Citations

AbstractBackgroundReproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear.MethodsAnalyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2–like, HER2-enriched–like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided.ResultsCompared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2–like, and HER2-enriched–like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like.ConclusionsThis large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction.

Abstract Background The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. Methods We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2– or 3–degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. Results The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2–degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10−4). Conclusion Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.

Abstract Background: Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer. Methods: Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (>28 g/day) with light-to-moderate drinkers (1–28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models. Results: For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 > 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose–response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06–1.17; OR for AA genotype = 1.22; 95% CI, 1.14–1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif. Conclusions: Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region. Impact: The study identifies multifaceted evidence of a possible functional effect for rs1318920.

Abstract Background: The etiology of colorectal cancer is not fully understood. Methods: Using genetic variants and metabolomics data including 217 metabolites from the Framingham Heart Study (n = 1,357), we built genetic prediction models for circulating metabolites. Models with prediction R2 > 0.01 (Nmetabolite = 58) were applied to predict levels of metabolites in two large consortia with a combined sample size of approximately 46,300 cases and 59,200 controls of European and approximately 21,700 cases and 47,400 controls of East Asian (EA) descent. Genetically predicted levels of metabolites were evaluated for their associations with colorectal cancer risk in logistic regressions within each racial group, after which the results were combined by meta-analysis. Results: Of the 58 metabolites tested, 24 metabolites were significantly associated with colorectal cancer risk [Benjamini–Hochberg FDR (BH-FDR) < 0.05] in the European population (ORs ranged from 0.91 to 1.06; P values ranged from 0.02 to 6.4 × 10−8). Twenty one of the 24 associations were replicated in the EA population (ORs ranged from 0.26 to 1.69, BH-FDR < 0.05). In addition, the genetically predicted levels of C16:0 cholesteryl ester was significantly associated with colorectal cancer risk in the EA population only (OREA: 1.94, 95% CI, 1.60−2.36, P = 2.6 × 10−11; OREUR: 1.01, 95% CI, 0.99−1.04, P = 0.3). Nineteen of the 25 metabolites were glycerophospholipids and triacylglycerols (TAG). Eighteen associations exhibited significant heterogeneity between the two racial groups (PEUR-EA-Het < 0.005), which were more strongly associated in the EA population. This integrative study suggested a potential role of lipids, especially certain glycerophospholipids and TAGs, in the etiology of colorectal cancer. Conclusions: This study identified potential novel risk biomarkers for colorectal cancer by integrating genetics and circulating metabolomics data. Impact: The identified metabolites could be developed into new tools for risk assessment of colorectal cancer in both European and EA populations.

