, BMI, smoking, oral contraceptive use, MHT use, and an interaction term between BMI and MHT use; the ovarian model included oral contraceptive use, MHT use, and family history or breast or ovarian cancer. In independent validation data (Nurses' Health Study cohort) the breast and ovarian cancer models were well calibrated; expected to observed cancer ratios were 1.00 (95% confidence interval [CI]: 0.96–1.04) for breast cancer and 1.08 (95% CI: 0.97–1.19) for ovarian cancer. The number of endometrial cancers was significantly overestimated, expected/observed = 1.20 (95% CI: 1.11–1.29). The areas under the receiver operating characteristic curves (AUCs; discriminatory power) were 0.58 (95% CI: 0.57–0.59), 0.59 (95% CI: 0.56–0.63), and 0.68 (95% CI: 0.66–0.70) for the breast, ovarian, and endometrial models, respectively.
Conclusions
These models predict absolute risks for breast, endometrial, and ovarian cancers from easily obtainable risk factors and may assist in clinical decision-making. Limitations are the modest discriminatory ability of the breast and ovarian models and that these models may not generalize to women of other races.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2008, just three types of cancer accounted for 10% of global cancer-related deaths. That year, about 460,000 women died from breast cancer (the most frequently diagnosed cancer among women and the fifth most common cause of cancer-related death). Another 140,000 women died from ovarian cancer, and 74,000 died from endometrial (womb) cancer (the 14th and 20th most common causes of cancer-related death, respectively). Although these three cancers originate in different tissues, they nevertheless share many risk factors. For example, current age, age at menarche (first period), and parity (the number of children a woman has had) are all strongly associated with breast, ovarian, and endometrial cancer risk. Because these cancers share many hormonal and epidemiological risk factors, a woman with a high breast cancer risk is also likely to have an above-average risk of developing ovarian or endometrial cancer.
Why Was This Study Done?
Several statistical models (for example, the Breast Cancer Risk Assessment Tool) have been developed that estimate a woman's absolute risk (probability) of developing breast cancer over the next few years or over her lifetime. Absolute risk prediction models are useful in the design of cancer prevention trials and can also help women make informed decisions about cancer prevention and treatment options. For example, a woman at high risk of breast cancer might decide to take tamoxifen for breast cancer prevention, but ideally she needs to know her absolute endometrial cancer risk before doing so because tamoxifen increases the risk of this cancer. Similarly, knowledge of her ovarian cancer risk might influence a woman's decision regarding prophylactic removal of her ovaries to reduce her breast cancer risk. There are few absolute risk prediction models for ovarian cancer, and none for endometrial cancer, so here the researchers develop models to predict the risk of these cancers and of breast cancer.
What Did the Researchers Do and Find?
Absolute risk prediction models are constructed by combining estimates for risk factors from cohorts with population-based incidence rates from cancer registries. Models are validated in an independent cohort by testing their ability to identify people with the disease in an independent cohort and their ability to predict the observed numbers of incident cases. The researchers used data on white, non-Hispanic women aged 50 years or older that were collected during two large prospective US cohort studies of cancer screening and of diet and health, and US cancer incidence and mortality rates provided by the Surveillance, Epidemiology, and End Results Program to build their models. The models all included parity as a risk factor, as well as other factors. The model for endometrial cancer, for example, also included menopausal status, age at menopause, body mass index (an indicator of the amount of body fat), oral contraceptive use, menopausal hormone therapy use, and an interaction term between menopausal hormone therapy use and body mass index. Individual women's risk for endometrial cancer calculated using this model ranged from 1.22% to 17.8% over the next 20 years depending on their exposure to various risk factors. Validation of the models using data from the US Nurses' Health Study indicated that the endometrial cancer model overestimated the risk of endometrial cancer but that the breast and ovarian cancer models were well calibrated—the predicted and observed risks for these cancers in the validation cohort agreed closely. Finally, the discriminatory power of the models (a measure of how well a model separates people who have a disease from people who do not have the disease) was modest for the breast and ovarian cancer models but somewhat better for the endometrial cancer model.
What Do These Findings Mean?
These findings show that breast, ovarian, and endometrial cancer can all be predicted using information on known risk factors for these cancers that is easily obtainable. Because these models were constructed and validated using data from white, non-Hispanic women aged 50 years or older, they may not accurately predict absolute risk for these cancers for women of other races or ethnicities. Moreover, the modest discriminatory power of the breast and ovarian cancer models means they cannot be used to decide which women should be routinely screened for these cancers. Importantly, however, these well-calibrated models should provide realistic information about an individual's risk of developing breast, ovarian, or endometrial cancer that can be used in clinical decision-making and that may assist in the identification of potential participants for research studies.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001492.
This study is further discussed in a PLOS Medicine Perspective by Lars Holmberg and Andrew Vickers
The US National Cancer Institute provides comprehensive information about cancer (in English and Spanish), including detailed information about breast cancer, ovarian cancer, and endometrial cancer;
Information on the Breast Cancer Risk Assessment Tool, the Surveillance, Epidemiology, and End Results Program, and on the prospective cohort study of screening and the diet and health study that provided the data used to build the models is also available on the NCI site
Cancer Research UK, a not-for-profit organization, provides information about cancer, including detailed information on breast cancer, ovarian cancer, and endometrial cancer
The UK National Health Service Choices website has information and personal stories about breast cancer, ovarian cancer, and endometrial cancer; the not-for-profit organization Healthtalkonline also provides personal stories about dealing with breast cancer and ovarian cancer
doi:10.1371/journal.pmed.1001492
PMCID: PMC3728034  PMID: 23935463
12.  Genetic architecture of cancer and other complex diseases: lessons learned and future directions 
Carcinogenesis  2011;32(7):945-954.
