Follicular lymphoma (FL) has been linked with cigarette smoking and, inconsistently, with other risk factors.
We assessed associations of medical, hormonal, family history, lifestyle, and occupational factors with FL risk in 3530 cases and 22639 controls from 19 case–control studies in the InterLymph consortium. Age-, race/ethnicity-, sex- and study-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression.
Most risk factors that were evaluated showed no association, except for a few modest or sex-specific relationships. FL risk was increased in persons: with a first-degree relative with non-Hodgkin lymphoma (OR = 1.99; 95% CI = 1.55 to 2.54); with greater body mass index as a young adult (OR = 1.15; 95% CI = 1.04 to 1.27 per 5kg/m2 increase); who worked as spray painters (OR = 2.66; 95% CI = 1.36 to 5.24); and among women with Sjögren syndrome (OR = 3.37; 95% CI = 1.23 to 9.19). Lower FL risks were observed in persons: with asthma, hay fever, and food allergy (ORs = 0.79–0.85); blood transfusions (OR = 0.78; 95% CI = 0.68 to 0.89); high recreational sun exposure (OR = 0.74; 95% CI = 0.65 to 0.86, fourth vs first quartile); who worked as bakers or millers (OR = 0.51; 95% CI = 0.28 to 0.93) or university/higher education teachers (OR = 0.58; 95% CI = 0.41 to 0.83). Elevated risks specific to women included current and longer duration of cigarette use, whereas reduced risks included current alcohol use, hay fever, and food allergies. Other factors, including other autoimmune diseases, eczema, hepatitis C virus seropositivity, hormonal drugs, hair dye use, sun exposure, and farming, were not associated with FL risk.
The few relationships observed provide clues suggesting a multifactorial etiology of FL but are limited in the extent to which they explain FL occurrence.
Although risk factors for diffuse large B-cell lymphoma (DLBCL) have been suggested, their independent effects, modification by sex, and association with anatomical sites are largely unknown.
In a pooled analysis of 4667 cases and 22639 controls from 19 studies, we used stepwise logistic regression to identify the most parsimonious multivariate models for DLBCL overall, by sex, and for selected anatomical sites.
DLBCL was associated with B-cell activating autoimmune diseases (odds ratio [OR] = 2.36, 95% confidence interval [CI] = 1.80 to 3.09), hepatitis C virus seropositivity (OR = 2.02, 95% CI = 1.47 to 2.76), family history of non-Hodgkin lymphoma (OR = 1.95, 95% CI = 1.54 to 2.47), higher young adult body mass index (OR = 1.58, 95% CI = 1.12 to 2.23, for 35+ vs 18.5 to 22.4 kg/m2), higher recreational sun exposure (OR = 0.78, 95% CI = 0.69 to 0.89), any atopic disorder (OR = 0.82, 95% CI = 0.76 to 0.89), and higher socioeconomic status (OR = 0.86, 95% CI = 0.79 to 0.94). Additional risk factors for women were occupation as field crop/vegetable farm worker (OR = 1.78, 95% CI = 1.22 to 2.60), hairdresser (OR = 1.65, 95% CI = 1.12 to 2.41), and seamstress/embroider (OR = 1.49, 95% CI = 1.13 to 1.97), low adult body mass index (OR = 0.46, 95% CI = 0.29 to 0.74, for <18.5 vs 18.5 to 22.4 kg/m2), hormone replacement therapy started age at least 50 years (OR = 0.68, 95% CI = 0.52 to 0.88), and oral contraceptive use before 1970 (OR = 0.78, 95% CI = 0.62 to 1.00); and for men were occupation as material handling equipment operator (OR = 1.58, 95% CI = 1.02 to 2.44), lifetime alcohol consumption (OR = 0.57, 95% CI = 0.44 to 0.75, for >400kg vs nondrinker), and previous blood transfusion (OR = 0.69, 95% CI = 0.57 to 0.83). Autoimmune disease, atopy, and family history of non-Hodgkin lymphoma showed similar associations across selected anatomical sites, whereas smoking was associated with central nervous system, testicular and cutaneous DLBCLs; inflammatory bowel disease was associated with gastrointestinal DLBCL; and farming and hair dye use were associated with mediastinal DLBCL.
