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Arai H , Elliott A , Xiu J , Wang J , Battaglin F , Kawanishi N , Soni S , Zhang W , Millstein J , Sohal D , Goldberg RM , Hall MJ , Scott AJ , Khushman M , Hwang JJ , Lou E , Weinberg BA , Marshall JL , Lockhart AC , Stafford P , Zhang J , Moretto R , Cremolini C , Korn WM , Lenz HJ
The landscape of alterations in DNA damage response pathways in colorectal cancer
Clin Cancer Res. 2021 Mar 25
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Abstract
PURPOSE: Defective DNA damage response (DDR) is a hallmark of cancer leading to genomic instability and is associated with chemosensitivity. While the mismatch repair system has been extensively studied, the clinical implications of other mechanisms associated with DDR alterations in patients with colorectal cancer (CRC) remain unclear. This study aimed to understand DDR pathways' alterations and their association with common clinical features in CRC patients. EXPERIMENTAL DESIGN: Next-generation sequencing and whole transcriptome sequencing were conducted using formalin-fixed paraffin-embedded samples submitted to a commercial CLIA-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 9321 CRC patients, 1290 (13.8%) were DDR-MT. The frequency of DDR-MT was significantly higher in MSI-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 CRC patients 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 CRC patients.
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1557-3265 Arai, Hiroyuki Elliott, Andrew Xiu, Joanne Wang, Jingyuan Battaglin, Francesca Kawanishi, Natsuko Orcid: 0000-0001-9799-9188 Soni, Shivani Zhang, Wu Millstein, Joshua Sohal, Davendra Goldberg, Richard M Orcid: 0000-0003-0308-8223 Hall, Michael J Scott, Aaron J Khushman, Moh'd Orcid: 0000-0002-3095-5073 Hwang, Jimmy J Lou, Emil Orcid: 0000-0002-1607-1386 Weinberg, Benjamin A Orcid: 0000-0002-0408-4817 Marshall, John L Orcid: 0000-0002-3449-2344 Lockhart, Albert C Stafford, Phillip Zhang, Jian Moretto, Roberto Cremolini, Chiara Korn, W Michael Orcid: 0000-0002-0124-6841 Lenz, Heinz-Josef Orcid: 0000-0003-2178-9568 Journal Article United States Clin Cancer Res. 2021 Mar 25:clincanres.3635.2020. doi: 10.1158/1078-0432.CCR-20-3635.