Comprehensive Analysis of Somatic Reversion Mutations in Homologous Recombination Repair (HRR) Genes in A Large Cohort of Chinese Pan-cancer Patients
Hong Zong, Jian Zhang, Zhengyang Xu, Jia-Ni Pan, Rong Wang, Jinming Han, Miao Jiang, Ruiping Ren, Li Hsin Zang, Haitao Wang, Wen‐Ming Cao
Abstract
Purpose: Mutations leading to homologous recombination deficiency (HRD) increase the tumor sensitivity to platinum-based chemotherapy and PARP inhibitors. However, reversion mutations often develop conferring acquired drug resistance. There is still a lack of comprehensive investigation on HRR reversion mutations in large pan-cancer cohorts, especially in the Eastern Asian population. This study aims to characterize reversion mutations in homologous recombination repair (HRR)-related genes in a large cohort of Chinese pan-cancer patients. Methods: Sequencing data from 23,375 patients across over 17 cancer types were retrospectively analyzed for pathogenic/likely pathogenic (P/LP) germline mutations in 15 HRR genes. Somatic mutations detected in tumor or circulating cell-free DNA predicted to restore the open reading frame of the deleterious allele were subsequently identified as reversion mutations. Results: 654 cases out of 23,375 (2.8%) unselected pan-cancer patients were identified with HRR germline mutations. Secondary somatic mutations were further analyzed in their matched tumor/plasma samples. The overall frequency of reversion mutation was 1.7% (11/654). The reversion mutations occurred only in 3 out of the 15 HRR genes: BRCA1 (3.8%), BRCA2 (3.5%) and PALB2 (2.0%) from 11 patients (6 breast cancers, 1 ovarian cancer, 1 pancreatic cancer, 1 lung cancer and 2 breast and ovarian dual cancers). We identified total 25 reversion events (BRCA1, n=9; BRCA2, n=8; PALB2, n=8), including 12 pure deletions, 10 missense single nucleotide variants, 2 insertions and 1 splice site mutation. Besides, we detected microhomology length >1bp in seven out of the reversion deletions (58.3%), suggestive of microhomology-mediated end-joining (MMEJ) repair signature. Intriguingly, a positive correlation (r=0.85, p=0.001) between the length of deletion and the microhomology length was also observed. We obtained disease courses from 6/11 patients with reversion events. Four acquired reversions after the failure of the PARP inhibitor treatment. Two patients had somatic reversion mutations identified after progressing on platinum-based treatment.