Our results support a complex and multifactorial etiology for DLBCL with some variation in risk observed by sex and anatomical site.
Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes.
We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case–control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P
Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P
NODE < 1.0×10−4), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P
NODE < 1.0×10−4). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.
Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.
Blood samples have traditionally been used as the main source of DNA for genetic analysis. However, this source can be difficult in terms of collection, transportation, and long-term storage. In this study, we investigated whether human nail clippings could be used as a source of DNA for SNP genotyping, null-allele detection, and whole-genome amplification. From extracted nail DNA, we achieved amplicons up to a length of ~400 bp and >96% concordance for SNP genotyping and 100% concordance for null-allele detection compared to DNA derived from matched blood samples. For whole-genome amplification, OmniPlex performed better than Multiple Displacement Amplification with a success rate of 89.3% and 76.8% for SNP genotyping and null-allele detection, respectively. Concordance was ~98% for both methods. When combined with OmniPlex whole-genome amplification, human nail clippings could potentially be used as an alternative to whole blood as a less invasive and more convenient source of DNA for genotyping studies.
Single Nucleotide Polymorphism (SNP); Nail Clippings; Genotyping; Whole Genome Amplification (WGA)
Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.
Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA.
Incidence of esophageal adenocarcinoma (EA) has increased substantially in recent decades. Multiple risk factors have been identified for EA and its precursor, Barrett’s esophagus (BE), such as reflux, European ancestry, male sex, obesity, and tobacco smoking, and several germline genetic variants were recently associated with disease risk. Using data from the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207 controls, we examined single nucleotide polymorphisms (SNPs) that potentially affect the biogenesis or biological activity of microRNAs (miRNAs), small non-coding RNAs implicated in post-transcriptional gene regulation, and deregulated in many cancers, including EA. Polymorphisms in three classes of genes were examined for association with risk of EA or BE: miRNA biogenesis genes (157 SNPs, 21 genes); miRNA gene loci (234 SNPs, 210 genes); and miRNA-targeted mRNAs (177 SNPs, 158 genes). Nominal associations (P<0.05) of 29 SNPs with EA risk, and 25 SNPs with BE risk, were observed. None remained significant after correction for multiple comparisons (FDR q>0.50), and we did not find evidence for interactions between variants analyzed and two risk factors for EA/BE (smoking and obesity). This analysis provides the most extensive assessment to date of miRNA-related SNPs in relation to risk of EA and BE. While common genetic variants within components of the miRNA biogenesis core pathway appear unlikely to modulate susceptibility to EA or BE, further studies may be warranted to examine potential associations between unassessed variants in miRNA genes and targets with disease risk.
Although several cohort studies report associations between chronic exposure to fine particles (PM2.5) and mortality, few have studied the effects of chronic exposure to ultrafine (UF) particles. In addition, few studies have estimated the effects of the constituents of either PM2.5 or UF particles.
We used a statewide cohort of > 100,000 women from the California Teachers Study who were followed from 2001 through 2007. Exposure data at the residential level were provided by a chemical transport model that computed pollutant concentrations from > 900 sources in California. Besides particle mass, monthly concentrations of 11 species and 8 sources or primary particles were generated at 4-km grids. We used a Cox proportional hazards model to estimate the association between the pollutants and all-cause, cardiovascular, ischemic heart disease (IHD), and respiratory mortality.
We observed statistically significant (p < 0.05) associations of IHD with PM2.5 mass, nitrate, elemental carbon (EC), copper (Cu), and secondary organics and the sources gas- and diesel-fueled vehicles, meat cooking, and high-sulfur fuel combustion. The hazard ratio estimate of 1.19 (95% CI: 1.08, 1.31) for IHD in association with a 10-μg/m3 increase in PM2.5 is consistent with findings from the American Cancer Society cohort. We also observed significant positive associations between IHD and several UF components including EC, Cu, metals, and mobile sources.
