Citations

3604 Background: Limited research has investigated the role of variation in the host genome as a determinant of colon carcinoma (CC) outcomes, including toxicity due to therapeutic agents. We examined the relationship between germline genetic factors and treatment-associated serious adverse events (SAEs) in a population of CC patients in which treatment was standardized and follow-up for outcomes was uniformly conducted. Methods: Using existing biospecimens from CC patients with resected stage III disease in a phase III randomized trial of FOLFOX adjuvant chemotherapy with and without cetuximab (NCCTG N0147), genome-wide genotyping arrays were conducted for 2200 patients for a total of ~20 million single nucleotide polymorphisms (SNPs). Using logistic regression models we assessed SNP-specific associations with SAEs, utilizing a discovery-based approach to search the genome in an unbiased manner. Detailed information on SAEs was collected using the Common Toxicity Criteria for Adverse Events (CTCAE, v3.0). Analyses evaluating associations with specific classes of common grade ≥3 SAEs were performed, including gastrointestinal toxicities, neutropenia, and paresthesias. A threshold of P < 5x10-8was used to denote genome-wide significance. Results: Among patients who received FOLFOX, several SNPs on chr 15 near the ANP32A gene and on chr 2 near the CD207 gene were statistically significantly associated with grade ≥3 neuropathy. The strongest SNP-specific associations in these regions were in the range of odds ratio (OR) = 1.3, P = 2.8×10−10 and OR = 1.5, P = 2.7×10−10, respectively. Conclusions: Findings from this genome-wide analysis demonstrate the potential importance of germline genetic variation in influencing CC patients’ experience of specific toxicities to FOLFOX regimens. These results highlight two genomic regions of potential interest for understanding the biological mechanism for such toxicities, although further evaluation and replication is needed. Support: U10CA180821, U10CA180882, U10CA180820, U10CA180863, U10CA180888, CCSRI 021039, R01CA176272, Eli Lilly & Co, Pfizer, Sanofi. Clinical trial information: NCT00079274 .

Abstract Genome-wide association studies of colorectal cancer (CRC) have identified over 50 susceptibility loci. These variants represent only a small fraction of total heritability for CRC. Gene-environment (GxE) interaction studies may help identify novel loci and biological interactions that give insight to the pathogenesis of CRC. Previous genome-wide GxE studies with dietary factors have identified interactions between loci and processed meat consumption and alcohol; however, limited statistical power remains a primary concern. Set-based SNP testing has the potential to increase statistical power to detect GxE interactions by aggregating functionally relevant SNPs. In this large pooled analysis using 14 case-control and nested case-control studies, we incorporated functional information from the transcriptome prediction tool, PrediXcan, into a novel set-based approach for testing GxE interactions. We used variant weights from the PrediXcan models of tissue-specific gene expression in the transverse colon as a priori variant information for a set-based GxE approach. We restricted our analysis to variants in the PrediXcan transverse colon gene models (n = 4,842). This discovery phase included 10,360 CRC and advanced adenoma cases, and 11,183 controls of European ancestry from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colon Cancer Family Registry. All 14 studies were analyzed together in a pooled data set using the Mixed Effects Score Tests for interactions. We tested for gene interactions with sex- and study- specific quartiles of dietary intake of red meat (servings/day), processed meat (servings/day), vegetables (servings/day), fruits (servings/day), and fiber (g/day). We detected two genes with suggestive interactions (false discovery rate (FDR) &lt; 0.2) with intake of red meat and risk of CRC: Superoxide Dismutase 2 (SOD2) and Ubiquitin Conjugating Enzyme E2 H (UBE2H). No interactions at FDR &lt; 0.2 were observed for processed meat, vegetables, fruits, or fiber. The SOD2 gene, which encodes an enzyme important in apoptotic signaling and clearing of reactive oxygen species, may regulate response to colonic exposure to heme iron or increased bile acid from high-fat content in red meat. UBE2H is part of the ubiquitin-proteasome system that has a role in Wnt signaling, which can be mediated by heme iron in red meat and is commonly found dysregulated in cancer. These findings highlight the efficacy of integrating functional information and set-based testing for novel discovery of genes interacting with known dietary risk factors of CRC. We plan to replicate these findings in additional studies. Citation Format: Paneen S. Petersen, Yu-Ru Su, Sonja I. Berndt, Stephanie A. Bien, Hermann Brenner, Graham Casey, Andrew T. Chan, Jenny Chang-Claude, Jane C. Figueiredo, Steven J. Gallinger, Robert W. Haile, Tabitha A. Harrison, Michael Hoffmeister, Mark A. Jenkins, Amit D. Joshi, Sébastien Küry, Loic Le Marchand, Yi Lin, Noralane M. Lindor, Polly A. Newcomb, John D. Potter, Robert Schoen, Martha L. Slattery, Stephen N. Thibodeau, Emily White, Li Hsu, Ulrike Peters, CCFR, GECCO. Interactions between genetic predictors of gene expression and dietary factors associated with risk of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5268.

