To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers.
Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and Breast Cancer Family Registry. Eligible women were BRCA1 and BRCA2 mutation carriers diagnosed with unilateral BC since 1970 and no other invasive cancer or tamoxifen use before first BC. Hazard ratios (HRs) for CBC associated with tamoxifen use were estimated using Cox regression, adjusting for year and age of diagnosis, country, and bilateral oophorectomy and censoring at contralateral mastectomy, death, or loss to follow-up.
Of 1,583 BRCA1 and 881 BRCA2 mutation carriers, 383 (24%) and 454 (52%), respectively, took tamoxifen after first BC diagnosis. There were 520 CBCs over 20,104 person-years of observation. The adjusted HR estimates were 0.38 (95% CI, 0.27 to 0.55) and 0.33 (95% CI, 0.22 to 0.50) for BRCA1 and BRCA2 mutation carriers, respectively. After left truncating at recruitment to the cohort, adjusted HR estimates were 0.58 (95% CI, 0.29 to 1.13) and 0.48 (95% CI, 0.22 to 1.05) based on 657 BRCA1 and 426 BRCA2 mutation carriers with 100 CBCs over 4,392 person-years of prospective follow-up. HRs did not differ by estrogen receptor status of the first BC (missing for 56% of cases).
This study provides evidence that tamoxifen use is associated with a reduction in CBC risk for BRCA1 and BRCA2 mutation carriers. Further follow-up of these cohorts will provide increased statistical power for future prospective analyses.
The effects of low-dose medical radiation on breast cancer risk are uncertain, and few studies have included genetically susceptible women, such as those who carry germline BRCA1 and BRCA2 mutations.
We studied 454 BRCA1 and 273 BRCA2 mutation carriers aged <50 years from three breast cancer family registries in the USA, Canada, and Australia/New Zealand. We estimated breast cancer risk associated with diagnostic chest x-rays by comparing mutation carriers with breast cancer (cases) with those without breast cancer (controls). Exposure to chest x-rays was self-reported. Mammograms were not considered in the analysis.
After adjusting for known risk factors for breast cancer, the odds ratio (OR) for a history of diagnostic chest x-rays, excluding those for tuberculosis or pneumonia, was 1.16 (95% confidence interval (CI) = 0.64–2.11) for BRCA1 mutations carriers and 1.22 (95% CI=0.62–2.42) for BRCA2 mutations carriers. The OR was statistically elevated for BRCA2 mutation carriers with 3–5 diagnostic chest x-rays (p = 0.01), but not for those with 6 or more chest x-rays. Few women reported chest fluoroscopy for tuberculosis or chest x-rays for pneumonia; the OR estimates were elevated, but not statistically significant, for BRCA1 mutation carriers.
Our findings do not support a positive association between diagnostic chest x-rays and breast cancer risk before age 50 years for BRCA1 or BRCA2 mutation carriers.
Given the increasing use of diagnostic imaging involving higher ionizing radiation doses, further studies of genetically predisposed women are warranted.
breast cancer; BRCA1; BRCA2; chest x-rays; diagnostic radiation; epidemiology
Women with germline BRCA1 and BRCA2 mutations have five- to 20-fold increased risks of developing breast and ovarian cancer. A recent study claimed that women testing negative for their family-specific BRCA1 or BRCA2 mutation (noncarriers) have a five-fold increased risk of breast cancer. We estimated breast cancer risks for noncarriers by using a population-based sample of patients with breast cancer and their female first-degree relatives (FDRs).
Patients and Methods
Patients were women with breast cancer and their FDRs enrolled in the population-based component of the Breast Cancer Family Registry; patients with breast cancer were tested for BRCA1 and BRCA2 mutations, as were FDRs of identified mutation carriers. We used segregation analysis to fit a model that accommodates familial correlation in breast cancer risk due to unobserved shared risk factors.
We studied 3,047 families; 160 had BRCA1 and 132 had BRCA2 mutations. There was no evidence of increased breast cancer risk for noncarriers of identified mutations compared with FDRs from families without BRCA1 or BRCA2 mutations: relative risk was 0.39 (95% CI, 0.04 to 3.81). Residual breast cancer correlation within families was strong, suggesting substantial risk heterogeneity in women without BRCA1 or BRCA2 mutations, with some 3.4% of them accounting for roughly one third of breast cancer cases.
These results support the practice of advising noncarriers that they do not have any increase in breast cancer risk attributable to the family-specific BRCA1 or BRCA2 mutation.
