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Background: While genome-wide association studies (GWAS) have identified germline variants influencing the risk of developing colorectal cancer (CRC), there has been limited examination of the possible role of inherited variation as a determinant of patient outcome., Patients and Methods: We performed a GWAS for overall survival (OS) in 1926 patients with advanced CRC from the COIN and COIN-B clinical trials. For single nucleotide polymorphisms (SNPs) showing an association with OS (P < 1.0 × 10 -5 ), we conducted sensitivity analyses based on the time from diagnosis to death and sought independent replications in 5675 patients from the Study of Colorectal Cancer in Scotland (SOCCS) and 16,964 patients from the International Survival Analysis in Colorectal cancer Consortium (ISACC). We analysed the Human Protein Atlas to determine if ERBB4 expression was associated with survival in 438 patients with colon adenocarcinomas., Results: The most significant SNP associated with OS was rs79612564 in ERBB4 (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 1.16-1.32, P = 1.9 × 10 -7 ). SNPs at 17 loci had suggestive associations for OS and all had similar effects on the time from diagnosis to death. No lead SNPs were independently replicated in the meta-analysis of all patients from SOCCS and ISACC. However, rs79612564 was significant in stage-IV patients from SOCCS (P = 2.1 × 10 -2 ) but not ISACC (P = 0.89) and SOCCS combined with COIN and COIN-B attained genome-wide significance (P = 1.7 × 10 -8 ). Patients with high ERBB4 expression in their colon adenocarcinomas had worse survival (HR = 1.50, 95% CI = 1.1-1.9, P = 4.6 × 10 -2 )., Conclusions: Genetic and expression data support a potential role for rs79612564 in the receptor tyrosine kinase ERBB4 as a predictive biomarker of survival., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Lung cancer is the leading cause of cancer-related death globally. An improved risk stratification strategy can increase efficiency of low-dose CT (LDCT) screening. Here we assessed whether individual's genetic background has clinical utility for risk stratification in the context of LDCT screening. On the basis of 13,119 patients with lung cancer and 10,008 controls with European ancestry in the International Lung Cancer Consortium, we constructed a polygenic risk score (PRS) via 10-fold cross-validation with regularized penalized regression. The performance of risk model integrating PRS, including calibration and ability to discriminate, was assessed using UK Biobank data ( N = 335,931). Absolute risk was estimated on the basis of age-specific lung cancer incidence and all-cause mortality as competing risk. To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial ( N = 50,772 participants). The lung cancer ORs for individuals at the top decile of the PRS distribution versus those at bottom 10% was 2.39 [95% confidence interval (CI) = 1.92-3.00; P = 1.80 × 10 -14 ] in the validation set ( P trend = 5.26 × 10 -20 ). The OR per SD of PRS increase was 1.26 (95% CI = 1.20-1.32; P = 9.69 × 10 -23 ) for overall lung cancer risk in the validation set. When considering absolute risks, individuals at different PRS deciles showed differential trajectories of 5-year and cumulative absolute risk. The age reaching the LDCT screening recommendation threshold can vary by 4 to 8 years, depending on the individual's genetic background, smoking status, and family history. Collectively, these results suggest that individual's genetic background may inform the optimal lung cancer LDCT screening strategy. SIGNIFICANCE: Three large-scale datasets reveal that, after accounting for risk factors, an individual's genetics can affect their lung cancer risk trajectory, thus may inform the optimal timing for LDCT screening., (©2021 American Association for Cancer Research.)

Purpose: Reducing colorectal cancer incidence and mortality through early detection would improve efficacy if targeted. We developed a colorectal cancer risk prediction model incorporating personal, family, genetic, and environmental risk factors to enhance prevention., Methods: A familial risk profile (FRP) was calculated to summarize individuals' risk based on detailed cancer family history (FH), family structure, probabilities of mutation in major colorectal cancer susceptibility genes, and a polygenic component. We developed risk models, including individuals' FRP or binary colorectal cancer FH, and colorectal cancer risk factors collected at enrollment using population-based colorectal cancer cases ( N = 4,445) and controls ( N = 3,967) recruited by the Colon Cancer Family Registry Cohort (CCFRC). Model validation used CCFRC follow-up data for population-based ( N = 12,052) and clinic-based ( N = 5,584) relatives with no cancer history at recruitment to assess model calibration [expected/observed rate ratio (E/O)] and discrimination [area under the receiver-operating-characteristic curve (AUC)]., Results: The E/O [95% confidence interval (CI)] for FRP models for population-based relatives were 1.04 (0.74-1.45) for men and 0.86 (0.64-1.20) for women, and for clinic-based relatives were 1.15 (0.87-1.58) for men and 1.04 (0.76-1.45) for women. The age-adjusted AUCs (95% CI) for FRP models for population-based relatives were 0.69 (0.60-0.78) for men and 0.70 (0.62-0.77) for women, and for clinic-based relatives were 0.77 (0.69-0.84) for men and 0.68 (0.60-0.76) for women. The incremental values of AUC for FRP over FH models for population-based relatives were 0.08 (0.01-0.15) for men and 0.10 (0.04-0.16) for women, and for clinic-based relatives were 0.11 (0.05-0.17) for men and 0.11 (0.06-0.17) for women., Conclusions: Both models calibrated well. The FRP-based model provided better risk stratification and risk discrimination than the FH-based model., Impact: Our findings suggest detailed FH may be useful for targeted risk-based screening and clinical management., (©2020 American Association for Cancer Research.)

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.

Background: Genome-wide association studies have identified approximately 100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Because of different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry. Methods: We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER, and ROOT). Results: Fifty-four of the 74 variants (73%) were found to have ORs that were directionally consistent with those previously reported, of which 12 were nominally statistically significant ( P < 0.05). Through fine-mapping, in six regions ( 3p24, 12p11, 14q13, 16q12/FTO, 16q23, 19p13 ), we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions ( 11q13, 16q12/TOX3 ), we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality. Conclusions: Through fine-mapping of known susceptibility regions, we have revealed alleles that better characterize breast cancer risk in women of African ancestry. Impact: The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry. Cancer Epidemiol Biomarkers Prev; 26(7); 1016-26. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: A common genetic variant (rs10993994) in the 5' region of the gene encoding β-microseminoprotein (MSP) is associated with circulating levels of MSP and prostate cancer risk. Whether MSP levels are predictive of prostate cancer risk has not been evaluated., Methods: We investigated the prospective relationship between circulating plasma levels of MSP and prostate cancer risk in a nested case-control study of 1503 case subjects and 1503 control subjects among black, Latino, Japanese, Native Hawaiian, and white men from the Multiethnic Cohort study. We also examined the ability of MSP to serve as a biomarker for discriminating prostate cancer case subjects from control subjects. All statistical tests are two-sided., Results: In all racial and ethnic groups, men with lower MSP levels were at greater risk of developing prostate cancer (odds ratio = 1.02 per one unit decrease in MSP, P < .001 in the prostate-specific antigen [PSA]-adjusted analysis). Compared with men in the highest decile of MSP, the multivariable PSA-adjusted odds ratio was 3.64 (95% confidence interval = 2.41 to 5.49) for men in the lowest decile. The positive association with lower MSP levels was observed consistently across racial and ethnic populations, by disease stage and Gleason score, for men with both high and low levels of PSA and across all genotype classes of rs10993994. However, we did not detect strong evidence of MSP levels in improving prostate cancer prediction beyond that of PSA., Conclusions: Regardless of race and ethnicity or rs10993994 genotype, men with low blood levels of MSP have increased risk of prostate cancer.