Abstract Background Regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer (CRC). Genome-wide interaction analysis (GxE) has identified a few variants that may modify the effects of NSAIDs on CRC risk. However, limited statistical power remains a concern. Restricting analyses by using functional genomic information to aggregate variants into biologically relevant sets can reduce the number of tests, thereby increasing statistical power. We tested the interactions between variant models of gene expression and NSAIDs use on CRC risk. Methods Functional weights of each variant were estimated using PrediXcan based on jointly measured transcriptomes and genomes data of transverse colon tissues from the Genotype-Tissue Expression (GTEx) Project for all genes with sufficient heritability (≥1%). A mixed-effects model was used to assess the GxE effects in a gene among 9,917 incident CRC cases and 10,533 controls from 17 (nested) case-control studies from the Colon Cancer Family Registry (CCFR) and Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). GxE analysis was done by modeling the interaction between predicted gene expression and NSAID use (fixed effects), and residual variant-specific GxE effects that are not accounted for (random effects). Regular user of aspirin and/or non-aspirin NSAIDs was compared to non-regular users. False discovery rate (FDR) was used to account for multiple comparison and FDR≤0.2 was considered genome-wide significant. Secondary analysis was performed on significant genes and duration of use among users. Results Regular use of aspirin was higher among controls (30.3%) compared to cases (24.3%). Among the 4,842 genes tested, SORD significantly modified the effect of regular use of aspirin on CRC risk (p-interaction = 1.45×10-5; FDR=0.07). The SORD gene encodes sorbitol dehydrogenase (SORD), which oxidizes sorbitol to fructose in the polyol pathway. Decreased SORD concentrations were previously observed to dramatically increase in colorectal adenoma cells when compared to normal mucosa cells, suggesting the involvement of dysregulated polyol metabolisms in colorectal tumorigenesis. However, the duration of aspirin use was not statistically significantly associated with SORD gene expression on CRC risk (p=0.149) among 5,560 aspirin users. No significant interactions were observed between genetically determined colon gene expression levels and any NSAID use or non-aspirin NSAID use at FDR&lt;0.2. Conclusions Incorporating functional information, we discovered a novel gene that may interact with aspirin use to confer CRC risk. These findings provide preliminary support for new biological insights that could help understand the chemopreventive mechanisms of aspirin on CRC. We aim to replicate these findings in additional studies. Citation Format: Xiaoliang Wang, Yu-Ru Su, Andrew T. Chan, Stephanie Bien, Sonja I. Bernt, Hermann Brenner, Graham Casey, Jenny Chang-Claude, Steven J. Gallinger, Robert W. Haile, Tabitha A. Harrison, Michael Hoffmeister, Mark A. Jenkins, Amit Joshi, Yi Lin, Noralane M. Lindor, Loic Le Marchand, Hongmei Nan, Polly A. Newcomb, John D. Potter, Martha L. Slattery, Steve N. Thibodeau, Emily White, Li Hsu, Ulrike Peters. Functionally informed genome-wide interaction analysis of nonsteroidal anti-inflammatory drugs on colorectal cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2965.