Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival

• Type of Material: Article
• Authors: Syed H. Zaidi, Ontario Institute for Cancer Research; Tabitha A. Harrison, Fred Hutchinson Cancer Research Center; Amanda I. Phipps, Fred Hutchinson Cancer Research Center; Robert Steinfelder, Fred Hutchinson Cancer Research Center; quang M. Trinh, Ontario Institute for Cancer Research; Conghui Qu, Fred Hutchinson Cancer Research Center; Alton Farris III, Emory University; Peter T. Campbell, Emory University
• Language: English
• Date: 2020-12-01
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2020, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-020-17386-z
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 11
• Issue: 1
• Start Page: 3644
• End Page: 3644
• Grant/Funding Information: The Colon Cancer Family Registry (CFR) is supported by funding from the National Cancer Institute (NCI), National Institutes of Health (NIH) (grant numbers U01 CA167551).; OICR is supported by the Ontario Ministry of Research and Innovation, Ontario, Canada.; The Colon CFR participant recruitment and collection of data and biospecimens used in this study were supported through cooperative agreements with Ontario Familial Colorectal Cancer Registry (NCI/NIH U01/U24 CA074783) and Seattle Colorectal Cancer Family Registry (NCI/NIH U01/U24 CA074794).; PMH study is funded by National Institutes of Health (R01 CA076366 to P.A.N).; The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study-II (CPS-II) cohort.; Additional funding toward genetic analyses of OFCCR includes the Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation.; National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783).; This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. GECCO: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088, U01 CA164930 and R01 CA176272).; This work was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1 and BR 1704/17-1), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A and 01ER1505B).
• Keywords: CRC; cancer genomics; mutation; tumour-suppressor proteins; gene; colorectal cancer; mutational profile; targeted sequencing; heterogeneous disease
• Research Categories: Biology, Genetics; Health Sciences, Oncology

Abstract

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21–0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21–1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features.