Zanke, Brent W.

Abstract Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Telomeres cap chromosome ends, protecting them from degradation, double‐strand breaks, and end‐to‐end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset‐based meta‐analyses of 204,993 directly‐measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene‐level p value cutoffs ≤3.08 × 10−5). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere‐related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk.

Abstract To identify genetic variants that contribute to colorectal cancer (CRC) susceptibility, we performed a meta-analysis of two genome-wide association studies in 2,627 cases and 3,797 controls of Japanese ancestry and 1,894 cases and 4,703 controls of African ancestry, followed by a replication of genome-wide statistically significant associations (P &lt; 5E-8) in 16,823 cases and 18,211 controls of European ancestry. This study revealed a new pan-ethnic CRC risk locus at 10q25 (rs12241008, intronic to VTI1A; P=1.5E-9), providing additional insight into the etiology of CRC and highlighting the value of association mapping in diverse populations. Citation Format: Hansong Wang, Terrilea Burnett, Suminori Kono, Christopher Haiman, Motoki Iwasaki, Lynne Wilkens, Lenora Loo, David Van Den Berg, Laurence Kolonel, Brian Henderson, Temitope Keku, Robert Sandler, Lisa Signorello, William Blot, Polly Newcomb, Mala Pande, Christopher Amos, Dee West, Stéphane Bézieau, Sonja Berndt, Brent Zanke, Li Hsu, Noralane Lindor, Robert Haile, John Hopper, Mark Jenkins, Steven Gallinger, Graham Casey, Stephanie Stenzel, Fredrick Schumacher, Ulrike Peters, Stephen Gruber, Shoichiro Tsugane, Dan Stram, Loic Le Marchand. Transethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-282. doi:10.1158/1538-7445.AM2014-LB-282

Abstract Background: Genetic and environmental factors influence colorectal cancer (CRC) risk. Previous studies have provided additional etiologic insight by examining multiplicative gene-environment interactions for individual susceptibility loci. However, individual loci confer only modest risks, which may limit statistical power and clinical significance. A genetic risk score comprising known CRC loci may provide a more comprehensive assessment of risk. Further, there is a paucity of data on the role of additive gene-environment interactions, which may have greater public health implications than multiplicative interactions. We thus evaluated both additive and multiplicative interactions between a genetic risk score and 15 key environmental factors on risk of CRC. Methods: We conducted an analysis of 10,491 CRC cases and 10,725 controls of European ancestry in 7 cohort and 6 case-control studies participating in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) or Colon Cancer Family Registry (CCFR). To provide a global measure of genetic predisposition, information across multiple risk variants was combined by calculating a genetic risk score based on 24 polymorphisms near 21 genetic loci identified in previous genome-wide association studies. For the genetic score and environmental factors, the reference category corresponded to that associated with lower CRC risk. We tested for additive interactions by estimating relative excess risk due to interactions (RERIs) using logistic regression; for multiplicative interactions we used an empirical-Bayes approach. Nominal P values ≤ 0.05 were considered statistically significant. Results: After adjustment for age, sex, center, study, principal components, and total energy, as appropriate, we observed super-additive gene-environment interactions for CRC risk between the genetic risk score and body mass index (RERI=0.15; 95% CI: 0.00-0.31), ever smoking (RERI=0.14; 95% CI: 0.00-0.28), pack-years of smoking (RERI=0.23; 95% CI: 0.05-0.41), postmenopausal hormone therapy use (RERI=0.38; 95% CI: 0.17-0.59), and intake of processed meat (RERI=0.23; 95% CI: 0.06-0.40). Of the 15 environmental risk factors, 12 showed RERIs &gt; 0 – suggesting an overall trend toward super-additive interactions for these factors. In addition, we observed evidence of sub-multiplicative interactions for use of aspirin and non-steroidal anti-inflammatory drugs. There were no other statistically significant multiplicative interactions. Conclusions: We observed evidence for super-additive effects of genetic predisposition and environmental risk factors on risk of CRC. Our findings suggest that certain environmental risk factors have stronger effects on absolute risk among individuals with higher genetic risk of CRC. If confirmed in future studies, these results may have implications for targeted prevention strategies. Citation Format: Mengmeng Du, Sonja I. Berndt, Hermann Brenner, Bette J. Caan, Peter T. Campbell, Graham Casey, Andrew Chan, Jenny Chang-Claude, Stephen J. Chanock, Nilanjan Chatterjee, David V. Conti, David Duggan, Jane C. Figueiredo, Steven Gallinger, Jian Gong, Robert W. Haile, Tabitha A. Harrison, Richard B. Hayes, Michael Hoffmeister, John L. Hopper, Li Hsu, Thomas J. Hudson, Carolyn M. Hutter, Eric J. Jacobs, Mark A. Jenkins, Shuo Jiao, Laurence N. Kolonel, Peter Kraft, Loic Le Marchand, Mathieu Lemire, Yi Lin, Noralane M. Lindor, Polly A. Newcomb, John D. Potter, Robert E. Schoen, Fredrick R. Schumacher, Daniela Seminara, Martha L. Slattery, Stephen N. Thibodeau, Cornelia M. Ulrich, Aung Ko Win, Emily White, Brent W. Zanke, Ulrike Peters. Additive and multiplicative gene-environment interactions for colorectal cancer risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4831. doi:10.1158/1538-7445.AM2013-4831

Objective Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer. Design We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92×10 −4 was used to determine statistical significance of the associations. Results Two correlated SNPs—rs10090154 and rs4242382—in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74×10 −5 ), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites. Conclusions This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24.