Using an emissions-based model with a 4-km spatial scale, we observed significant positive associations between IHD mortality and both fine and ultrafine particle species and sources. Our results suggest that the exposure model effectively measured local exposures and facilitated the examination of the relative toxicity of particle species.
Ostro B, Hu J, Goldberg D, Reynolds P, Hertz A, Bernstein L, Kleeman MJ. 2015. Associations of mortality with long-term exposures to fine and ultrafine particles, species and sources: results from the California Teachers Study cohort. Environ Health Perspect 123:549–556; http://dx.doi.org/10.1289/ehp.1408565
In a genome-wide scan, we show that 30 variants in 25 genomic regions are associated with risk of TN breast cancer. Women carrying many of the risk variants may have 4-fold increased risk relative to women with few variants.
Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10−
8) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10−
4] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10−
9) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46–4.70, P = 4.8 × 10−
69). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.
While carotid artery disease and strokes have been documented in adult cancer patients treated with neck irradiation, little information is available on pediatric patients. The purpose of this study is to determine if carotid disease is more prevalent among pediatric cancer survivors treated with neck irradiation than among healthy controls.
Thirty pediatric cancer survivors who received neck irradiation (2,000–6,660 cGy) and 30 healthy subjects underwent bilateral carotid ultrasounds. Study outcome measures were common carotid intima-media thickness (IMT) and plaque (present or absent). Multivariate methods were used to compare cases and controls and to identify risk factors related to carotid disease in childhood cancer survivors.
IMT was greater for cancer survivors than controls (0.46mm (SD 0.12) vs. 0.41mm (SD 0.06), P < 0.001). Plaque was present in 18% of irradiated vessels and 2% of non-irradiated vessels (P < 0.01). Among cancer survivors, IMT was positively associated with female gender (P < 0.05), nonwhite ethnicity (P < 0.01), positive family history of stroke/heart attack (P < 0.05), BMI (P < 0.001), total cholesterol (P < 0.01), cancer relapse (P < 0.001), and years off treatment (P < 0.0001). Plaque was positively associated with relapse (P < 0.05) and C-reactive protein (P < 0.01). There was no significant relationship between radiation dose at levels ≥2,000 cGy and IMT or plaque.
Carotid artery disease was more prevalent among cancer survivors treated with neck irradiation than among controls. Due to the high risk of stroke associated with advanced carotid disease, larger prospective studies are needed to better define disease risk in these long-term survivors.
carotid artery disease; childhood cancer survivors; late effects; neck irradiation; radiation therapy
Progressive telomere shortening with cell division is a hallmark of aging. Short telomeres are associated with increased cancer risk, but there are conflicting reports about telomere length and mortality in breast cancer survivors.
We measured peripheral blood leukocyte telomere length at two time points in women enrolled in a multiethnic, prospective cohort of stage I to stage IIIA breast cancer survivors diagnosed between 1995 and 1999 with a median follow-up of 11.2 years. We evaluated associations between telomere length measured at mean 6 (baseline; LTL0; n = 611) and 30 months (LTL30; n = 478) after diagnosis and the change between those time points (n = 478), with breast cancer–specific and all-cause mortality using Cox proportional hazards models adjusted for possible confounders. Statistical tests were two-sided.
There were 135 deaths, of which 74 were due to breast cancer. Neither baseline nor 30-month telomere length was associated with either all-cause or breast cancer–specific mortality (LTL0: hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.67 to 1.02; HR = 0.88; 95% CI = 0.67 to 1.15; LTL30: HR = 0.78, 95% CI = 0.59 to 1.05; HR = 0.86; 95% = CI = 0.58 to 1.26, respectively). However, participants whose telomeres shortened between baseline and 30 months were at a statistically significantly increased risk of breast cancer–specific (HR = 3.03; 95% CI = 1.11 to 8.18) and all-cause mortality (HR = 2.38; 95% CI = 1.28 to 4.39) compared with participants whose telomeres lengthened. When follow-up was censored at 5-years after diagnosis, LTL0 (HR = 0.66; 95% CI = 0.45 to 0.96), LTL30 (HR = 0.51; 95% CI = 0.29 to 0.92), and change in telomere length (HR = 3.45; 95% CI = 1.11 to 10.75) were statistically significantly associated with all-cause mortality.
