e15093 Background: Mutations leading to homologous recombination deficiency increases the sensitivity towards platinum-based chemotherapy, as well as the PARP inhibitor. The acquired resistance caused by reversion mutations diminishes the prolonged benefit from the treatment. Herein, we aimed to investigate the prevalence and characteristics of reversion mutations in Chinese population. Methods: The next-generation sequencing data from 23,712 pan-cancer patients (including over 17 cancer types) were retrospectively analyzed for pathogenic/likely pathogenic (P/LP) germline mutations in homologous recombination repair (HRR) genes and possible somatic reversion mutations emerged later. Somatic mutations predicted to restore the open reading frame were identified and further classified into definitive or putative reversion mutations depending on whether the somatic mutation could be confirmed to occur on the same allele as the germline mutation by sequencing reads. Results: From the 23,712 patients, 685 (2.9%) were identified with P/LP germline HRR gene mutations, among which we identified 11 cases with 21 definitive and 4 putative somatic reversion mutations upon treatment, including 8 cases of breast cancer, 3 cases of ovarian cancer, 1 case of pancreatic cancers, and another case of lung cancer. The reversion mutations occurred in 3 genes: BRCA1 (7 cases), BRCA2 (5 cases) and PALB2 (1 case), but not in any other HRR genes in our cohort. Therefore, the incidence of reversion mutations in HRR genes was 1.6% (11/685), with the highest incidence observed in BRCA1 (5.26%) followed by BRCA2 (2.7%) and PALB2 (1.96%). Interestingly, multiple somatic reversion mutations could be observed in 3 patients, indicating heterogeneity in the resistance mechanisms. Among 6 patients with detailed treatment history available, 5 of them had reversion mutations detected after systemic platinum-based chemotherapy and/or PARP inhibitor treatment. The other patient of metastatic breast cancer had 6 prior lines of treatment including 2 cycles of thoracic perfusion of endostatin and lobaplatin before BRCA2 reversion mutation was detected. This patient subsequently received olaparib monotherapy with a progression free survival of only 2 months. Conclusions: This retrospective study demonstrated that the reversion mutations were observed in three HRR-associated genes ( BRCA1, BRCA2 and PALB2) with four cancer types (breast cancer, ovarian cancer, lung cancer and pancreatic cancer) from this Chinese patient cohort. The reversion mutations frequently occurred after resistance to platinum-based chemotherapy and/or PARP inhibitor, and may predict poor outcome from ensuing PARP inhibition therapy. Therefore, monitoring HRR mutation status along the course of the disease could be beneficial especially to informing resistance mechanism and guiding subsequent therapies.
A CDC7 inhibitor sensitizes DNA-damaging chemotherapies by suppressing homologous recombination repair to delay DNA damage recovery