Genome-wide association studies have broadened our understanding of the genetic architecture of cancer to include common variants, in addition to the rare variants previously identified by linkage analysis. We review current knowledge on the genetic architecture of four cancers—breast, lung, prostate and colorectal—for which the balance of common and rare alleles identified ranges from fewer common alleles (lung cancer) to more common alleles (prostate cancer). Although most variants are cancer specific, pleiotropy has been observed for several variants, for example, variants at the 8q24 locus and breast, ovarian and prostate cancers or variants in KITLG in relation to hair color and testicular cancer. Although few studies have been adequately powered to investigate heterogeneity among ancestry groups, effect sizes associated with common variants have been reported to be fairly homogenous among ethnic groups. Some associations appear to be ancestry specific, such as HNF1B, which is associated with prostate cancer in European Americans and Latinos but not in African-Americans. Studies of cancer and other complex diseases suggest that a simple dichotomy between rare and common allelic architectures may be too simplistic and that future research is needed to characterize a fuller spectrum of allele frequency (common (>5%), uncommon (1–5%) and rare (<<1%) alleles) and effect size. In addition, a broadening of the concept of genetic architecture to encompass both population architecture, which reflects differences in exposures, genetic factors and population level risk among diverse groups of people, and genomic architecture, which includes structural, epigenomic and somatic variation, is envisioned.
doi:10.1093/carcin/bgr056
PMCID: PMC3140138  PMID: 21459759
13.  Risk of a Second Primary Cancer after Non-melanoma Skin Cancer in White Men and Women: A Prospective Cohort Study 
PLoS Medicine  2013;10(4):e1001433.
Studies have suggested a positive association between history of non-melanoma skin cancer (NMSC) and risk of subsequent cancer at other sites. This prospective study found a modestly increased risk of subsequent malignancies among individuals with a history of NMSC, specifically breast and lung cancer in women and melanoma in both men and women.
Background
Previous studies suggest a positive association between history of non-melanoma skin cancer (NMSC) and risk of subsequent cancer at other sites. The purpose of this study is to prospectively examine the risk of primary cancer according to personal history of NMSC.
Methods and Findings
In two large US cohorts, the Health Professionals Follow-up Study (HPFS) and the Nurses' Health Study (NHS), we prospectively investigated this association in self-identified white men and women. In the HPFS, we followed 46,237 men from June 1986 to June 2008 (833,496 person-years). In the NHS, we followed 107,339 women from June 1984 to June 2008 (2,116,178 person-years). We documented 29,447 incident cancer cases other than NMSC. Cox proportional hazard models were used to calculate relative risks (RRs) and 95% confidence intervals (CIs). A personal history of NMSC was significantly associated with a higher risk of other primary cancers excluding melanoma in men (RR = 1.11; 95% CI 1.05–1.18), and in women (RR = 1.20; 95% CI 1.15–1.25). Age-standardized absolute risk (AR) was 176 in men and 182 in women per 100,000 person-years. For individual cancer sites, after the Bonferroni correction for multiple comparisons (n = 28), in men, a personal history of NMSC was significantly associated with an increased risk of melanoma (RR = 1.99, AR = 116 per 100,000 person-years). In women, a personal history of NMSC was significantly associated with an increased risk of breast (RR = 1.19, AR = 87 per 100,000 person-years), lung (RR = 1.32, AR = 22 per 100,000 person-years), and melanoma (RR = 2.58, AR = 79 per 100,000 person-years).
Conclusion
This prospective study found a modestly increased risk of subsequent malignancies among individuals with a history of NMSC, specifically breast and lung cancer in women and melanoma in both men and women.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In the United Kingdom and the United States, about one in three people develop cancer during their lifetime and, worldwide, cancer is responsible for 13% of all deaths. Primary cancer, which can develop anywhere in the body, occurs when a cell begins to divide uncontrollably because of alterations (mutations) in its genes. Additional mutations allow the malignancy to spread around the body (metastasize) and form secondary cancers. The mutations that initiate cancer can be triggered by exposure to carcinogens such as cigarette smoke (lung cancer) or the ultraviolet (UV) radiation in sunlight (skin cancers). Other risk factors for the development of cancer include an unhealthy diet, physical inactivity, and alcohol use. In the United States, the most common cancer is non-melanoma skin cancer (NMSC). Although more than 2 million new cases of NMSC occur each year, fewer than 1,000 people die annually in the United States from the condition because the two types of NMSC—basal cell carcinoma and squamous cell carcinoma—rarely metastasize and can usually be treated by surgically removing the tumor.
Why Was This Study Done?