Genome-wide association studies (GWAS) have identified common polymorphisms in or near GC, CYP2R1, CYP24A1, and NADSYN1/DHCR7 genes to be associated with circulating levels of 25-hydroxyvitamin D [25(OH)D] in European populations. To replicate these GWAS findings, we examined six selected polymorphisms from these regions and their relation with circulating 25(OH)D levels in 1,605 Hispanic women (629 U.S. Hispanics and 976 Mexicans) and 354 non-Hispanic White (NHW) women. We also assessed the potential interactions between these variants and known non-genetic predictors of 25(OH)D levels, including body mass index (BMI), sunlight exposure and vitamin D intake from diet and supplements. The minor alleles of the two GC polymorphisms (rs7041 and rs2282679) were significantly associated with lower 25(OH)D levels in both Hispanic and NHW women. The CYP2R1 polymorphism, rs2060793, also was significantly associated with 25(OH)D levels in both groups. We found no significant associations for the polymorphisms in the CYP24A1. In Hispanic controls, 25(OH)D levels were significantly associated with the rs12785878T and rs1790349G haplotype in the NADSYN1/DHCR7 region. Significant interactions between GC rs2282679 and BMI and between rs12785878 and time spent in outdoor activities were observed. These results provide further support for the contribution of common genetic variants to individual variability in circulating 25(OH)D levels. The observed interactions between SNPs and non-genetic factors warrant confirmation.
Circulating levels; Hispanics; genetic polymorphisms; SNPs; genotype-phenotype correlation; vitamin D
To fully characterize the risk of contralateral breast cancer (CBC) in patients with breast cancer with a family history who test negative for BRCA1 and BRCA2 mutations.
Patients and Methods
From our population-based case-control study comparing women with CBC to women with unilateral breast cancer (UBC), we selected women who tested negative for BRCA1 and BRCA2 mutations (594 patients with CBC/1,119 control patients with UBC). Rate ratios (RRs) and 95% CIs were estimated to examine the association between family history of breast cancer and risk of asynchronous CBC. Age- and family history–specific 10-year cumulative absolute risks of CBC were estimated.
Family history of breast cancer was associated with increased CBC risk; risk was highest among young women (< 45 years) with first-degree relatives affected at young ages (< 45 years; RR, 2.5; 95% CI, 1.1 to 5.3) or women with first-degree relatives with bilateral disease (RR, 3.6; 95% CI, 2.0 to 6.4). Women diagnosed with UBC before age 55 years with a first-degree family history of CBC had a 10-year risk of CBC of 15.6%.
Young women with breast cancer who have a family history of breast cancer and who test negative for deleterious mutations in BRCA1 and BRCA2 are at significantly greater risk of CBC than other breast cancer survivors. This risk varies with diagnosis age, family history of CBC, and degree of relationship to an affected relative. Women with a first-degree family history of bilateral disease have risks of CBC similar to mutation carriers. This has important implications for the clinical management of patients with breast cancer with family history of the disease.
To determine the prevalence and type of BRCA1 and BRCA2 (BRCA) mutations among Hispanics in the Southwestern United States and their potential impact on genetic cancer risk assessment (GCRA).
Patients and Methods
Hispanics (n = 746) with a personal or family history of breast and/or ovarian cancer were enrolled in an institutional review board–approved registry and received GCRA and BRCA testing within a consortium of 14 clinics. Population-based Hispanic breast cancer cases (n = 492) enrolled in the Northern California Breast Cancer Family Registry, negative by sequencing for BRCA mutations, were analyzed for the presence of the BRCA1 ex9-12del large rearrangement.
Deleterious BRCA mutations were detected in 189 (25%) of 746 familial clinic patients (124 BRCA1, 65 BRCA2); 21 (11%) of 189 were large rearrangement mutations, of which 62% (13 of 21) were BRCA1 ex9-12del. Nine recurrent mutations accounted for 53% of the total. Among these, BRCA1 ex9-12del seems to be a Mexican founder mutation and represents 10% to 12% of all BRCA1 mutations in clinic- and population-based cohorts in the United States.
BRCA mutations were prevalent in the largest study of Hispanic breast and/or ovarian cancer families in the United States to date, and a significant proportion were large rearrangement mutations. The high frequency of large rearrangement mutations warrants screening in every case. We document the first Mexican founder mutation (BRCA1 ex9-12del), which, along with other recurrent mutations, suggests the potential for a cost-effective panel approach to ancestry-informed GCRA.
We tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer–specific death, and risk of a second breast cancer in women with a first breast cancer.
Patients and Methods
From 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer–specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies.
CHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor–positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P = .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P < .001) for breast cancer–specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P < .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P < .001) in women with estrogen receptor–positive first breast cancer only.
Among women with estrogen receptor–positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer–specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer.
We investigated body size and survival by race/ethnicity in 11,351 breast cancer patients diagnosed from 1993 to 2007 with follow-up through 2009 by using data from questionnaires and the California Cancer Registry. We calculated hazard ratios and 95% confidence intervals from multivariable Cox proportional hazard model–estimated associations of body size (body mass index (BMI) (weight (kg)/height (m)2) and waist-hip ratio (WHR)) with breast cancer–specific and all-cause mortality. Among 2,744 ascertained deaths, 1,445 were related to breast cancer. Being underweight (BMI <18.5) was associated with increased risk of breast cancer mortality compared with being normal weight in non-Latina whites (hazard ratio (HR) = 1.91, 95% confidence interval (CI): 1.14, 3.20), whereas morbid obesity (BMI ≥40) was suggestive of increased risk (HR = 1.43, 95% CI: 0.84, 2.43). In Latinas, only the morbidly obese were at high risk of death (HR = 2.26, 95% CI: 1.23, 4.15). No BMI–mortality associations were apparent in African Americans and Asian Americans. High WHR (quartile 4 vs. quartile 1) was associated with breast cancer mortality in Asian Americans (HR = 2.21, 95% CI: 1.21, 4.03; P for trend = 0.01), whereas no associations were found in African Americans, Latinas, or non-Latina whites. For all-cause mortality, even stronger BMI and WHR associations were observed. The impact of obesity and body fat distribution on breast cancer patients' risk of death may vary across racial/ethnic groups.
adiposity; body mass index; breast cancer; mortality; obesity; race/ethnicity; survival; waist-hip ratio
Approximately half of the familial aggregation of breast cancer remains unexplained. A multiple-case breast cancer family exome sequencing study identified three likely pathogenic mutations in RINT1 (NM_021930.4) not present in public sequencing databases: RINT1 c.343C>T (p.Q115X), c.1132_1134del (p.M378del) and c.1207G>T (p.D403Y). Based on this finding, a population-based case-control mutation-screening study was conducted and identified 29 carriers of rare (MAF < 0.5%), likely pathogenic variants: 23 in 1,313 early-onset breast cancer cases and 6 in 1,123 frequency-matched controls (OR=3.24, 95%CI 1.29-8.17; p=0.013). RINT1 mutation screening of probands from 798 multiple-case breast cancer families identified 4additional carriers of rare genetic variants. Analysis of the incidence of first primary cancers in families of women in RINT1-mutation carrying families estimated that carriers were at increased risks of Lynch syndrome-spectrum cancers (SIR 3.35, 95% CI 1.7-6.0; P=0.005), particularly for relatives diagnosed with cancer under age 60 years (SIR 10.9, 95%CI 4.7-21; P=0.0003).
Breast Cancer; RINT1; Lynch Syndrome; Genetic Susceptibility
Multiple studies have reported that Latina women in the U.S. are diagnosed with breast cancer at more advanced stages and have poorer survival than non-Latina White women. However, Latinas are a heterogeneous group with individuals having different proportions of European, Indigenous American and African genetic ancestry. In this study we evaluated the association between genetic ancestry and survival after breast cancer diagnosis among 899 Latina women from the San Francisco Bay Area. Genetic ancestry was estimated from single nucleotide polymorphisms from an Affymetrix 6.0 array and we used Cox proportional hazards models to evaluate the association between genetic ancestry and breast cancer-specific mortality (tests were two-sided). Women were followed for an average of 9 years during which 75 died from breast cancer. Our results showed that Individuals with higher Indigenous American ancestry had increased risk of breast cancer-specific mortality [hazard ratio (HR): 1.57 per 25% increase in Indigenous American ancestry; 95% confidence interval (CI): 1.08–2.29]. Adjustment for demographic factors, tumor characteristics, and some treatment information did not explain the observed association [HR: 1.75, 95%CI: 1.12–2.74]. In an analysis in which ancestry was dichotomized, the hazard of mortality showed a two-fold increase when comparing women with <50% Indigenous American ancestry to women with ≥50% [HR: 1.89, 95%CI: 1.10–3.24]. This was also reflected by Kaplan-Meier survival estimates (P for Log-Rank test of 0.003). Overall, results suggest that genetic factors and/or unmeasured differences in treatment or access to care should be further explored to understand and reduce ethnic disparities in breast cancer outcomes.