Telomere shortening was associated with increased risk of breast cancer–specific and all-cause mortality, suggesting that change in blood telomere length over time could be a biomarker of prognosis. Research on determinants of telomere length and change is needed.
To investigate the association between body mass index (BMI) and mortality among Asian Americans
We pooled data from prospective cohort studies that included 20,672 Asian American adults with no history of cancer or heart disease at baseline. Hazard ratios and 95% confidence intervals (CI) were estimated using Cox proportional hazards models.
A high, but not low, BMI was associated with an increased risk of total mortality among individuals 35–69 years old. BMI was not related to total mortality among individuals ≥70 years old. With a BMI 22.5–<25 as the reference category among 35–69 year old never smokers the hazard ratios (95% CI) for total mortality were 0.83 (0.47–1.47) for BMI 15–<18.5, 0.91 (0.62–1.32) for BMI 18.5–<20, 1.08 (0.86–1.36) for BMI 20–<22.5, 1.14 (0.90–1.44) for BMI 25–<27.5, 1.13 (0.79–1.62) for BMI 27.5–<30, 1.82 (1.25–2.64) for BMI 30–<35, and 2.09 (1.06–4.11) for BMI 35–50. Higher BMI was also related to an increased mortality from cardiovascular disease and cancer.
A high BMI is associated with increased risk of mortality among Asian Americans.
To assess the independent impact of waist circumference on mortality across the entire range of body mass index (BMI), and to estimate the loss in life expectancy related to a higher waist circumference.
We pooled data from 11 prospective cohort studies with 650,386 white adults aged 20–83 years and enrolled from January 1, 1986 through December 31, 2000. We used proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) for the association of waist circumference with mortality.
During a median follow-up of 9 years (maximum=21 years), 78,268 participants died. After accounting for age, study, BMI, smoking status, alcohol consumption, and physical activity, there was a strong positive linear association of waist circumference with all-cause mortality was observed for men (HR=1.52 for 110+ versus <90cm, 95%CI, 1.45–1.59; HR=1.07 per 5cm increment, 95%CI, 1.06–1.08) and women (HR=1.80 for 95+ versus <70cm, 95%CI, 1.70–1.89; HR=1.09 per 5cm increment, 95%CI, 1.08–1.09). The estimated decrease in life expectancy for highest versus lowest waist circumference was ~3 years for men and ~5 years for women. The HR per 5cm increment in waist circumference was similar for both sexes at all BMI levels from 20–50 kg/m2, but it was higher at younger ages, higher for longer follow-up, and lower among male current smokers. The associations were stronger for heart and respiratory disease mortality than for cancer.
In white adults, higher waist circumference was positively associated with higher mortality at all levels of BMI from 20–50 kg/m2. Waist circumference should be assessed in combination with BMI, even for those in the normal BMI range, as part of risk assessment for obesity-related premature mortality.
Background & Aims
Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations.
We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls.
We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09–1.18; P = 1.8 × 10−11) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86–0.93; P = 7.5 × 10−9). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87–0.93; P = 3.72 × 10−9).
We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.
EAC; Intestinal Metaplasia; Susceptibility; Cancer; ASE, allele-specific expression; BE, Barrett’s esophagus; BEACON, Barrett's and Esophageal Adenocarcinoma Consortium; CI, confidence interval; EAC, esophageal adenocarcinoma; eQTL, expression quantitative trait locus; GWAS, genome-wide association study; LD, linkage disequilibrium; OR, odds ratio; PC, principal component; SNP, single nucleotide polymorphism; TCGA, The Cancer Genome Atlas
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
Cancer has traditionally been studied using the disease site of origin as the organizing framework. However, recent advances in molecular genetics have begun to challenge this taxonomy, as detailed molecular profiling of tumors has led to discoveries of subsets of tumors that have profiles that possess distinct clinical and biological characteristics. This is increasingly leading to research that seeks to investigate whether these subtypes of tumors have distinct etiologies. However, research in this field has been opportunistic and anecdotal, typically involving the comparison of distributions of individual risk factors between tumors classified on the basis of candidate tumor characteristics. The purpose of this article is to place this area of investigation within a more general conceptual and analytic framework, with a view to providing more efficient and practical strategies for designing and analyzing epidemiologic studies to investigate etiologic heterogeneity. We propose a formal definition of etiologic heterogeneity and show how classifications of tumor subtypes with larger etiologic heterogeneities inevitably possess greater disease risk predictability overall. We outline analytic strategies for estimating the degree of etiologic heterogeneity among a set of subtypes and for choosing subtypes that optimize the heterogeneity, and we discuss technical challenges that require further methodologic research. We illustrate the ideas by using a pooled case-control study of breast cancer classified by expression patterns of genes known to define distinct tumor subtypes.