Some studies have suggested that people who have had NMSC have a higher risk of developing primary cancer at other sites than people who have not had NMSC. Such a situation could arise if exposure to certain carcinogens initiates both NMSC and other cancers or if NMSC shares a molecular mechanism with other cancers such as a deficiency in the DNA repair mechanisms that normally remove mutations. If people with a history of NMSC are at a greater risk of developing further cancers, a specific surveillance program for such people might help to catch subsequent cancers early when they can be successfully treated. In this prospective cohort study, the researchers examine the risk of primary cancer according to personal history of NMSC in two large US cohorts (groups)—the Health Professionals Follow-up Study (HPFS) and the Nurses' Health Study (NHS). The HPFS, which enrolled 51,529 male health professionals in 1986, and the NHS, which enrolled 121,700 female nurses in 1976, were both designed to investigate associations between nutritional factors and the incidence of serious illnesses. Study participants completed a baseline questionnaire about their lifestyle, diet and medical history. This information is updated biennially through follow-up questionnaires.
What Did the Researchers Do and Find?
The researchers identified 36,102 new cases of NMSC and 29,447 new cases of other primary cancers from 1984 in white NHS participants and from 1986 in white HPFS participants through 2008. They then used statistical models to investigate whether a personal history of NMSC was associated with a higher risk of subsequent primary cancers after accounting for other factors (confounders) that might affect cancer risk. A history of NMSC was significantly associated with an 11% higher risk of other primary cancers excluding melanoma (another type of skin cancer that, like NMSC, is linked to overexposure to UV light) in men and a 20% higher risk of other primary cancers excluding melanoma in women; a significant association is one that is unlikely to have happened by chance. The absolute risk of a primary cancer among men and women with a history of NMSC was 176 and 182 per 100,000 person-years, respectively. For individual cancer sites, after correction for multiple comparisons (when several conditions are compared in groups of people, statistically significant differences between the groups can occur by chance), a history of NMSC was significantly associated with an increased risk of breast and lung cancer in women and of melanoma in men and women.
What Do These Findings Mean?
These findings suggest that there is a modestly increased risk of subsequent malignancies among white individuals with a history of NMSC. Although the researchers adjusted for many confounding lifestyle factors, the observed association between NMSC and subsequent primary cancers may nevertheless be the result of residual confounding, so it is still difficult to be sure that there is a real biological association (due to, for example, a deficiency in DNA repair) between NMSC and subsequent primary cancers. Because of this and other study limitations, the findings reported here should be interpreted cautiously and do not suggest that individuals who have had NMSC should undergo increased cancer surveillance. These findings do, however, support the need for continued investigation of the apparent relationship between NMSC and subsequent cancers.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001433.
The US National Cancer Institute provides information on all aspects of cancer and has detailed information about non-melanoma skin cancer for patients and professionals (in English and Spanish)
The non-profit organization American Cancer Society provides information on cancer and how it develops and specific information on skin cancer (in several languages); its website includes personal stories about cancer
The UK National Health Service Choices website includes an introduction to cancer and a page on non-melanoma skin cancer
The non-profit organization Cancer Research UK provides basic information about cancer and detailed information on non-melanoma skin cancer
doi:10.1371/journal.pmed.1001433
PMCID: PMC3635863  PMID: 23630459
14.  Short rare hTERT-VNTR2-2nd alleles are associated with prostate cancer susceptibility and influence gene expression 
BMC Cancer  2010;10:393.
Background
The hTERT (human telomerase reverse transcriptase) gene contains five variable number tandem repeats (VNTR) and previous studies have described polymorphisms for hTERT-VNTR2-2nd. We investigated how allelic variation in hTERT-VNTR2-2nd may affect susceptibility to prostate cancer.
Methods
A case-control study was performed using DNA from 421 cancer-free male controls and 329 patients with prostate cancer. In addition, to determine whether the VNTR polymorphisms have a functional consequence, we examined the transcriptional levels of a reporter gene linked to these VNTRs and driven by the hTERT promoter in cell lines.
Results
Three new rare alleles were detected from this study, two of which were identified only in cancer subjects. A statistically significant association between rare hTERT-VNTR2-2nd alleles and risk of prostate cancer was observed [OR, 5.17; 95% confidence interval (CI), 1.09-24.43; P = 0.021]. Furthermore, the results indicated that these VNTRs inserted in the enhancer region could influence the expression of hTERT in prostate cancer cell lines.
Conclusions
This is the first study to report that rare hTERT VNTRs are associated with prostate cancer predisposition and that the VNTRs can induce enhanced levels of hTERT promoter activity in prostate cancer cell lines. Thus, the hTERT-VNTR2-2nd locus may function as a modifier of prostate cancer risk by affecting gene expression.
doi:10.1186/1471-2407-10-393
PMCID: PMC2915984  PMID: 20659312
15.  A Functional Variant at a Prostate Cancer Predisposition Locus at 8q24 Is Associated with PVT1 Expression 
PLoS Genetics  2011;7(7):e1002165.
Genetic mapping studies have identified multiple cancer susceptibility regions at chromosome 8q24, upstream of the MYC oncogene. MYC has been widely presumed as the regulated target gene, but definitive evidence functionally linking these cancer regions with MYC has been difficult to obtain. Here we examined candidate functional variants of a haplotype block at 8q24 encompassing the two independent risk alleles for prostate and breast cancer, rs620861 and rs13281615. We used the mapping of DNase I hypersensitive sites as a tool to prioritise regions for further functional analysis. This approach identified rs378854, which is in complete linkage disequilibrium (LD) with rs620861, as a novel functional prostate cancer-specific genetic variant. We demonstrate that the risk allele (G) of rs378854 reduces binding of the transcription factor YY1 in vitro. This factor is known to repress global transcription in prostate cancer and is a candidate tumour suppressor. Additional experiments showed that the YY1 binding site is occupied in vivo in prostate cancer, but not breast cancer cells, consistent with the observed cancer-specific effects of this single nucleotide polymorphism (SNP). Using chromatin conformation capture (3C) experiments, we found that the region surrounding rs378854 interacts with the MYC and PVT1 promoters. Moreover, expression of the PVT1 oncogene in normal prostate tissue increased with the presence of the risk allele of rs378854, while expression of MYC was not affected. In conclusion, we identified a new functional prostate cancer risk variant at the 8q24 locus, rs378854 allele G, that reduces binding of the YY1 protein and is associated with increased expression of PVT1 located 0.5 Mb downstream.
