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Genome-wide interaction study with smoking for colorectal cancer risk identifies novel genetic loci related to tumor suppression, inflammation and immune response.
Pubmed ID
36576985 (View this publication on the PubMed website)
Digital Object Identifier
Cancer Epidemiol Biomarkers Prev. 2022 Dec 28
Carreras-Torres R , Kim AE , Lin Y , Díez-Obrero V , Bien SA , Qu C , Wang J , Dimou N , Aglago EK , Albanes D , Arndt V , Baurley JW , Berndt SI , Bézieau S , Bishop DT , Bouras E , Brenner H , Budiarto A , Campbell PT , Casey G , more Chan AT , Chang-Claude J , Chen X , Conti DV , Dampier CH , Devall MA , Drew DA , Figueiredo JC , Gallinger S , Giles GG , Gruber SB , Gsur A , Gunter MJ , Harrison TA , Hidaka A , Hoffmeister M , Huyghe JR , Jenkins MA , Jordahl KM , Kawaguchi E , Keku TO , Kundaje A , Le Marchand L , Lewinger JP , Li L , Mahesworo B , Morrison JL , Murphy N , Nan H , Nassir R , Newcomb PA , Obón-Santacana M , Ogino S , Ose J , Pai RK , Palmer JR , Papadimitriou N , Pardamean B , Peoples AR , Pharoah PDP , Platz EA , Rennert G , Ruiz-Narvaez E , Sakoda LC , Scacheri PC , Schmit SL , Schoen RE , Shcherbina A , Slattery ML , Stern MC , Su YR , Tangen CM , Thomas DC , Tian Y , Tsilidis KK , Ulrich CM , van Duijnhoven FJB , Van Guelpen B , Visvanathan K , Vodicka P , Cenggoro TW , Weinstein SJ , White E , Wolk A , Woods MO , Hsu L , Peters U , Moreno V , Gauderman WJ
  • Girona Biomedical Research Institute, Salt, Girona, Spain.
  • University of Southern California, Los Angeles, CA, United States.
  • Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
  • Novo Nordisk Foundation Center for Basic Metabolic Research, Denmark.
  • Fred Hutchinson Cancer Research Center, United States.
  • University of Southern California, Los angeles, CA, United States.
  • International Agency For Research On Cancer, Lyon, France.
  • National Cancer Institute, Bethesda, MD, United States.
  • German Cancer Research Center, Heidelberg, Germany.
  • Bina Nusantara University, Jakarta, Indonesia. more
  • Service de Génétique Médicale, Centre Hospitalier Universitaire Hôtel Dieu, Nantes, Nantes, France.
  • University of Leeds, Leeds, West Yorkshire, United Kingdom.
  • University of Ioannina School of Medicine, Ioannina, Greece.
  • Albert Einstein College of Medicine, Bronx, NY, United States.
  • University of Virginia, Charlottesville, United States.
  • Massachusetts General Hospital, Boston, MA, United States.
  • University of Connecticut Health Center, Boston, MA, United States.
  • Cedars-Sinai Medical Center Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, United States.
  • University Health Network, Canada.
  • Cancer Council Victoria, Melbourne, VIC, Australia.
  • City of Hope National Medical Center Center for Precision Medicine, Duarte, CA, United States.
  • Medical University of Vienna, Vienna, Austria.
  • International Agency For Research On Cancer, Lyon Cedex 08, France.
  • Fred Hutchinson Cancer Research Center, Seattle, United States.
  • Fred Hutchinson Cancer Research Center, Seattle, Washington, United States.
  • Fred Hutchinson Cancer Center, Seattle, United States.
  • University of Melbourne, Victoria, Victoria, Australia.
  • University of Washington, Seattle, Washington, United States.
  • University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States.
  • Stanford University School of Medicine, Palo Alto, CA, United States.
  • University of Hawaii Cancer Center, Honolulu, Hawaii, United States.
  • Case Western Reserve University, Cleveland, United States.
  • Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, United States.
  • Umm al-Qura University, Makkah, Saudi Arabia.
  • Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain.
  • Brigham and Women's Hospital, Boston, MA, United States.
  • University of Utah, Salt Lake City, Utah, United States.
  • Mayo Clinic Arizona, Scottsdale, AZ, United States.
  • Boston University, Boston, MA, United States.
  • Bina Nusantara University, Indonesia.
  • Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, United States.
  • Cedars-Sinai Medical Center, West Hollywood, CA, United States.
  • Johns Hopkins Bloomberg School of Public Health, Baltimore, United States.
  • Carmel Medical Center and Faculty of Medicine, Technion, Haifa, Israel.
  • University of Michigan-Ann Arbor, Ann Arbor, MI, United States.
  • Kaiser Permanente Northern California, Oakland, CA, United States.
  • Cleveland Clinic, Cleveland, OH, United States.
  • University of Pittsburgh Medical Center, Pittsburgh, PA, United States.
  • Stanford University, Stanford, United States.
  • University of Utah Health Sciences Center, Salt Lake City, Utah, United States.
  • University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA, United States.
  • Kaiser Permanente Washington Health Research Institute, Seattle, WA, United States.
  • Keck School of Medicine, Los Angeles, CA, United States.
  • Capital Medical University, Beijing, China.
  • Huntsman Cancer Institute, Salt Lake City, UT, United States.
  • Wageningen University & Research, Wageningen, Netherlands.
  • Umeå University, Umeå, Sweden.
  • Johns Hopkins Bloomberg School of Public Health and Kimmel Cancer Center, Baltimore, MD, United States.
  • Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
  • Karolinska Institute, Stockholm, Sweden.
  • Memorial University of Newfoundland, St. John's, NL, Canada.
  • Catalan Institute of Oncology, Hopitalet de Llobregat, Barcelona, Spain.

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

METHODS: A genome-wide interaction scan was performed including 33,756 CRC 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=4.58x10-8), with higher associated risk in subjects carrying the GG genotype (OR 1.25, 95%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=1.72x10-8) and 8q24.23 (rs7005722, p=2.88x10-8). 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 CRC 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 CRC of smoking status and intensity, linked to tumor suppression and immune response.

IMPACT: These findings can guide potential prevention treatments.

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