Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response
Authors: Carreras-Torres Robert , Kim Andre E. , Lin Yi , Díez-Obrero Virginia , Bien Stephanie A. , Qu Conghui , Wang Jun , Dimou Niki , Aglago Elom K. , Albanes Demetrius , Arndt Volker , Baurley James W. , Berndt Sonja I. , Bézieau Stéphane , Bishop D. Timothy , Bouras Emmanouil , Brenner Hermann , Budiarto Arif , Campbell Peter T. , Casey Graham , Chan Andrew T. , Chang-Claude Jenny , Chen Xuechen , Conti David V. , Dampier Christopher H. , Devall Matthew A.M. , Drew David A. , Figueiredo Jane C. , Gallinger Steven , Giles Graham G. , Gruber Stephen B. , Gsur Andrea , Gunter Marc J. , Harrison Tabitha A. , Hidaka Akihisa , Hoffmeister Michael , Huyghe Jeroen R. , Jenkins Mark A. , Jordahl Kristina M. , Kawaguchi Eric , Keku Temitope O. , Kundaje Anshul , Le Marchand Loic , Lewinger Juan Pablo , Li Li , Mahesworo Bharuno , Morrison John L. , Murphy Neil , Nan Hongmei , Nassir Rami , Newcomb Polly A. , Obón-Santacana Mireia , Ogino Shuji , Ose Jennifer , Pai Rish K. , Palmer Julie R. , Papadimitriou Nikos , Pardamean Bens , Peoples Anita R. , Pharoah Paul D.P. , Platz Elizabeth A. , Rennert Gad , Ruiz-Narvaez Edward , Sakoda Lori C. , Scacheri Peter C. , Schmit Stephanie L. , Schoen Robert E. , Shcherbina Anna , Slattery Martha L. , Stern Mariana C. , Su Yu-Ru , Tangen Catherine M. , Thomas Duncan C. , Tian Yu , Tsilidis Konstantinos K. , Ulrich Cornelia M. , van Duijnhoven Fränzel J.B. , Van Guelpen Bethany , Visvanathan Kala , Vodicka Pavel , Cenggoro Tjeng Wawan , Weinstein Stephanie J. , White Emily , Wolk Alicja , Woods Michael O. , Hsu Li , Peters Ulrike , Moreno Victor , Gauderman W. James 
Published: December 2022

Background:

Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer.

Methods:

A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia.

Results:

Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10−8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20–1.30] compared with the other genotypes (OR &lt;1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10−8) and 8q24.23 (rs7005722, P = 2.88 × 10−8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09–1.16) compared with the other genotypes (OR &lt;1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07–1.28) compared with the other genotypes (OR &lt;1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33).

Conclusions:

Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response.

Impact:

These findings can guide potential prevention treatments.