Abstract Introduction: The risk of specific clinical subtype of breast cancer (defined by ER and HER2 status) among women in the general population who are carriers of germline pathogenic variants (PVs) in cancer predisposition genes is not well-defined. Methods: A total of 13,153 women with breast cancer (ER+/HER2-: 9381; ER+/HER2+: 1462; ER-/HER2+: 690; and ER-/HER2-: 1620) and 25,005 unaffected women (controls) from nine studies within the CAnceR RIsk Estimates Related to Susceptibility (CARRIERS) consortium that were not enriched for family history or early onset disease were included in the present analysis. A multiplex amplicon-based panel was used to perform germline sequencing for cancer predisposition genes. Case-control associations for each of the four clinical subtype of breast cancer was performed for PVs in 5 common breast cancer predisposition genes (ATM, BRCA1, BRCA2, CHEK2 and PALB2) utilizing a logistic regression model adjusting for study, age at diagnosis, race/ethnicity and family history of breast cancer. Results: The frequency of PVs in 5 genes was 3.8% for ER+/HER2-, 6.2% for ER+/HER2+, 4.2% for ER-/HER2+ and 9.3% for ER-/HER2- subtypes. PVs in BRCA1 and BRCA2 were associated with high risk (Odds Ratio (OR) >4) for all clinical subtypes of breast cancer, but the risk was highest (OR>8) for ER-/HER2- breast cancer. PVs in PALB2 were associated with high risk (OR>4) of ER-/HER2- and ER+/HER2+ subtypes and moderate risk (OR: 2-4) of ER+/HER2- breast cancer. Irrespective of the HER2 status, PVs in ATM were associated with a moderately increased risk (OR: 2-4) of ER+ breast cancer but the risk of ER- breast cancer was not elevated. In contrast, PVs in CHEK2 were associated with high risk (OR>4) of ER+/HER2+ breast cancer and moderate risk (OR: 2-4) of ER+/HER2- and ER-/HER2+ breast cancer, but the risk of ER-/HER2- breast cancer was not elevated. Conclusions: This study provides population-based estimates of risk of specific clinical subtypes of breast cancer which will be useful for genetic counseling and targeting appropriate screening strategies in PV carriers based on subtype specific risks of breast cancer. Citation Format: Siddhartha Yadav, Chunling Hu, Nicholas J. Boddicker, Eric Polley, Steven Hart, Rohan Gnanaolivu, Jie Na, Hongyan Huang, Song Yao, Celine M. Vachon, Lauren Teras, Jack A. Taylor, Dale P. Sandler, Julie R. Palmer, Janet E. Olson, Susan Neuhausen, Elena Martinez, Sara Lindstroem, Loic Le Marchand, Charles Kooperberg, Christopher Haiman, Mia M. Gaudet, James V. Lacey, Kimberly A. Bertrand, Leslie Bernstein, Paul W. Auer, Christine Ambrosone, Jeffrey N. Weitzel, Peter Kraft, David E. Goldgar, Katherine L. Nathanson, Susan M. Domchek, Fergus J. Couch, CARRIERS Consortium. Population-based risk estimates of clinical subtypes of breast cancer among carriers of germline pathogenic variants in cancer predisposition genes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-09-01.

Abstract Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene–sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 [odds ratio (OR) = 0.71, P = 4.29×10−8); rs79942605 (OR = 2.17, P = 2.81×10−8) and rs208908 (OR = 0.70, P = 4.54×10−8) were identified with different risk effect of lung cancer between men and women. Further expression quantitative trait loci and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of Coxsackie virus and adenovirus receptor gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.

Abstract Background: Somatic EGFR mutations define a subset of non–small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches. Methods: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status. Results: Of 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4,231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance index of 0.75 (95% CI, 0.74–0.77) in the training and 0.77 (95% CI, 0.74–0.79) in the testing dataset. At an optimal cut-point of probability-score = 0.335, sensitivity = 69% and specificity = 72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of patients with NSCLC, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients. Conclusions: We introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC. Impact: The proposed method is generalizable in the common occurrence in which EGFR-status data are missing.

