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

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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
Issue number11
StatePublished - Jun 1 2021

Bibliographical note

Funding Information:
J. Xiu reports other from Caris Life Sciences during the conduct of the study. D. Sohal reports personal fees from InCyte and Ability Pharma; other from Amgen, Apexigen, BMS, Celgene, FibroGen, Genentech, Medimmune, Merck, OncoMed, and Rafael outside the submitted work. R.M. Goldberg reports personal fees from Amgen, Taiho, Genentech, Merck, Novartis, AstraZeneca, Adaptimmune, and Bayer outside the submitted work. M.J. Hall reports a patent for U.S. 9,157,124 B2 issued. J.J. Hwang reports personal fees from Bristol Myers Squibb, Genentech, Taiho, Bayer, Amgen, Boehringer Ingelheim, Celgene, Eisai, and Lilly outside the submitted work. B.A. Weinberg reports personal fees from Lilly, Sirtex, Bayer, Daiichi Sankyo, AstraZeneca, and Taiho; grants from Ipsen and Novartis; and nonfinancial support from Caris Life Sciences outside the submitted work. J.L. Marshall reports personal fees from Caris and Indivumed outside the submitted work. W.M. Korn reports employment at Caris Life Sciences and personal fees from Merck outside the submitted work. No disclosures were reported by the other authors.

Funding Information:
This work was supported by the NCI (P30CA 014089, to H.-J. Lenz), Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Victoria and Philip Wilson Research Fund, San Pedro Peninsula Cancer Guild, and Daniel Butler Research Fund. We thank all patients who contributed to this study.

Publisher Copyright:
© 2021 American Association for Cancer Research.

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