cancer epidemiology; clustering; etiologic heterogeneity
Mammographic density (MD) is a strong biomarker of breast cancer risk. MD increases after women start estrogen plus progestin therapy (EPT) and decreases after women quit EPT. A large interindividual variation in EPT-associated MD change has been observed, but few studies have investigated genetic predictors of the EPT-associated MD change. Here, we evaluate the association between polymorphisms in hormone metabolism pathway genes and MD changes when women quit EPT.
We collected mammograms before and after women quit EPT and genotyped 405 tagging single nucleotide polymorphisms (SNPs) in 30 hormone metabolism pathway genes in 284 non-Hispanic white participants of the California Teachers Study (CTS). Participants were ages 49 to 71 years at time of mammography taken after quitting EPT. We assessed percent MD using a computer-assisted method. MD change was calculated by subtracting MD of an ‘off-EPT’ mammogram from MD of an ‘on-EPT’ (that is baseline) mammogram. Linear regression analysis was used to investigate the SNP-MD change association, adjusting for the baseline ‘on-EPT’ MD, age and BMI at time of baseline mammogram, and time interval and BMI change between the two mammograms. An overall pathway and gene-level summary was obtained using the adaptive rank truncated product (ARTP) test. We calculated ‘P values adjusted for correlated tests (PACT)’ to account for multiple testing within a gene.
The strongest associations were observed for rs7489119 in SLCO1B1, and rs5933863 in ARSC. SLCO1B1 and ARSC are involved in excretion and activation of estrogen metabolites of EPT, respectively. MD change after quitting was 4.2% smaller per minor allele of rs7489119 (P = 0.0008; PACT = 0.018) and 1.9% larger per minor allele of rs5933863 (P = 0.013; PACT = 0.025). These individual SNP associations did not reach statistical significance when we further used Bonferroni correction to consider the number of tested genes. The pathway level summary ARTP P value was not statistically significant.
Data from this longitudinal study of EPT quitters suggest that genetic variation in two hormone metabolism pathway genes, SLCO1B1 and ARSC, may be associated with change in MD after women stop using EPT. Larger longitudinal studies are needed to confirm our findings.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0477-8) contains supplementary material, which is available to authorized users.
Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett’s esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA.
We used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h2
g) and the genetic correlation (rg) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were two-sided, except in the case of variance-explained estimation where one-sided tests were used.
We estimated a statistically significant genetic variance explained for BE (h2
g = 35%; standard error [SE] = 6%; one-sided P = 1 × 10−9) and for EA (h2
g = 25 %; SE = 5%; one-sided P = 2 × 10−7). The genetic correlation between BE and EA was found to be high (rg = 1.0; SE = 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P = 1 × 10−6), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD.
We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases.