Author Summary
Genome-wide association studies have been very successful at identifying gene loci that are associated with common diseases. However for many of these it has been very difficult to elucidate the identity and function of the risk variant and how altered function predisposes to disease. A 1.2-Mb gene-poor region upstream of the MYC oncogene has been shown to contain at least 12 risk loci associated with different types of cancer. In this study, we use the analysis of chromatin conformation as a tool to identify sub-regions within this 1.2 Mb region that are involved in the control of gene expression, and we identify molecular mechanisms which may confer risk of different specific cancer types. In particular, we examine a risk locus that is associated with predisposition to prostate cancer and identify a DNA sequence variation that results in a change in the binding site for the nuclear factor YY1 as a potential causative mechanism. We show that the risk locus is able to interact with two downstream genes, MYC and PVT1, and present evidence that PVT1 is a candidate new target gene regulated by the 8q24 risk region.
doi:10.1371/journal.pgen.1002165
PMCID: PMC3140991  PMID: 21814516
16.  Genetic Variation in Adiponectin (ADIPOQ) and the Type-1 Receptor (ADIPOR1), Obesity and Prostate Cancer in African Americans 
Background
Adiponectin is a protein derived from adipose tissue suspected to play an important role in prostate carcinogenesis. Variants in the adiponectin gene (ADIPOQ) and its type I receptor (ADIPOR1) have been recently linked to risk of both breast and colorectal cancer. Therefore, we set out to examine the relationship between polymorphisms in these genes, obesity and prostate cancer in study of African American men.
Methods
Ten single nucleotide polymorphisms (SNPs) in ADIPOQ and ADIPOR1 were genotyped in DNA samples from 131 African American prostate cancer cases and 344 controls participating in the Flint Men's Health Study. Logistic regression was then used to estimate their association with prostate cancer and obesity.
Results
While no significant associations were detected between any of the tested SNPs and prostate cancer, the rs1501299 SNP in ADIPOQ was significantly associated with body mass (p=0.03).
Conclusions
Genetic variation in ADIPOQ and ADIPOR1 did not predict risk of prostate cancer in this study of African American men. However, the rs1501299 SNP in ADIPOQ was associated with obesity. Further investigation is warranted to determine if racial differences exist in the influence of the adiponectin pathway on prostate cancer risk.
doi:10.1038/pcan.2010.27
PMCID: PMC2978765  PMID: 20697428
adipokines; body mass index; genetic susceptibility; single nucleotide polymorphism; racial differences
17.  Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk 
Gaudet, Mia M. | Kuchenbaecker, Karoline B. | Vijai, Joseph | Klein, Robert J. | Kirchhoff, Tomas | McGuffog, Lesley | Barrowdale, Daniel | Dunning, Alison M. | Lee, Andrew | Dennis, Joe | Healey, Sue | Dicks, Ed | Soucy, Penny | Sinilnikova, Olga M. | Pankratz, Vernon S. | Wang, Xianshu | Eldridge, Ronald C. | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Hogervorst, Frans B. L. | Peock, Susan | Stoppa-Lyonnet, Dominique | Peterlongo, Paolo | Schmutzler, Rita K. | Nathanson, Katherine L. | Piedmonte, Marion | Singer, Christian F. | Thomassen, Mads | Hansen, Thomas v. O. | Neuhausen, Susan L. | Blanco, Ignacio | Greene, Mark H. | Garber, Judith | Weitzel, Jeffrey N. | Andrulis, Irene L. | Goldgar, David E. | D'Andrea, Emma | Caldes, Trinidad | Nevanlinna, Heli | Osorio, Ana | van Rensburg, Elizabeth J. | Arason, Adalgeir | Rennert, Gad | van den Ouweland, Ans M. W. | van der Hout, Annemarie H. | Kets, Carolien M. | Aalfs, Cora M. | Wijnen, Juul T. | Ausems, Margreet G. E. M. | Frost, Debra | Ellis, Steve | Fineberg, Elena | Platte, Radka | Evans, D. Gareth | Jacobs, Chris | Adlard, Julian | Tischkowitz, Marc | Porteous, Mary E. | Damiola, Francesca | Golmard, Lisa | Barjhoux, Laure | Longy, Michel | Belotti, Muriel | Ferrer, Sandra Fert | Mazoyer, Sylvie | Spurdle, Amanda B. | Manoukian, Siranoush | Barile, Monica | Genuardi, Maurizio | Arnold, Norbert | Meindl, Alfons | Sutter, Christian | Wappenschmidt, Barbara | Domchek, Susan M. | Pfeiler, Georg | Friedman, Eitan | Jensen, Uffe Birk | Robson, Mark | Shah, Sohela | Lazaro, Conxi | Mai, Phuong L. | Benitez, Javier | Southey, Melissa C. | Schmidt, Marjanka K. | Fasching, Peter A. | Peto, Julian | Humphreys, Manjeet K. | Wang, Qin | Michailidou, Kyriaki | Sawyer, Elinor J. | Burwinkel, Barbara | Guénel, Pascal | Bojesen, Stig E. | Milne, Roger L. | Brenner, Hermann | Lochmann, Magdalena | Aittomäki, Kristiina | Dörk, Thilo | Margolin, Sara | Mannermaa, Arto | Lambrechts, Diether | Chang-Claude, Jenny | Radice, Paolo | Giles, Graham G. | Haiman, Christopher A. | Winqvist, Robert | Devillee, Peter | García-Closas, Montserrat | Schoof, Nils | Hooning, Maartje J. | Cox, Angela | Pharoah, Paul D. P. | Jakubowska, Anna | Orr, Nick | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Hall, Per | Couch, Fergus J. | Simard, Jacques | Altshuler, David | Easton, Douglas F. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Offit, Kenneth
PLoS Genetics  2013;9(3):e1003173.
Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80–0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
Author Summary
Women who carry BRCA2 mutations have an increased risk of breast cancer that varies widely. To identify common genetic variants that modify the breast cancer risk associated with BRCA2 mutations, we have built upon our previous work in which we examined genetic variants across the genome in relation to breast cancer risk among BRCA2 mutation carriers. Using a custom genotyping platform with 211,155 genetic variants known as single nucleotide polymorphisms (SNPs), we genotyped 3,881 women who had breast cancer and 4,330 women without breast cancer, which represents the largest possible, international collection of BRCA2 mutation carriers. We identified that a SNP located at 6p24 in the genome was associated with lower risk of breast cancer. Importantly, this SNP was not associated with breast cancer in BRCA1 mutation carriers or in a general population of women, indicating that the breast cancer association with this SNP might be specific to BRCA2 mutation carriers. Combining this BRCA2-specific SNP with 13 other breast cancer risk SNPs also known to modify risk in BRCA2 mutation carriers, we were able to derive a risk prediction model that could be useful in helping women with BRCA2 mutations weigh their risk-reduction strategy options.
doi:10.1371/journal.pgen.1003173
PMCID: PMC3609647  PMID: 23544012
18.  Linkage Disequilibrium Mapping of CHEK2: Common Variation and Breast Cancer Risk  
PLoS Medicine  2006;3(6):e168.
Background
Checkpoint kinase 2 (CHEK2) averts cancer development by promoting cell cycle arrest and activating DNA repair in genetically damaged cells. Previous investigation has established a role for the CHEK2 gene in breast cancer aetiology, but studies have largely been limited to the rare 1100delC mutation. Whether common polymorphisms in this gene influence breast cancer risk remains unknown. In this study, we aimed to assess the importance of common CHEK2 variants on population risk for breast cancer by capturing the majority of diversity in the gene using haplotype tagging single nucleotide polymorphisms (tagSNPs).
Methods and Findings
We analyzed 14 common SNPs spanning 52 kilobases (kb) of the CHEK2 gene in 92 Swedish women. Coverage evaluation indicated that these typed SNPs would efficiently convey association signal also from untyped SNPs in the same region. Six of the 14 SNPs predicted well both the haplotypic and single SNP variations within CHEK2. We genotyped these six tagSNPs in 1,577 postmenopausal breast cancer cases and 1,513 population controls, but found no convincing association between any common CHEK2 haplotype and breast cancer risk. The 1100delC mutation was rare in our Swedish population—0.7% in cases and 0.4% in controls—with a corresponding odds ratio for carriers versus noncarriers of 2.26 (95% confidence interval, 0.99–5.15). Estimates of the population frequency and the odds ratio of 1100delC indicate that our sample is representative of a Northern European population.
Conclusions
Notwithstanding the involvement of the CHEK2 gene in breast cancer aetiology, we show that common polymorphisms do not influence postmenopausal breast cancer risk.
Rare mutations in the CHEK2 gene are involved in familial breast cancer. This large study among Swedish women did not find an association between common CHEK2 variants and breast cancer.
doi:10.1371/journal.pmed.0030168
PMCID: PMC1457009  PMID: 16671833
19.  Genetic variation in the upstream region of ERG and prostate cancer 
Cancer causes & control : CCC  2009;20(7):1173-1180.
Objective
A considerable fraction of prostate cancers harbor a gene fusion between the androgen-regulated TMPRSS2 and ERG, one of the most frequently over-expressed proto-oncogenes in prostate cancer. Here, we investigated if inherited genetic variation upstream of ERG alters prostate cancer risk and survival.
Methods
We genotyped 21 haplotype tagging SNPs (htSNPs) covering 123 kb of 5′UTR DNA including exon 3 of ERG in 2,760 incident prostate cancer cases and 1,647 controls from a population-based Swedish case–control study (CAPS). Individual SNPs and haplotypes were tested for association with prostate cancer risk and survival.
Results
One haplotype—′CTCGTATG′ located 100 kb upstream of ERG—was associated with lethal prostate cancer (HR, 1.36; 95% CI, 1.2–1.9, p = 0.006). Carriers of the variant ‘T’ allele of rs2836626 were diagnosed with higher TNM-stage (p = 0.009) and had an increased risk of prostate cancer-specific death (HR = 1.3; 95% CI, 1.1–1.7, p = 0.009). However, this association did not remain statistically significant after adjusting for multiple testing. We found overall no association between ERG variation and prostate cancer risk.
