20P Unexpected germline pathogenic variants in gynaecologic cancers identified through a comprehensive cancer genome profiling programme

There is a growing utilization of comprehensive cancer genome profiling (CGP) to assess patients' eligibility for target therapies. Potential pathogenic germline variants (PPGVs) may be identified via CGP. Large series indicate that PPGVs in cancer risk genes are found in 10-23% of patients tested by CGP and 3-7% were confirmed to be germline. The present study reports the frequency of PGVs in a cohort of gynaecologic cancers patients on a prospective CGP programme. PPGVs were indicated for 1.069 tumor samples of ovarian (OC, n=632) and endometrial (EC, n=437) cancer patients analyzed by TruSight Oncology 500 High-Throughput (TSO500HT) solution from January 2022 to June 2023. PPGVs focused on 40 cancer risk genes as indicated by the European Society for Medical Oncology recommendations. Overall, 22.5% of patients (29.3% of OC and 12.8% of EC) had at least one PPGVs in cancer risk genes; in detail, 71 PPGVs were identified for EC and 206 for OC. Considering the association between variants and tumor type, 46.5% of PPGVs in EC and 65% in OC were referred to genes involved in well-known hereditary conditions (MLH1, MSH2, MSH6, PMS2 in EC and BRCA 1/2 in OC). Data on germinal confirmation are available for 207/277 variants (74.7%). 153 out of 207 variants (73.9%, of which 64.4% for EC and 76.5% for OC) were confirmed of germline origin. 30.7% (9/29 of EC and 38/124 of OC) of the confirmed PGVs were not related to Lynch syndrome and BRCA1/2 genes in EC and OC, respectively (Table).Table: 20POCECGenePPGV (n)Confirmed PGV (n)PPGV (n)Confirmed PGV (n)ATM5471BRCA1975930BRCA2372751BRIP15311CHEK21140DICER12010MLH14362MSH2311810MSH66387MUTYH11653NF18010PALB27621PMS21111POLD11010POLE1130PTCH12010PTEN0010RAD51C9600RAD51D3211RET0010SDHA2111SMARCB11000Total2061247129 Open table in a new tab Besides therapeutic and prognostic implications, CGP can identify variants related to hereditary cancer predisposition conditions allowing cascade prevention and identification of affected relatives. Approximately one-third of gynecological cancer patients were discovered to have PGVs in genes other than those commonly recommended.