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.
Highlights
Colorectal cancer (CRC) is a biologically heterogeneous disease
To construct an AmpliSeq panel, we prioritized a list of 205 genes selected based on analysis of whole exome sequencing data for CRC from TCGA2,6, and two prospective cohort studies, the Health Professionals’ Follow-Up Study (HPFS) and the Nurses’ Health Study (NHS)[7], as well as a literature search
In addition to previous known genes, we identified PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as significantly mutated by MutSigCV, which had not been reported in previous studies[2,4,6,7], suggesting putative driver status of these genes
Summary
To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. 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. Next-generation sequencing (NGS) has identified a diversity of driver mutations in genes and altered signaling pathways in CRC2–5 Limitations of these studies are the scarcity of clinical data, as well as the inability to achieve statistical significance due to small sample size. We constructed a custom AmpliSeq panel of 205 genes, prioritized from the analyses of CRC mutation datasets and literature review[2,6,7], and conducted targeted deep sequencing on DNA from FFPE tumors and matching normal tissues from five-wellcharacterized studies. The profiling of mutations in the largest population-based CRC sequencing study to date provides a deep insight into the mutational landscape of CRC and associations with survival
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