Breast cancer mortality; U.S. Latinas; Genetic ancestry
The relationship between tobacco smoking and prostate cancer (PCa) remains inconclusive. This study examined the association between tobacco smoking and PCa risk taking into account polymorphisms in carcinogen metabolism enzyme genes as possible effect modifiers (9 polymorphisms and 1 predicted phenotype from metabolism enzyme genes). The study included cases (n = 761 localized; n = 1199 advanced) and controls (n = 1139) from the multiethnic California Collaborative Case–Control Study of Prostate Cancer. Multivariable conditional logistic regression was performed to evaluate the association between tobacco smoking variables and risk of localized and advanced PCa risk. Being a former smoker, regardless of time of quit smoking, was associated with an increased risk of localized PCa (odds ratio [OR] = 1.3; 95% confidence interval [CI] = 1.0–1.6). Among non-Hispanic Whites, ever smoking was associated with an increased risk of localized PCa (OR = 1.5; 95% CI = 1.1–2.1), whereas current smoking was associated with risk of advanced PCa (OR = 1.4; 95% CI = 1.0–1.9). However, no associations were observed between smoking intensity, duration or pack-year variables, and advanced PCa. No statistically significant trends were seen among Hispanics or African-Americans. The relationship between smoking status and PCa risk was modified by the CYP1A2 rs7662551 polymorphism (P-interaction = 0.008). In conclusion, tobacco smoking was associated with risk of PCa, primarily localized disease among non-Hispanic Whites. This association was modified by a genetic variant in CYP1A2, thus supporting a role for tobacco carcinogens in PCa risk.
CYP1A2; prostate cancer; smoking
Consumption of red meat, particularly well done meat, has been associated with increased prostate cancer risk. High temperature cooking methods such as grilling and barbequeing may produce heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) which are known carcinogens. We assessed the association with meat consumption and estimated HCA and PAH exposure in a population-based case-control study of prostate cancer. Newly diagnosed cases aged 40–79 years (531 advanced cases, 195 localized cases) and 527 controls were asked about dietary intake, including usual meat cooking methods and doneness levels. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariate logistic regression. For advanced prostate cancer, but not localized disease, increased risks were associated with higher consumption of hamburgers (OR=1.79. CI=1.10–2.92), processed meat (OR=1.57, CI=1.04, 2.36), grilled red meat (OR=1.63, CI=0.99–2.68), and well done red meat (OR=1.52, CI=0.93–2.46), and intermediate intake of 2-amino-1-methyl1-6-phenylimidazo[4,5-b]pyridine (PhIP) (quartile 2 vs. 1: OR=1.41, CI=0.98–2.01; quartile 3 vs. 1: OR=1.42, CI=0.98–2.04), but not for higher intake. White meat consumption was not associated with prostate cancer. These findings provide further evidence that consumption of processed meat and red meat cooked at high temperature is associated with increased risk of advanced, but not localized prostate cancer.
Cooking methods; heterocyclic amines; processed meat; prostate cancer; red meat
Adult body size has long been known to influence breast cancer risk, and there is now increasing evidence that childhood and adolescent body size may also play a role.
We assessed the association with body size at ages 10, 15, and 20 years in 475 premenopausal and 775 postmenopausal Hispanic women who participated in a population-based case-control study of breast cancer conducted from 1995 to 2004 in the San Francisco Bay Area. We used unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations with self-reported relative weight compared to peers and body build at ages 10, 15, and 20 years.
In premenopausal women, we found inverse associations with relative weight compared to peers, with ORs of 0.63 (Ptrend = 0.05), 0.31 (Ptrend < 0.01), and 0.44 (Ptrend = 0.02) for heavier vs. lighter weight at ages 10, 15, and 20 years, respectively. These inverse associations were stronger in currently overweight women and US-born women and did not differ significantly for case groups defined by estrogen receptor status. Inverse associations were stronger in US-born than foreign-born Hispanics. In postmenopausal women not currently using hormone therapy, inverse associations with relative weight were limited to US-born Hispanics.
Large body size at a young age may have a long-lasting influence on breast cancer risk in premenopausal, and possibly postmenopausal, Hispanic women that is independent of current BMI.
