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Genetic architectures of proximal and distal colorectal cancer are partly distinct

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Huyghe, Jeroen R 
Bien, Stephanie A 
Easton, Douglas F 
Pharoah, Paul DP 
Peters, Ulrike 


Objective An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. Design To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48,214 CRC cases and 64,159 controls of European ancestry. We characterized effect heterogeneity at CRC risk loci using multinomial modeling. Results We identified 13 loci that reached genome-wide significance (P<5×10-8) and that were not reported by previous GWAS for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. Conclusion Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumor.



31 Biological Sciences, 32 Biomedical and Clinical Sciences, 3105 Genetics, 4202 Epidemiology, 42 Health Sciences, 3211 Oncology and Carcinogenesis, Prevention, Genetics, Colo-Rectal Cancer, Human Genome, Digestive Diseases, Women's Health, Cancer Genomics, Cancer, 2.1 Biological and endogenous factors, 2 Aetiology, Cancer, 3 Good Health and Well Being

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BMJ Publishing Group


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