Conclusions
Genetic variation upstream of ERG may alter prostate cancer stage and ultimately prostate cancer-specific death but it is unlikely that it plays a role in prostate cancer development.
doi:10.1007/s10552-009-9305-3
PMCID: PMC3755494  PMID: 19205910
Prostate cancer; ERG; Haplotype; Polymorphism; Survival
20.  Eighteen Insulin-like Growth Factor (IGF) pathway genes, circulating levels of IGF-1 and its binding protein (IGFBP-3), and risk of prostate and breast cancer 
Background
Circulating levels of insulin-like growth factor I (IGF-1) and its main binding protein, IGF binding protein 3 (IGFBP-3), have been associated with risk of several types of cancer. Heritable factors explain up to 60% of the variation in IGF-1 and IGFBP-3 in studies of adult twins.
Methods
We systematically examined common genetic variation in 18 genes in the IGF signaling pathway for associations with circulating levels of IGF-1 and IGFBP-3. A total of 302 single nucleotide polymorphisms (SNPs) were genotyped in over 5500 Caucasian men and 5500 Caucasian women from the Breast and Prostate Cancer Cohort Consortium (BPC3).
Results
After adjusting for multiple testing, SNPs in the IGF1 and SSTR5 genes were significantly associated with circulating IGF-1 (p<2.1×10−4); SNPs in the IGFBP3 and IGFALS genes were significantly associated with circulating IGFBP-3. Multi-SNP models explained R2=0.62% of the variation in circulating IGF-1 and 3.9% of the variation in circulating IGFBP-3. We saw no significant association between these multi-SNP predictors of circulating IGF-1 or IGFBP-3 and risk of prostate or breast cancers.
Conclusion
Common genetic variation in the IGF1 and SSTR5 genes appears to influence circulating IGF-1 levels, and variation in IGFBP3 and IGFALS appears to influence circulating IGFBP-3. However, these variants explain only a small percentage of the variation in circulating IGF-1 and IGFBP-3 in Caucasian men and women.
Impact
Further studies are needed to explore contributions from other genetic factors such as rare variants in these genes and variation outside of these genes.
doi:10.1158/1055-9965.EPI-10-0507
PMCID: PMC2989404  PMID: 20810604
insulin-like growth factors; genetic association; breast cancer; prostate cancer
21.  Rare Copy Number Variants Observed in Hereditary Breast Cancer Cases Disrupt Genes in Estrogen Signaling and TP53 Tumor Suppression Network 
PLoS Genetics  2012;8(6):e1002734.
Breast cancer is the most common cancer in women in developed countries, and the contribution of genetic susceptibility to breast cancer development has been well-recognized. However, a great proportion of these hereditary predisposing factors still remain unidentified. To examine the contribution of rare copy number variants (CNVs) in breast cancer predisposition, high-resolution genome-wide scans were performed on genomic DNA of 103 BRCA1, BRCA2, and PALB2 mutation negative familial breast cancer cases and 128 geographically matched healthy female controls; for replication an independent cohort of 75 similarly mutation negative young breast cancer patients was used. All observed rare variants were confirmed by independent methods. The studied breast cancer cases showed a consistent increase in the frequency of rare CNVs when compared to controls. Furthermore, the biological networks of the disrupted genes differed between the two groups. In familial cases the observed mutations disrupted genes, which were significantly overrepresented in cellular functions related to maintenance of genomic integrity, including DNA double-strand break repair (P = 0.0211). Biological network analysis in the two independent breast cancer cohorts showed that the disrupted genes were closely related to estrogen signaling and TP53 centered tumor suppressor network. These results suggest that rare CNVs represent an alternative source of genetic variation influencing hereditary risk for breast cancer.
Author Summary
Although genetic susceptibility to breast cancer has been well-established, the majority of the predisposing factors still remain unidentified. Here, we have taken advantage of recent technical and methodological advances to examine the role of a new class of genomic variation, rare copy number variants (CNVs), in hereditary predisposition to breast cancer. By examining 103 BRCA1/2 and PALB2 mutation negative familial and 75 young breast cancer cases, together with 128 geographically matched healthy female controls, we show that the frequency of rare CNVs is increased in cases when compared to controls and that the genes disrupted in individuals of specifically the two case groups are closely related to estrogen signaling and TP53 centered tumor suppressor network. The variety of disrupted genes belonging to these networks underscores that diverse mechanisms are likely to be relevant to breast cancer pathogenesis. The current results warrant the investigation of rare CNVs as new susceptibility factors in other cancer types as well.
doi:10.1371/journal.pgen.1002734
PMCID: PMC3380845  PMID: 22737080
22.  Association between Melanocytic Nevi and Risk of Breast Diseases: The French E3N Prospective Cohort 
PLoS Medicine  2014;11(6):e1001660.
Using data from the French E3N prospective cohort, Marina Kvaskoff and colleagues examine the association between number of cutaneous nevi and the risk for breast cancer.
Please see later in the article for the Editors' Summary
Background
While melanocytic nevi have been associated with genetic factors and childhood sun exposure, several observations also suggest a potential hormonal influence on nevi. To test the hypothesis that nevi are associated with breast tumor risk, we explored the relationships between number of nevi and benign and malignant breast disease risk.