These findings need to be weighed against adverse health effects associated with early-life obesity.
Adolescence; BMI; body size; breast cancer; estrogen receptor
The single nucleotide polymorphism 5p12-rs10941679has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium.
Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS) and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression.
For white Europeans, the per-allele odds ratio (OR) associated with 5p12-rs10941679 was 1.11 (95% confidence interval [CI] =1.08–1.14, P=7×10−18) for invasive breast cancer and 1.10 (95%CI=1.01–1.21, P=0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR=1.07, 95%CI=0.99–1.15, P=0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per-allele OR=1.16, 95%CI=1.12–1.20, P=1×10−18 versus OR=1.03, 95%CI=0.99–1.07, P=0.2 for PR-negative disease; P-heterogeneity=2×10−7); heterogeneity by estrogen receptor status was not observed (P=0.2) once PR status was accounted for. The association was also stronger for lower-grade tumors (per-allele OR [95%CI]=1.20 [1.14–1.25], 1.13 [1.09–1.16] and 1.04 [0.99–1.08] for grade 1, 2 and 3/4, respectively; P–trend=5×10−7).
5p12 is a breast cancer susceptibility locus for PR-positive, lower gradebreast cancer.
Multi-centre fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants.
Breast cancer; SNP; susceptibility; disease subtypes
The TGF-β signaling pathway has a significant role in breast cancer initiation and promotion by regulating various cellular processes. We evaluated whether genetic variation in eight genes (TGF-β1, TGF-β2, TGF-βR1, TGF-βR2, TGF-βR3, RUNX1, RUNX2, and RUNX3) is associated with breast cancer risk in women from the Breast Cancer Health Disparities Study. A total of 3,524 cases (1,431 non-Hispanic whites (NHW); 2,093 Hispanics/Native Americans(NA)) and 4,209 population-based controls (1,599 NHWs; 2,610 Hispanics/NAs) were included in analyses. Genotypes for 47 single nucleotide polymorphisms (SNPs) were determined. Additionally, 104 ancestral informative markers estimated proportion of NA ancestry. Associations with breast cancer risk overall, by menopausal status, NA ancestry, and estrogen receptor (ER)/progesterone receptor tumor phenotype were evaluated. After adjustment for multiple comparisons, two SNPs were significantly associated with breast cancer risk: RUNX3 (rs906296 ORCG/GG = 1.15 95 % CI 1.04–1.26) and TGF-β1 (rs4803455 ORCA/AA = 0.89 95 % CI 0.81–0.98). RUNX3 (rs906296) and TGF-βR2 (rs3773644) were associated with risk in pre-menopausal women (padj = 0.002 and 0.02, respectively) and in those with intermediate to high NA ancestry (padj = 0.04 and 0.01, respectively). Self-reported race was strongly correlated with NA ancestry (r = 0.86). There was a significant interaction between NA ancestry and RUNX1 (rs7279383, padj = 0.04). Four RUNX SNPs were associated with increased risk of ER-tumors. Results provide evidence that genetic variation in TGF-β and RUNX genes are associated with breast cancer risk. This is the first report of significant associations between genetic variants in TGF-β and RUNX genes and breast cancer risk among women of NA ancestry.
reast cancer risk; Breast Cancer Health Disparities Study; TGF-β; signaling pathway; Native American ancestry; Hispanic; Non-Hispanic white
Large body size has been associated with a reduced risk of premenopausal breast cancer in non-Hispanic white women. Data on other racial/ethnic populations are limited. The authors examined the association between premenopausal breast cancer risk and adult body size in 672 cases and 808 controls aged ≥35 years from a population-based case-control study conducted in 1995–2004 in the San Francisco Bay Area (Hispanics: 375 cases, 483 controls; African Americans: 154 cases, 160 controls; non-Hispanic whites: 143 cases, 165 controls). Multivariate adjusted odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. Height was associated with increased breast cancer risk (highest vs. lowest quartile: odds ratio = 1.77, 95% confidence interval: 1.23, 2.53; Ptrend < 0.01); the association did not vary by hormone receptor status or race/ethnicity. Body mass index (measured as weight (kg) divided by height (m) squared) was inversely associated with risk in all 3 racial/ethnic groups, but only for estrogen receptor– and progesterone receptor–positive tumors (body mass index ≥30 vs. <25: odds ratio = 0.42; 95% confidence interval: 0.29, 0.61). Other body size measures (current weight, body build, adult weight gain, young adult weight and body mass index, waist circumference, and waist-to-height ratio) were similarly inversely associated with risk of estrogen receptor– and progesterone receptor–positive breast cancer but not estrogen receptor– and progesterone receptor–negative disease. Despite racial/ethnic differences in body size, inverse associations were similar across the 3 racial/ethnic groups when stratified by hormone receptor status.
