Several risk factors have been established for colorectal carcinoma (CRC), yet their direct mutagenic effects in patients' tumours remain to be elucidated. Here, we leveraged whole-exome sequencing data from 900 CRC cases that had occurred in three US-wide prospective studies with extensive dietary and lifestyle information. We found an alkylating signature which was previously undescribed in CRC, and then showed the existence of a similar mutational process in normal colonic crypts. This alkylating signature is associated with high intakes of processed and unprocessed red meat prior to diagnosis. Additionally, this signature was more abundant in the distal colorectum, predicted to target cancer driver mutations KRAS p.G12D, KRAS p.G13D and PIK3CA p.E5454K, and associated with poor survival. Together, these results link for the first time a colorectal mutational signature to a component of diet, and further implicate the role of red meat in CRC initiation and progression.
Gurjao, C., Zhong, R., Haruki, K., Li, Y. Y., Spurr, L. F., Lee-Six, H., … Giannakis, M. (2021). Discovery and Features of an Alkylating Signature in Colorectal Cancer. Cancer Discovery. https://doi.org/10.1158/2159-8290.cd-20-1656