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Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2022 Apr 19. pii: 694506. doi: 10.1158/1055-9965.EPI-21-1003

Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region.

Jordahl KM¹, Shcherbina A², Kim AE³, Su YR⁴, Lin Y⁵, Wang J⁶, Qu C⁷, Albanes D⁸, Arndt V⁹, Baurley JW¹⁰, Berndt SI¹¹, Bien SA¹², Bishop DT¹³, Bouras E¹⁴, Brenner H¹⁵, Buchanan DD¹⁶, Budiarto A¹⁷, Campbell PT¹⁸, Carreras-Torres R¹⁹, Casey G²⁰, Cenggoro TW²¹, Chan AT²², Conti DV²³, Dampier CH²⁴, Devall MA²⁵, Díez-Obrero V²⁶, Dimou N²⁷, Drew DA²⁸, Figueiredo JC²⁹, Gallinger S³⁰, Giles GG³¹, Gruber SB³², Gsur A³³, Gunter MJ³⁴, Hampel H³⁵, Harlid S³⁶, Harrison TA³⁷, Hidaka A³⁸, Hoffmeister M³⁹, Huyghe JR⁴⁰, Jenkins MA⁴¹, Joshi AD⁴², Keku TO⁴³, Larsson SC⁴⁴, Le Marchand L⁴⁵, Lewinger JP⁴⁶, Li L⁴⁷, Mahesworo B⁴⁸, Moreno V⁴⁹, Morrison JL⁵⁰, Murphy N⁵¹, Nan H⁵², Nassir R⁵³, Newcomb PA⁵⁴, Obón-Santacana M⁵⁵, Ogino S⁵⁶, Ose J⁵⁷, Pai RK⁵⁸, Palmer JR⁵⁹, Papadimitriou N⁶⁰, Pardamean B⁶¹, Peoples AR⁶², Pharoah PDP⁶³, Platz EA⁶⁴, Potter JD⁶⁵, Prentice RL⁶⁶, Rennert G⁶⁷, Ruiz-Narvaez E⁶⁸, Sakoda LC⁶⁹, Scacheri PC⁷⁰, Schmit SL⁷¹, Schoen RE⁷², Slattery ML⁷³, Stern MC⁷⁴, Tangen CM⁷⁵, Thibodeau SN⁷⁶, Thomas DC⁷⁷, Tian Y⁷⁸, Tsilidis KK⁷⁹, Ulrich CM⁸⁰, van Duijnhoven FJB⁸¹, Van Guelpen B⁸², Visvanathan K⁸³, Vodicka P⁸⁴, White E⁸⁵, Wolk A⁸⁶, Woods MO⁸⁷, Wu AH⁸⁸, Zemlianskaia N⁸⁹, Chang-Claude J⁹⁰, Gauderman WJ⁹¹, Hsu L⁹², Kundaje A⁹³, Peters U⁹⁴

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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.

Publikations ID: 35438744
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