African Americans; body size; breast neoplasms; Hispanic Americans; premenopause; receptors, estrogen; receptors, progesterone
African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single-nucleotide polymorphisms (SNPs) in a total of 18 089 AA women in 15 studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2850 women (Stage 2). First, while no SNP passed the pre-specified P < 5 × 10−8 threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified in EA women. Secondly, an investigation of SNPs in 42 previously identified menarche loci in EA women demonstrated that 25 (60%) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women.
The role of moderate physical activity and life patterns of activity in reducing endometrial cancer risk remains uncertain.
We assessed lifetime histories of activity from recreation, transportation, chores, and occupation and other risk factors in a population-based case-control study of endometrial cancer conducted in the San Francisco Bay area. The analysis was based on 472 newly diagnosed cases ascertained by the regional cancer registry and 443 controls identified by random-digit dialing who completed an in-person interview.
Reduced risks associated with greater lifetime physical activity (highest vs. lowest tertile) were found for both total activity (odds ratio (OR) = 0.61 (95% confidence interval (CI) = 0.43–0.87, ptrend = 0.01) and activity of moderate intensity (OR=0.44, 95% CI=0.30–0.64, ptrend < 0.0001). Compared to women with low lifetime physical activity (below median), those with greater activity throughout life had the highest reduction in risk (OR=0.62, 95% CI=0.44–0.88). Inverse associations were stronger in obese and overweight women, but differences were not statistically significantly different from those in normal weight women.
These findings suggest that physical activity in adulthood, even of moderate intensity, may be effective in lowering the risk of endometrial cancer, particularly among those at highest risk for this disease.
The results emphasize the importance of evaluating lifetime histories of physical activity from multiple sources, including both recreational and non-recreational activities of various intensities, in order to fully understand the relation between physical activity and disease risk.
Physical activity; exercise; endometrial cancer; corpus uteri
Growth factors (GF) stimulate cell proliferation through binding to
cell membrane receptors and are thought to be involved in cancer risk and
We examined how genetic variation in epidermal growth factor
(EGF), neuregulin 2 (NRG2),
ERBB2 (HER2/neu), fibroblast growth factors 1 and 2
(FGF1 and FGF2) and its receptor 2
(FGFR2), and platelet derived growth factor B
(PDGFB) independently and collectively influence breast
cancer risk and survival. We analyzed data from the Breast Cancer Health
Disparities Study which includes Hispanic (2111 cases, 2597 controls) and
non-Hispanic white (NHW) (1481 cases, 1586 controls) women. Adaptive Rank
Truncated Product (ARTP) analysis was conducted to determine gene
significance. Odds ratios (OR) and 95% confidence intervals were
obtained from conditional logistic regression models to estimate breast
cancer risk and Cox Proportional Hazard models were used to estimate hazard
ratios (HR) of dying from breast cancer. We assessed Native American (NA)
ancestry using 104 Ancestry Informative Markers.
We observed few significant associations with breast cancer risk
overall or by menopausal status other than for FGFR2
rs2981582. This SNP was significantly associated with
ER+/PR+ (OR 1.66 95% CI 1.37, 2.00) and
ER+/PR- (OR 1.54 95% CI 1.03, 2.31) tumors. Multiple SNPs in
FGF1, FGF2, and NRG2 significantly interacted with
multiple SNPs in EGFR, ERBB2,
FGFR2, and PDGFB, suggesting that
breast cancer risk is dependent on the collective effects of genetic
variants in other GFs. Both FGF1 and ERBB2
significantly influenced overall survival, especially among women with low
levels of NA ancestry (PARTP = 0.007 and 0.003,
Our findings suggest that genetic variants in growth factors
signaling appear to influence breast cancer risk through their combined
effects. Genetic variation in ERBB2 and
FGF1 appear to be associated with survival after
diagnosis with breast cancer.
