Research Paper Volume 13, Issue 2 pp 2365—2378

The mutational pattern of homologous recombination-related (HRR) genes in Chinese colon cancer and its relevance to immunotherapy responses

Pei Zhou1, *, , Xueying Wu2, *, , Huan Chen2, , Ying Hu3, , Henghui Zhang4, , Lijia Wu2, , Ying Yang2, , Beibei Mao2, *, , Huaqing Wang1, *, ,

  • 1 Department of Medical Oncology, Tianjin Union Medical Center, The Affiliated Hospital of Nankai University, Tianjin, China
  • 2 Genecast Precision Medicine Technology Institute, Beijing, China
  • 3 Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
  • 4 Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
* Equal contribution

Received: May 23, 2020       Accepted: November 3, 2020       Published: December 9, 2020
How to Cite

Copyright: © 2020 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Background: Microsatellite-stable (MSS) colon adenocarcinoma (COAD) patients are not sensitive to immune checkpoint inhibitors. Here, we focused on analyzing the relationship between homologous recombination repair (HRR)-related gene mutations and clinical immunotherapy responses in MSS COAD.

Methods: The mutational landscape was profiled in a cohort of 406 Chinese COAD patients via next-generation sequencing (NGS). Correlations between HRR gene mutations and tumor immunity or clinical outcomes in two COAD genomic datasets were analyzed via bioinformatics.

Results: In the Chinese cohort, seventy (17%) patients exhibited genomic alterations in HRR genes; ATM (9%), BRCA2 (4%), ATR (3%), RAD50 (3%) and BRIP1 (3%) were the most frequently mutated. In the MSK-IMPACT COAD cohort (immune checkpoint inhibitor-treated), HRR-mut patients (n=34) survived longer than HRR-wt patients (n=50) (log-rank P < 0.01). Based on the TCGA MSS COAD cohort, HRR gene mutations increased immune activities, such as infiltration of cytotoxic cells (P < 0.05) and exhausted CD8+ T cells (P < 0.01), and increased the IFN-γ scores (P < 0.05). The results differed in MSI-H COAD patients (all P > 0.05).

Conclusion: HRR gene mutations significantly increased immune activities in MSS COAD patients, implying the feasibility of the HRR-mut status as an immunotherapy response predictor in MSS COAD.


CNV: copy number variation; COAD: colon adenocarcinoma; CRCs: colorectal cancers; EGFR: epidermal growth factor receptor; HRD: homologous recombination deficiency; HRR: homologous recombination; ICIs: immune checkpoint inhibitors; LOH: loss of heterozygosity; MMR: mismatch repair; MSS: microsatellite stable; MSI-H: microsatellite instability-high; MSI-L: microsatellite instability-low; MHC: major histocompatibility complex; NGS: next-generation sequencing; NK: natural killer; OS: overall survival; PARPi: poly(ADP ribose) polymerase inhibitors; TCGA: The Cancer Genome Atlas; TILs: tumor-infiltrating lymphocyte; TMB: tumor mutation burden.