Objective Colorectal cancer is typically classified into proximal colon, distal colon and rectal cancer. Tumour genetic and epigenetic features differ by tumour location. Considering a possible role of bowel contents (including microbiome) in carcinogenesis, this study hypothesised that tumour molecular features might gradually change along bowel subsites, rather than change abruptly at splenic flexure.
Design Utilising 1443 colorectal cancers in two US nationwide prospective cohort studies, the frequencies of molecular features (CpG island methylator phenotype (CIMP), microsatellite instability (MSI), LINE-1 methylation and BRAF, KRAS and PIK3CA mutations) were examined along bowel subsites (rectum, rectosigmoid junction, sigmoid, descending colon, splenic flexure, transverse colon, hepatic flexure, ascending colon and caecum). The linearity and non-linearity of molecular relations along subsites were statistically tested by multivariate logistic or linear regression analysis.
Results The frequencies of CIMP-high, MSI-high and BRAF mutations gradually increased from the rectum (<2.3%) to ascending colon (36–40%), followed by falls in the caecum (12–22%). By linearity tests, these molecular relations were significantly linear from rectum to ascending colon (p<0.0001), and there was little evidence of non-linearity (p>0.09). Caecal cancers exhibited the highest frequency of KRAS mutations (52% vs 27–35% in other sites; p<0.0001).
Conclusions The frequencies of CIMP-high, MSI-high and BRAF mutations in cancer increased gradually along colorectum subsites from the rectum to ascending colon. These novel data challenge the common conception of discrete molecular features of proximal versus distal colorectal cancers, and have a substantial impact on clinical, translational and epidemiology research, which has typically been performed with the dichotomous classification of proximal versus distal tumours.
- cancer epidemiology
- cancer prevention
- colon cancer
- colorectal cancer
- colorectal pathology
- genomic instability
- non-steroidal anti-inflammatory drugs
- 2,4,6-trinitrobenzene sulphonic acid
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Funding This work was supported by US National Institutes of Health grants (P01CA87969 (to SE Hankinson), P01CA55075 (to WC Willett), P50CA127003 (to CSF), R01CA151993 (to SO) and R01CA137178 (to ATC)); the Bennett Family Fund for Targeted Therapies Research; and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. TM was supported by a fellowship grant from the Japan Society for the Promotion of Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH. Funding agencies did not have any role in the design of the study, the collection, analysis, or interpretation of the data, the decision to submit the manuscript for publication or the writing of the manuscript.
Competing interests None.
Ethics approval This study was approved by the Harvard School of Public Health and Brigham and Women's Hospital institutional review boards.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.