Abstract Introduction: Prostate Cancer (PCa) risk is influenced by both rare germline pathogenic variants (GPVs) in DNA damage repair genes and common variants as measured by polygenic risk scores (PRS) however, the combined effect of GPVs and PRS on PCa risk in men of African ancestry has not been investigated. Methods: We examined the combined effect of rare GPVs and PRS on PCa risk in 1,795 PCa cases and 1,424 controls of African ancestry men from the Multiethnic Cohort, the Los Angeles Study of Aggressive Prostate Cancer, and the Uganda Prostate Cancer Study. GPVs in 19 DNA genes were defined as clinically validated missense variants and variants that alter the protein sequence. The PRS was constructed as a weighted sum of 267 established PCa risk variants. The combined effect of the PRS and GPV status on PCa risk was evaluated using logistic regression models adjusting for age, study, and the first 10 principal components of ancestry to account for population stratification. Results: We identified 91 GPVs carried by 31 controls and 68 cases. Among GPV non-carriers, compared to those with average PRS (33.3-66.7%), odds ratios for PCa ranged from 0.56 (95% CI=0.45-0.70; P=1.2E-7) in low PRS men (0-33.3%) to 3.04 (95% CI=2.54-3.63; P=5.6E-35) in high PRS men (66.7-100%). Among GPV carriers, odds ratios for PCa ranged from 2.09 (95% CI=0.85-5.12; P=0.11) in low PRS men to 5.03 (95% CI=2.37-10.66; P=2.5E-5) in high PRS men, compared to GPV non-carriers with average PRS. Next, we restricted GPVs to ATM, BRCA2, PALB2, and NBN[BD2] (n=51 variants carried by 8 controls and 44 cases), which we previously reported as being the genes most strongly associated with advanced PCa in this population and study sample. Among GPV non-carriers, odds ratios for PCa ranged from 0.56 (95% CI=0.46-0.71; P=2.7E-7) in low PRS men to 5.03 (95% CI=0.85-5.12; P=0.11) in high PRS men, while among GPV carriers, odd ratios for PCa ranged from 2.08 (95% CI=0.58-7.49; P=0.26) in low PRS men to 18.06 (95% CI=4.24-76.84; P=9.0E-5) in high PRS men, compared to average PRS GPV non-carriers. When comparing aggressive cases to controls, considering the top four genes, GPV non-carrier odds ratios for PCa ranged from 0.52 (95% CI=0.40-0.70; P=6.2E-6) in low PRS men to 3.16 (95% CI=2.56-3.91; P=1.6E-26) in high PRS men, while among GPV carriers, odd ratios for PCa ranged from 2.97 (95% CI=073-12.16; P=0.13) in low PRS men to 23.58 (95% CI=5.39-103.20; P=2.7E-5) in high PRS men, compared to average PRS GPV non-carriers. Conclusion: We found that PCa risk in African ancestry men carrying GPVs in DNA damage repair and cancer predisposition genes, particularly ATM, BRCA2, PALB2, and NBN, varied depending on an individual's PRS. This implies that to comprehensively assess genetic risk of PCa, it is important to consider both rare and common variants. These findings could have implications for risk stratification in this high-risk population and emphasize the need for larger genetic studies of PCa in African ancestry men to identify and characterize genetic risk factors in this population. Citation Format: Raymond W. Hughley, Burcu F. Darst, Marco Matejcic, Yesha Patel, Jenna Lilyquist, Steven N. Hart, Eric C. Polley, Lucy Xia, Xin Sheng, Alexander Lubmawa, Sue A. Ingles, Lynne Wilkens, Loïc L. Marchand, Stephen Watya, Fergus J. Couch, David V. Conti, Christopher A. Haiman. Combined effect of a prostate cancer polygenic risk score and germline pathogenic variants in DNA damage repair genes on prostate cancer risk in men of African ancestry [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-197.

AbstractBackgroundThe incidence of colorectal cancer (CRC) among individuals aged younger than 50 years has been increasing. As screening guidelines lower the recommended age of screening initiation, concerns including the burden on screening capacity and costs have been recognized, suggesting that an individualized approach may be warranted. We developed risk prediction models for early-onset CRC that incorporate an environmental risk score (ERS), including 16 lifestyle and environmental factors, and a polygenic risk score (PRS) of 141 variants.MethodsRelying on risk score weights for ERS and PRS derived from studies of CRC at all ages, we evaluated risks for early-onset CRC in 3486 cases and 3890 controls aged younger than 50 years. Relative and absolute risks for early-onset CRC were assessed according to values of the ERS and PRS. The discriminatory performance of these scores was estimated using the covariate-adjusted area under the receiver operating characteristic curve.ResultsIncreasing values of ERS and PRS were associated with increasing relative risks for early-onset CRC (odds ratio per SD of ERS = 1.14, 95% confidence interval [CI] = 1.08 to 1.20; odds ratio per SD of PRS = 1.59, 95% CI = 1.51 to 1.68), both contributing to case-control discrimination (area under the curve = 0.631, 95% CI = 0.615 to 0.647). Based on absolute risks, we can expect 26 excess cases per 10 000 men and 21 per 10 000 women among those scoring at the 90th percentile for both risk scores.ConclusionsPersonal risk scores have the potential to identify individuals at differential relative and absolute risk for early-onset CRC. Improved discrimination may aid in targeted CRC screening of younger, high-risk individuals, potentially improving outcomes.