Methods and Findings
We prospectively analyzed data from E3N, a cohort of French women aged 40–65 y at inclusion in 1990. Number of nevi was collected at inclusion. Hazard ratios (HRs) for breast cancer and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. Associations of number of nevi with personal history of benign breast disease (BBD) and family history of breast cancer were estimated using logistic regression. Over the period 15 June 1990–15 June 2008, 5,956 incident breast cancer cases (including 5,245 invasive tumors) were ascertained among 89,902 women. In models adjusted for age, education, and known breast cancer risk factors, women with “very many” nevi had a significantly higher breast cancer risk (HR = 1.13, 95% CI = 1.01–1.27 versus “none”; ptrend = 0.04), although significance was lost after adjustment for personal history of BBD or family history of breast cancer. The 10-y absolute risk of invasive breast cancer increased from 3,749 per 100,000 women without nevi to 4,124 (95% CI = 3,674–4,649) per 100,000 women with “very many” nevi. The association was restricted to premenopausal women (HR = 1.40, ptrend = 0.01), even after full adjustment (HR = 1.34, ptrend = 0.03; phomogeneity = 0.04), but did not differ according to breast cancer type or hormone receptor status. In addition, we observed significantly positive dose–response relationships between number of nevi and history of biopsy-confirmed BBD (n = 5,169; ptrend<0.0001) and family history of breast cancer in first-degree relatives (n = 7,472; ptrend = 0.0003). The main limitations of our study include self-report of number of nevi using a qualitative scale, and self-reported history of biopsied BBD.
Conclusions
Our findings suggest associations between number of nevi and the risk of premenopausal breast cancer, BBD, and family history of breast cancer. More research is warranted to elucidate these relationships and to understand their underlying mechanisms.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2012, nearly 1.7 million women worldwide discovered they had breast cancer, and about half a million women died from the disease. Breast cancer begins when cells in the breast acquire genetic changes that allow them to divide uncontrollably and to move around the body (metastasize). Uncontrolled cell division leads to the formation of a lump that can be detected by mammography (a breast X-ray) or by manual breast examination. Breast cancer is treated by surgical removal of the lump, or, if the cancer has started to spread, by removal of the whole breast (mastectomy). Surgery is usually followed by radiotherapy or chemotherapy to kill any remaining cancer cells. Because the female sex hormones estrogen and progesterone stimulate the growth of some tumors, drugs that block hormone receptors are also used to treat receptor-positive breast cancer. Nowadays, the prognosis (outlook) for women with breast cancer is good, and in developed countries, nearly 90% of affected women are still alive five years after diagnosis.
Why Was This Study Done?
Several hormone-related factors affect a woman's chances of developing breast cancer. For example, women who have no children or who have them late in life have a higher breast cancer risk than women who have several children when they are young because pregnancy alters sex hormone levels. Interestingly, the development of moles (nevi)—dark skin blemishes that are risk factors for the development of melanoma, a type of skin cancer—may also be affected by estrogen and progesterone. Thus, the number of nevi might be a marker of blood hormone levels and might predict breast cancer risk. In this prospective cohort study, the researchers test this hypothesis by investigating the association between how many moles a woman has and her breast cancer risk. A prospective cohort study enrolls a group (cohort) of people, determines their baseline characteristics, and follows them over time to see which characteristics are associated with the development of specific diseases.
What Did the Researchers Do and Find?
In 1990, the E3N prospective cohort study enrolled nearly 100,000 French women (mainly school teachers) aged 40–65 years to investigate cancer risk factors. The women completed a baseline questionnaire about their lifestyle and medical history, and regular follow-up questionnaires that asked about cancer occurrence. In the initial questionnaire, the women indicated whether they had no, a few, many, or very many moles. Between 1990 and 2008, nearly 6,000 women in the cohort developed breast cancer. Using statistical methods to calculate hazard ratios (an “HR” compares how often a particular event happens in two groups with different characteristics; an HR greater than one indicates that a specific characteristic is associated with an increased risk of the event), the researchers report that women with “very many” nevi had a significantly higher breast cancer risk (a higher risk that was unlikely to have occurred by chance) than women with no nevi. Specifically, the age-adjusted HR for breast cancer among women with “very many” nevi compared to women with no nevi was 1.17. After adjustment for a personal history of benign (noncancerous) breast disease and a family history of breast cancer (two established risk factors for breast cancer), the association between nevi and breast cancer risk among the whole cohort became nonsignificant. Notably, however, the association among only premenopausal women remained significant after full adjustment (HR = 1.34), which corresponded to an increase in ten-year absolute risk of invasive breast cancer from 2,515 per 100,000 women with no nevi to 3,370 per 100,000 women with “very many” nevi.
What Do These Findings Mean?
These findings suggest that among premenopausal women there is a modest association between nevi number and breast cancer risk. This noncausal relationship may indicate that nevi and breast diseases are affected in similar ways by hormones or share common genetic factors, but the accuracy of these findings may be limited by aspects of the study design. For example, self-report of nevi numbers using a qualitative scale may have introduced some inaccuracies into the estimates of the association between nevi number and breast cancer risk. Most importantly, these findings are insufficient to support the use of nevi counts in breast cancer screening or diagnosis. Rather, together with the findings reported by Zhang et al. in an independent PLOS Medicine Research Article, they suggest that further studies into the biological mechanisms underlying the relationship between nevi and breast cancer and the association itself should be undertaken.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001660.
