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Clinical and genetic characterization of cancer patients with multiple germline variants.

e22523 Background: Hereditary tumors are generally monogenic diseases with autosomal dominant inheritance. However, we noticed that some individuals may harbor ≥2 germline mutations in one or multiple genes, which remains to be explored. Methods: Genetic mutations were reviewed in more than 50,000 cancer patients who underwent hybridization capture based next-generation sequencing (NGS). Germline variants were interpreted following ACMG guideline, and only pathogenic and likely pathogenic variants were included in this study. Results: Multiple germline variants were identified in 42 individuals with the detection rate of 0.075%. The median age at diagnosis was 48 years (range 31-73). Two thirds of patients were female and 26.2% of patients has cancer family history. Prostate cancer is the most common cancer type (0.6%, 2/332), followed by carcinomas of ovarian or fallopian tube (0.48%, 7/1461), breast (0.24%, 8/3302), pancreas (0.2%, 2/982) and so on. Surprisingly, 7 patients with lung cancer also harbored ≥2 germline mutations (0.02%). Most of these germline variants affected DNA damage repair pathways [75.6% homologous recombination repair (HR), 8.1% mismatch repair (MMR), 1.2% base excision repair (BER)]. Four patients had two germline variants identified on a single gene (2 ATM, 1 BRCA1, 1 BRCA2). Three variants were identified in 2 patients, and 2 variants were identified in the remaining 36 patients. Two or more germline variants in HRR pathway were identified in 64.3% of patients, among which 18.5% patients had BRCA1+ BRCA2 double variants. The efficacy of poly ADP-ribose polymerase inhibitors (PARPi) in this specific population should raise concern. Besides, double variants in HRR and MMR pathway were found in 5 patients, which suggested the potential benefit of immunotherapy and PARPi combination therapy. Conclusions: In addition to identify variants contributing to the personal and family cancer history, NGS can accidentally identify germline variants that may suggest the susceptibility of other hereditary tumors. Multiple variants on HRR or MMR genes may have important implications for the treatment strategy for these patients.