Female steroid hormones are hypothesized to play a protective role in pancreatic cancer risk. However, results from epidemiologic studies that examined hormone-related exposures have been inconsistent. The California Teachers Study is a cohort study of female public school professionals that was established in 1995–1996. Of the 118,164 eligible study participants, 323 women were diagnosed with incident invasive pancreatic cancer through December 31, 2009. Multivariable Cox proportional hazards regression methods were used to estimate hazard ratios and 95% confidence intervals for the association of pancreatic cancer risk with reproductive factors and exogenous hormone use. Current users of estrogen-only therapy at baseline (1995–1996) had a lower risk of pancreatic cancer than did participants who had never used hormone therapy (hazard ratio = 0.59, 95% confidence interval: 0.42, 0.84). Use of estrogen-plus-progestin therapy was not associated with the risk of pancreatic cancer. A longer duration of oral contraceptive use (≥10 years of use compared with never use) was associated with an increased risk of cancer (hazard ratio = 1.72, 95% confidence interval: 1.19, 2.49). Reproductive factors, including age at menarche, parity, breastfeeding, and age at menopause, were not associated with pancreatic cancer risk. Our results suggest that increased estrogen exposure through estrogen-only therapy may reduce pancreatic cancer risk in women.
hormone therapy; oral contraceptives; pancreatic cancer
cancer-related fatigue; breast cancer survivors; measurement; Piper Fatigue Scale; health-related quality of life
Women with germline BRCA1 or BRCA2 (BRCA1/BRCA2) mutations are at very high risk of developing breast cancer, including asynchronous contralateral breast cancer (CBC). BRCA1/BRCA2 genes help maintain genome stability and assist in DNA repair. We examined whether the risk of CBC associated with radiation treatment was higher among women with germline BRCA1/BRCA2 mutations than among non-carriers.
A population-based, nested case-control study was conducted within a cohort of 52,536 survivors of unilateral breast cancer (UBC). Cases were 603 women with CBC and controls were 1199 women with UBC individually matched on age at diagnosis, race, year of first diagnosis and cancer registry. All women were tested for BRCA1 and BRCA2 mutations. Radiation absorbed dose from the initial radiotherapy (RT) to the CBC location within the contralateral breast was reconstructed from measurements in a tissue-equivalent phantom and details available in the therapy records.
Among women treated with radiation, the mean radiation dose was 1.1 Gy (range=0.02-6.2 Gy). Risk of developing CBC was elevated among women who carried a deleterious BRCA1/BRCA2 mutation (rate ratio, RR=4.5, confidence interval, CI=3.0-6.8), and also among those treated with RT (RR=1.2, CI=1.0-1.6). However, among mutation carriers, an incremental increase in risk associated with radiation dose was not statistically significant.
Multiplicative interaction of RT with mutation status would be reflected by a larger association of RT with CBC among carriers than among non-carriers, but this was not apparent. Accordingly, there was no clear indication that carriers of deleterious BRCA/BRCA2 mutations were more susceptible to the carcinogenic effects of radiation than non-carriers. These findings are reassuring and have important clinical implications for treatment decisions and the clinical management of patients harboring deleterious BRCA1/BRCA2 mutations.
All work associated with this study was supported by the U.S. National Cancer Institute [R01CA097397, U01CA083178].
Contralateral Breast Cancer; Radiotherapy; BRCA1/BRCA2
Lymphedema is a potentially debilitating condition that occurs among breast
cancer survivors. This study examines the incidence of self-reported lymphedema,
timing of lymphedema onset, and associations between sociodemographic, clinical
and lifestyle factors and lymphedema risk across racial-ethnic groups using data
from a multicenter, multiethnic prospective cohort study of breast cancer
survivors, the Health, Eating, Activity and Lifestyle Study.
A total of 666 women diagnosed with breast cancer staged as in situ, localized or regional disease at ages 35 to
64 years were recruited through the Surveillance, Epidemiology, and End Results
registries in New Mexico (non-Hispanic white and Hispanic white), Los Angeles
County (black), and Western Washington (non-Hispanic white) and followed for a
median of 10.2 years. We evaluated sociodemographic factors, breast cancer- and
treatment-related factors, comorbidities, body mass index (BMI), hormonal factors,
and lifestyle factors in relation to self-reported lymphedema by fitting Cox
proportional hazards models, estimating hazard ratios (HR) and 95% confidence
Over the follow-up period, 190 women (29%) reported lymphedema. The median
time from breast cancer diagnosis to onset of lymphedema was 10.5 months (range:
0.5 to 134.9 months). Factors independently associated with lymphedema were
total/modified radical mastectomy (versus partial/less than total mastectomy;
HR = 1.37, 95% CI: 1.01 to 1.85), chemotherapy (versus no chemotherapy; HR = 1.48,
95% CI: 1.09 to 2.02), no lymph nodes removed (versus ≥10 lymph nodes removed;
HR = 0.17, 95% CI: 0.08 to 0.33), pre-diagnostic BMI
≥30 kg/m2 (versus BMI
<25 kg/m2; HR = 1.59, 95% CI: 1.09 to 2.31), and
hypertension (versus no hypertension; HR = 1.49, 95% CI: 1.06 to 2.10). After
adjusting for demographics and breast cancer- and treatment-related factors, no
significant difference in lymphedema risk was observed across racial/ethnic
groups. Analyses stratified by race/ethnicity showed that hypertension and
chemotherapy were lymphedema risk factors only for black women.
