The landscape of alterations in DNA damage response pathways in colorectal cancer

Hiroyuki Arai, Andrew Elliott, Joanne Xiu, Jingyuan Wang, Francesca Battaglin, Natsuko Kawanishi, Shivani Soni, Wu Zhang, Joshua Millstein, Davendra Sohal, Richard M. Goldberg, Michael J. Hall, Aaron J. Scott, Moh'd Khushman, Jimmy J. Hwang, Emil Lou, Benjamin A. Weinberg, John L. Marshall, Albert C. Lockhart, Phillip StaffordJian Zhang, Roberto Moretto, Chiara Cremolini, W. Michael Korn, Heinz Josef Lenz

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Defective DNA damage response (DDR) is a hallmark of cancer leading to genomic instability and is associated with chemosensitivity. Although the mismatch repair system has been extensively studied, the clinical implications of other mechanisms associated with DDR alterations in patients with colorectal cancer remain unclear. This study aimed to understand DDR pathways alterations and their association with common clinical features in patients with colorectal cancer. Experimental Design: Next-generation sequencing and whole-transcriptome sequencing were conducted using formalin-fixed paraffin-embedded samples submitted to a commercial Clinical Laboratory Improvement Amendments-certified laboratory. Samples with pathogenic or presumed pathogenic mutations in 29 specific DDR-related genes were considered as DDR-mutant (DDR-MT) and the remaining samples as DDR-wild type (DDR-WT). Results: Of 9,321 patients with colorectal cancer, 1,290 (13.8%) were DDR-MT. The frequency of DDR-MT was significantly higher in microsatellite instability-high (MSI-H) cases than in microsatellite stable cases (76.4% vs. 9.5%). The DDR-MT genotype was higher in the right-sided, RAS-wild, BRAF-mutant, and CMS1 subgroups. However, these associations were primarily confounded by the distribution of MSI status. Compared with the DDR-WT tumors, the DDR-MT tumors had a higher mutational burden and gene expression levels in the immune-related pathway, which were independent of MSI status. Conclusions: We characterized a distinct subgroup of patients with colorectal cancer with tumors harboring mutations in the DDR-related genes. These patients more commonly had MSI-H tumors and exhibited an activated immune signature regardless of their tumor's MSI status. These findings warrant further investigations to develop personalized treatment strategies in this significant subgroup of patients with colorectal cancer.

Original languageEnglish (US)
Pages (from-to)3234-3242
Number of pages9
JournalClinical Cancer Research
Volume27
Issue number11
DOIs
StatePublished - Jun 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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