Breast Cancer; FGF1; FGFR2; ERBB2; PDGFB; Survival; Hispanic; ER/PR
Hispanic women in the USA have lower breast cancer incidence than non-Hispanic white (NHW) women. Genetic factors may contribute to this difference. Breast cancer genome-wide association studies (GWAS) conducted in women of European or Asian descent have identified multiple risk variants. We tested the association between 10 previously reported single nucleotide polymorphisms (SNPs) and risk of breast cancer in a sample of 4697 Hispanic and 3077 NHW women recruited as part of three population-based case–control studies of breast cancer. We used stratified logistic regression analyses to compare the associations with different genetic variants in NHWs and Hispanics classified by their proportion of Indigenous American (IA) ancestry. Five of 10 SNPs were statistically significantly associated with breast cancer risk. Three of the five significant variants (rs17157903-RELN, rs7696175-TLR1 and rs13387042-2q35) were associated with risk among Hispanics but not in NHWs. The odds ratio (OR) for the heterozygous at 2q35 was 0.75 [95% confidence interval (CI) = 0.50–1.15] for low IA ancestry and 1.38 (95% CI = 1.04–1.82) for high IA ancestry (P interaction 0.02). The ORs for association at RELN were 0.87 (95% CI = 0.59–1.29) and 1.69 (95% CI = 1.04–2.73), respectively (P interaction 0.03). At the TLR1 locus, the ORs for women homozygous for the rare allele were 0.74 (95% CI = 0.42–1.31) and 1.73 (95% CI = 1.19–2.52) (P interaction 0.03). Our results suggest that the proportion of IA ancestry modifies the magnitude and direction of the association of 3 of the 10 previously reported variants. Genetic ancestry should be considered when assessing risk in women of mixed descent and in studies designed to discover causal mutations.
Numerous single nucleotide polymorphisms (SNPs) associated with breast cancer
susceptibility have been identified by genome-wide association studies (GWAS). However,
these SNPs were primarily discovered and validated in women of European and Asian
ancestry. Because linkage disequilibrium is ancestry-dependent and heterogeneous among
racial/ethnic populations, we evaluated common genetic variants at 22 GWAS-identified
breast cancer susceptibility loci in a pooled sample of 1502 breast cancer cases and 1378
controls of African ancestry. None of the 22 GWAS index SNPs could be validated,
challenging the direct generalizability of breast cancer risk variants identified in
Caucasians or Asians to other populations. Novel breast cancer risk variants for women of
African ancestry were identified in regions including 5p12 (odds ratio [OR] = 1.40,
95% confidence interval [CI] = 1.11–1.76; P =
0.004), 5q11.2 (OR = 1.22, 95% CI = 1.09–1.36; P
= 0.00053) and 10p15.1 (OR = 1.22, 95% CI = 1.08–1.38;
P = 0.0015). We also found positive association signals in three
regions (6q25.1, 10q26.13 and 16q12.1–q12.2) previously confirmed by fine mapping
in women of African ancestry. In addition, polygenic model indicated that eight best
markers in this study, compared with 22 GWAS-identified SNPs, could better predict breast
cancer risk in women of African ancestry (per-allele OR = 1.21, 95% CI =
1.16–1.27; P = 9.7 × 10–16). Our
results demonstrate that fine mapping is a powerful approach to better characterize the
breast cancer risk alleles in diverse populations. Future studies and new GWAS in women of
African ancestry hold promise to discover additional variants for breast cancer
susceptibility with clinical implications throughout the African diaspora.
Telomeres are involved in maintaining genomic stability. Previous studies
have linked both telomere length (TL) and telomere-related genes with cancer. We
evaluated associations between telomere-related genes, TL, and breast cancer
risk in an admixed population of US non-Hispanic white (1,481 cases, 1,586
controls) and U.S. Hispanic and Mexican women (2,111 cases, 2,597 controls) from
the Breast Cancer Health Disparities Study. TL was assessed in 1,500 women based
on their genetic ancestry. TL-related genes assessed were MEN1, MRE11A,
RECQL5, TEP1, TERC, TERF2, TERT, TNKS, and TNKS2.
Longer TL was associated with increased breast cancer risk [odds ratio
(OR) 1.87, 95% confidence interval (CI) 1.38, 2.55], with the
highest risk (OR 3.11, 95% CI 1.74, 5.67 p interaction 0.02) among women
with high Indigenous American ancestry. Several TL-related single nucleotide
polymorphisms had modest association with breast cancer risk overall, including
TEP1 rs93886 (OR 0.82, 95% CI 0.70,0.95);
TERF2 rs3785074 (OR 1.13, 95% CI 1.03,1.24);
TERT rs4246742 (OR 0.85, 95% CI 0.77,0.93);
TERT rs10069690 (OR 1.13, 95% CI 1.03,1.24);
TERT rs2242652 (OR 1.51, 95% CI 1.11,2.04); and
TNKS rs6990300 (OR 0.89, 95% CI 0.81,0.97). Several
differences in association were detected by hormone receptor status of tumors.