Breast cancer patients who have undergone extensive surgery or extensive lymph
node dissection, or who have a higher BMI should be closely monitored for
detection and treatment of lymphedema. Further studies are needed to understand
the roles of chemotherapy and hypertension in the development of
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0414-x) contains supplementary material, which is available to authorized
Adult height is determined by genetics and childhood nutrition, but childhood infections may also play a role. Monozygotic twins are genetically matched and offer an advantage when identifying environmental determinants. In 2005–2007, we examined the association of childhood infections with adult height in 140 height-discordant monozygotic twin pairs from the California Twin Program. To obtain information on childhood infections and growth, we interviewed the mothers of monozygotic twins who differed in self-reported adult height by at least 1-inch (2.5 cm). Within-pair differences in the relative frequency of childhood infections were highly correlated, especially within age groups. A conditional logistic regression analysis demonstrated that more reported episodes of febrile illness occurred in the twin with shorter stature (odds ratio = 2.00, 95% confidence interval: 1.18, 3.40). The association was strongest for differences in the relative frequency of infection during the toddler years (ages 1–5: odds ratio = 3.34, 95% confidence interval: 1.47, 7.59) and was similar when restricted to twin pairs of equal birth length. The association was not explained by differential nutritional status. Measures of childhood infection were associated with height difference in monozygotic twin pairs, independent of genome, birth length, and available measures of diet.
body height; case-control studies; growth; infection; pediatrics; twins
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.
Cancer prevention has been associated with decreased rates of cancer incidence and increased survival. Cancer prevention, however, can have a greater impact if barriers to implementing cancer prevention into practice are removed and opportunities are both fostered and seized. The purpose of this article is to identify barriers and opportunities to cancer prevention in clinical practice and provide recommendations for the future. A multidisciplinary team participated in “The Future Directions Cancer Prevention and Control: Workforce Implications for Training, Practice and Policy” workshop on October 17-18, 2009 at The University of Texas MD Anderson Cancer Center in Houston, TX. During the meeting, the team discussed barriers and opportunities for the implementation of cancer prevention into clinical practice. Further data were collected from peer-reviewed journals and published government and cancer agencies reports. Several issues were identified: 1) The funding allocated to basic cancer prevention research and application is not optimal and less than that for cancer treatment; 2) Participation in cancer prevention behaviors and screening practices are lower than desired, especially among the uninsured; 3) A shortage in healthcare professionals is a major challenge in meeting the future needs of cancer prevention; 4) Demands on medical schools to balance increased enrollment, incorporate cancer prevention in an already crowded curriculum, and develop faculty are daunting; and 5) Healthcare reforms in 2010 provide both opportunities and additional challenges for cancer prevention. Based on the current state of cancer prevention, we formed six recommendations: 1) Additional funding for cancer prevention research with a focus on implementation into practice; 2) Improved tracking of cancer prevention research funding and the outcomes associated with it; 3) Continued monitoring of cancer prevention services participation with emphasis on closing the gap in health disparities; 4) Financial and technical assistance to healthcare professional schools for incorporating cancer prevention into curricula; 5) Assessment of the current state of technology in cancer prevention care; and 6) The use of effective multidisciplinary teams in cancer prevention care. Improved delivery of cancer prevention services can have a tremendous impact on cancer incidence and survival rates.
Prevention; Control; Workforce; Cancer