Dataset Information

Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response.

ABSTRACT:

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 <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 <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 <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.

SUBMITTER: Carreras-Torres R

PROVIDER: S-EPMC9992283 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response.

Carreras-Torres Robert R Kim Andre E AE Lin Yi Y Díez-Obrero Virginia V Bien Stephanie A SA Qu Conghui C Wang Jun J Dimou Niki N Aglago Elom K EK Albanes Demetrius D Arndt Volker V Baurley James W JW Berndt Sonja I SI Bézieau Stéphane S Bishop D Timothy DT Bouras Emmanouil E Brenner Hermann H Budiarto Arif A Campbell Peter T PT Casey Graham G Chan Andrew T AT Chang-Claude Jenny J Chen Xuechen X Conti David V DV Dampier Christopher H CH Devall Matthew A M MAM Drew David A DA Figueiredo Jane C JC Gallinger Steven S Giles Graham G GG Gruber Stephen B SB Gsur Andrea A Gunter Marc J MJ Harrison Tabitha A TA Hidaka Akihisa A Hoffmeister Michael M Huyghe Jeroen R JR Jenkins Mark A MA Jordahl Kristina M KM Kawaguchi Eric E Keku Temitope O TO Kundaje Anshul A Le Marchand Loic L Lewinger Juan Pablo JP Li Li L Mahesworo Bharuno B Morrison John L JL Murphy Neil N Nan Hongmei H Nassir Rami R Newcomb Polly A PA Obón-Santacana Mireia M Ogino Shuji S Ose Jennifer J Pai Rish K RK Palmer Julie R JR Papadimitriou Nikos N Pardamean Bens B Peoples Anita R AR Pharoah Paul D P PDP Platz Elizabeth A EA Rennert Gad G Ruiz-Narvaez Edward E Sakoda Lori C LC Scacheri Peter C PC Schmit Stephanie L SL Schoen Robert E RE Shcherbina Anna A Slattery Martha L ML Stern Mariana C MC Su Yu-Ru YR Tangen Catherine M CM Thomas Duncan C DC Tian Yu Y Tsilidis Konstantinos K KK Ulrich Cornelia M CM van Duijnhoven Fränzel J B FJB Van Guelpen Bethany B Visvanathan Kala K Vodicka Pavel P Cenggoro Tjeng Wawan TW Weinstein Stephanie J SJ White Emily E Wolk Alicja A Woods Michael O MO Hsu Li L Peters Ulrike U Moreno Victor V Gauderman W James WJ

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20230301 3

<h4>Background</h4>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.<h4>Methods</h4>A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia.<h4>Results</h4>Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs ...[more]

PMID: 36576985

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Project description:BackgroundCancer associated fibroblasts are activated in the tumor microenvironment and contribute to tumor progression, angiogenesis, extracellular matrix remodeling, and inflammation.MethodsTo identify proteins characteristic for fibroblasts in colorectal cancer we used liquid chromatography-tandem mass spectrometry to derive protein abundance from whole-tissue homogenates of human colorectal cancer/normal mucosa pairs. Alterations of protein levels were determined by two-sided t test with greater than threefold difference and an FDR of < 0.05. Public available datasets were used to predict proteins of stromal origin and link protein with mRNA regulation. Immunohistochemistry confirmed the localization of selected proteins.ResultsWe identified a set of 24 proteins associated with inflammation, matrix organization, TGFβ receptor signaling and angiogenesis mainly originating from the stroma. Most prominent were increased abundance of SerpinB5 in the parenchyme and latent transforming growth factor β-binding protein, thrombospondin-B2, and secreted protein acidic-and-cysteine-rich in the stroma. Extracellular matrix remodeling involved collagens type VIII, XII, XIV, and VI as well as lysyl-oxidase-2. In silico analysis of mRNA levels demonstrated altered expression in the tumor and the adjacent normal tissue as compared to mucosa of healthy individuals indicating that inflammatory activation affected the surrounding tissue. Immunohistochemistry of 26 tumor specimen confirmed upregulation of SerpinB5, thrombospondin B2 and secreted protein acidic-and-cysteine-rich.ConclusionsThis study demonstrates the feasibility of detecting tumor- and compartment-specific protein-signatures that are functionally meaningful by proteomic profiling of whole-tissue extracts together with mining of RNA expression datasets. The results provide the basis for further exploration of inflammation-related stromal markers in larger patient cohorts and experimental models.

Dataset Information

Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response.

Background

Methods

Results

Conclusions

Impact

Publications

Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response.

Similar Datasets

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