Most notable were associations with TERT rs2736118
(ORadj 6.18, 95% CI 2.90, 13.19) with estrogen receptor
negative/progesterone receptor positive (ER−/PR+) tumors and
TERT rs2735940 (ORadj 0.73, 95% CI 0.59,
0.91) with ER−/PR− tumors. These data provide support for an
association between TL and TL-related genes and risk of breast cancer. The
association may be modified by hormone receptor status and genetic ancestry.
The ability to establish genetic risk models is critical for early identification and optimal treatment of breast cancer. For such a model to gain clinical utility, more variants must be identified beyond those discovered in previous genome wide association studies (GWAS). This is especially true for women at high risk because of family history, but without BRCA1/2 mutations.
This study incorporates three datasets in a GWAS analysis of women with Ashkenazi Jewish (AJ) homogeneous ancestry. Two independent discovery cohorts were comprised of 239 and 238 AJ women with invasive breast cancer or preinvasive ductal carcinoma in situ and strong family histories of breast cancer, but lacking the three BRCA1/2 founder mutations, along with 294 and 230 AJ controls, respectively. An independent, third cohort of 203 AJ cases with familial breast cancer history and 263 healthy controls of AJ women was used for validation.
A total of 19 SNPs were identified as associated with familial breast cancer risk in AJ women. Among these SNPs, 13 were identified from a panel of 109 discovery SNPs, including an FGFR2 haplotype. Additionally, 6 previously identified breast cancer GWAS SNPs were confirmed in this population. Seven of the 19 markers were significant in a multivariate predictive model of familial breast cancer in AJ women, 3 novel SNPs [rs17663555(5q13.2), rs566164(6q21), and rs11075884(16q22.2)], the FGFR2 haplotype, and 3 previously published SNPs [rs13387042(2q35), rs2046210(ESR1), and rs3112612(TOX3)], yielding moderate predictive power with an area under the curve (AUC) of the ROC (receiver-operator characteristic curve) of 0.74.
Population-specific genetic variants in addition to variants shared with populations of European ancestry may improve breast cancer risk prediction among AJ women from high-risk families without founder BRCA1/2 mutations.
Ashkenazi Jewish; breast cancer; genome-wide association study; SNP; risk model; AUC
Bone morphogenetic proteins (BMP) are thoughtx to be important in breast cancer promotion and progression. We evaluated genetic variation in BMP-related genes and breast cancer risk among Hispanic (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1586 controls) women who participated in the 4-Corner’s Breast Cancer Study, the Mexico Breast Cancer Study, and the San Francisco Bay Area Breast Cancer Study. BMP genes and their receptors evaluated include ACVR1, AVCR2A, ACVR2B, ACVRL1, BMP1, BMP2, BMP4, BMP6, BMP7, BMPR1A, BMPR1B, BMPR2, MSTN and GDF10. Additionally, 104 ancestral informative markers were assessed to discriminate between European and Native American ancestry. The importance of estrogen on BMP-related associations was suggested through unique associations by menopausal status and estrogen (ER) and progesterone (PR) receptor status of tumors. After adjustment for multiple comparisons ACVR1 (8 SNPs) was modestly associated with ER+PR+ tumors [odds ratios (ORs between 1.18 and 1.39 padj< 0.05]. ACVR1 (3 SNPs) and BMP4 (3 SNPs) were associated with ER+PR− tumors (ORs 0.59 to 2.07 padj< 0.05). BMPR2 was associated with ER−PR+ tumors (OR 4.20, 95% CI 1.62, 10.91 padj< 0.05) as was GDF10 (2 SNPs ORs 3.62 and 3.85 padj< 0.05). After adjustment for multiple comparisons several SNPs remained associated with ER−PR− tumors (padj< 0.05) including ACVR1 BMP4, and GDF10 (ORs between 0.53 and 2.12). Differences in association also were observed by percentage of Native ancestry and menopausal status. Results support the hypothesis that genetic variation in BMPs is associated with breast cancer in this admixed population.
BMP; ACVR1; BMPRIB; breast cancer; Hispanic; genetic admixture; survival; ER status