This study is further discussed in a PLOS Medicine Perspective by Fuhrman and Cardenas
An independent PLOS Medicine Research Article by Zhang et al. also investigates the relationship between nevi number and breast cancer risk
The US National Cancer Institute provides comprehensive information about cancer (in English and Spanish), including detailed information for patients and professionals about breast cancer; it also has a fact sheet on moles
Cancer Research UK, a not-for profit organization, provides information about cancer, including detailed information on breast cancer
The UK National Health Service Choices website has information and personal stories about breast cancer; the not-for profit organization Healthtalkonline also provides personal stories about dealing with breast cancer
More information about the E3N prospective cohort study is available; detailed information is available in French
doi:10.1371/journal.pmed.1001660
PMCID: PMC4051602  PMID: 24915306
23.  Association Between a Germline OCA2 Polymorphism at Chromosome 15q13.1 and Estrogen Receptor–Negative Breast Cancer Survival 
Background
Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival.
Methods
We evaluated possible associations between overall survival after a breast cancer diagnosis and 10 621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26 978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5′ nuclease assay or mass spectrometry and overall survival information for up to 14 096 patients with invasive breast cancer (including 2303 deaths and 70 019 person-years at risk) from 15 international case–control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided.
Results
In the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor–negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 × 10−5). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P = .03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 × 10−4).
Conclusion
The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor–negative breast cancer.
doi:10.1093/jnci/djq057
PMCID: PMC2864289  PMID: 20308648
24.  Risk of prostate, ovarian, and endometrial cancer among relatives of women with breast cancer. 
BMJ : British Medical Journal  1992;305(6858):855-857.
OBJECTIVE--To investigate the risk of prostate, ovarian, and endometrial cancer among relatives of patients with breast cancer. DESIGN--Cohort study of 947 pedigrees in which the proband had breast cancer, linked with the Icelandic cancer registry. SETTING--Iceland. SUBJECTS--The 947 pedigrees included 29,725 people, of whom 1539 had breast cancer, 467 had prostate cancer, 135 ovarian cancer, and 105 endometrial cancer. MAIN OUTCOME MEASURES--Risk of prostate, ovarian, and endometrial cancer among blood relatives of women with breast cancer compared with risk in spouses. RESULTS--The risk of prostate cancer was significantly raised for all relatives (1.5), first degree relatives (1.4), and second degree relatives (1.3) of women with breast cancer. Risk of ovarian cancer was raised for all relatives (1.9) and first degree relatives (1.9) and risk of endometrial cancer was raised for all relatives only (1.9). The risk of prostate cancer was raised if the proband with breast cancer had a first degree relative with prostate cancer. CONCLUSIONS--Coaggregation exists between breast cancer and cancers of the prostate, ovaries, and endometrium. This risk relation is probably based on genes which act by increasing the risk for cancer at these sites. Environmental factors that are common among relatives may also play a part. Continued research is required into pathophysiological mechanisms that could explain these observations.
PMCID: PMC1883041  PMID: 1422397
25.  Alcohol consumption and PSA-detected prostate cancer risk—A case-control nested in the ProtecT study 
Alcohol is an established carcinogen but not an established risk factor for prostate cancer, despite some recent prospective studies suggesting increased risk among heavy drinkers. The aim of this study was to investigate the role of alcohol on prostate-specific antigen (PSA) levels and prostate cancer risk. Two thousand four hundred PSA detected prostate cancer cases and 12,700 controls matched on age and general practice were identified through a case-control study nested in the PSA-testing phase of a large UK-based randomized controlled trial for prostate cancer treatment (ProtecT). Linear and multinomial logistic regression models were used to estimate ratios of geometric means (RGMs) of PSA and relative risk ratios (RRRs) of prostate cancer by stage and grade, with 95% confidence intervals (CIs), associated with weekly alcohol intake and drinking patterns. We found evidence of lower PSA (RGM 0.98, 95% CI: 0.98–0.99) and decreased risk of low Gleason-grade (RRR 0.96; 95%CI 0.93–0.99) but increased risk of high-grade prostate cancer (RRR 1.04; 95%CI 0.99–1.08; pdifference=0.004) per 10 units/week increase in alcohol consumption, not explained by current BMI, blood pressure, comorbidities, or reverse causation. This is the first large population-based study to find evidence of lower PSA levels for increasing alcohol consumption, with potential public health implications for the detection of prostate cancer. Our results also support a modestly higher risk of high-grade disease for heavy drinkers, but require independent replication to establish the nature of the association of alcohol with low-grade disease, preferably in cohorts with a heterogeneous case-mix.
What's new?
Alcohol is not an established risk factor for prostate cancer; however, the current work suggests that heavy drinking could cause a small increase in risk of the more aggressive forms. If the results are confirmed to be causal, prostate cancer risk will be added to the many long-term health risks of heavy drinking, and public health strategies will then also reduce high-risk, poorer prognosis prostate cancer. The authors also found that heavy drinkers have lower PSA levels, suggesting that heavy alcohol consumption could be used as a marker to identify men in whom some cancers might be missed.
doi:10.1002/ijc.27877
PMCID: PMC3786564  PMID: 23024014
alcohol; prostate cancer; prostate specific antigen; ProtecT, nested case–control

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