Genetic architectures of proximal and distal colorectal cancer are partly distinct

Abstract

ObjectiveAn 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.DesignTo 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 characterised effect heterogeneity at CRC risk loci using multinomial modelling.ResultsWe identified 13 loci that reached genome-wide significance (p<5×10−8) and that were not reported by previous GWASs 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.ConclusionGenetic 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 tumour.

Methylation of SDC2/TFPI2 and Its Diagnostic Value in Colorectal Tumorous Lesions

“…CRCs that arise proximally or distally to the splenic flexure show differences in epidemiologic incidence, morphology, and molecular alterations ( Huyghe et al, 2021 ). A previous investigation suggested that the degree of SDC2 methylation in the left colon and the right colon may be different ( McInnes et al, 2017 ).…”

Colorectal Cancer Study of Austria (CORSA): A Population-Based Multicenter Study

“…Therefore, CORSA represents an active and leading player in cooperation, support actions, and consortia. So far, CORSA contributed to multiple international consortia such as Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ], COlorectal cancer GENeTics (COGENT) and COnsortium of METabolomics Studies (COMETS) [ 13 ]. Furthermore, CORSA was a partner in two ERANET-TRANSCAN-funded projects: MetaboCCC [ 11 , 12 , 44 , 45 , 46 , 50 , 51 ], and “Biomarkers related to folate-dependent metabolism in colorectal cancer recurrence and survival” (FOCUS) [ 35 , 36 ].…”

“…So far, CORSA contributed to multiple international consortia such as Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ], COlorectal cancer GENeTics (COGENT) and COnsortium of METabolomics Studies (COMETS) [ 13 ]. Furthermore, CORSA was a partner in two ERANET-TRANSCAN-funded projects: MetaboCCC [ 11 , 12 , 44 , 45 , 46 , 50 , 51 ], and “Biomarkers related to folate-dependent metabolism in colorectal cancer recurrence and survival” (FOCUS) [ 35 , 36 ]. These interdisciplinary projects bring together multiple European CRC cohorts, including CORSA, the ColoCare study of the German Cancer Research Center in Heidelberg [ 14 ], the EnCoRe study of Maastricht University, the Netherlands [ 15 ], as well as the COLON study of Wageningen University, the Netherlands [ 16 ].…”

A 41-Gene Pair Signature for Predicting the Pathological Response of Locally Advanced Rectal Cancer to Neoadjuvant Chemoradiation

“…The information of these patients was in reference ( 17 ). Because rectal and colon cancers are almost genetically indistinguishable ( 25 ), we expected that the 41-GPS would also be applicable to patients with colon cancer. We also collected 158 The Cancer Genome Atlas Rectum Adenocarcinoma (TCGA-READ) to predict DFS benefits.…”