Discovery and Features of an Alkylating Signature in Colorectal Cancer
Autor: | Jeffrey A. Meyerhardt, Edward Giovannucci, Koichiro Haruki, Mingyang Song, Eliezer M. Van Allen, Kana Wu, Marios Giannakis, Shuji Ogino, Andrew D. Cherniack, Jonathan A. Nowak, Brendan Reardon, Rong Zhong, Charles S. Fuchs, Henry Lee-Six, Carino Gurjao, Liam F. Spurr, Xuehong Zhang, Yvonne Y. Li, Tomotaka Ugai |
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Rok vydání: | 2021 |
Předmět: |
Adult
Male Alkylating Agents Colorectal cancer medicine.disease_cause Article Cohort Studies Exome Sequencing Humans Medicine In patient Prospective Studies Tumor location Prospective cohort study neoplasms Aged business.industry Cancer Middle Aged medicine.disease digestive system diseases Oncology Red Meat Consumption Cancer research Red meat Female KRAS Colorectal Neoplasms business |
Zdroj: | Cancer Discov |
ISSN: | 2159-8290 2159-8274 |
Popis: | Several risk factors have been established for colorectal cancer, yet their direct mutagenic effects in patients' tumors remain to be elucidated. Here, we leveraged whole-exome sequencing data from 900 colorectal cancer cases that had occurred in three U.S.-wide prospective studies with extensive dietary and lifestyle information. We found an alkylating signature that was previously undescribed in colorectal cancer 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. In addition, this signature was more abundant in the distal colorectum, predicted to target cancer driver mutations KRAS p.G12D, KRAS p.G13D, and PIK3CA p.E545K, 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 colorectal cancer initiation and progression. Significance: Colorectal cancer has several lifestyle risk factors, but the underlying mutations for most have not been observed directly in tumors. Analysis of 900 colorectal cancers with whole-exome sequencing and epidemiologic annotations revealed an alkylating mutational signature that was associated with red meat consumption and distal tumor location, as well as predicted to target KRAS p.G12D/p.G13D. This article is highlighted in the In This Issue feature, p. 2355 |
Databáze: | OpenAIRE |
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