Abstract 5872: Investigation on the prevalence of germline and somatic mutations in gynecological malignancies: Implications for risk assessment and therapeutic decision-making
Authors: Wen Hao , Xu Qin , Sheng Xiujie , Li Huawen , Wang Xipeng , Wu Xiaohua 
Published: June 2022

Introduction: Heritable mutations in cancer predisposition genes increase the relative risk of developing malignant gynecological tumors, whereas actionable somatic mutations could serve as biomarker for therapeutic decision-making. Our study explored the prevalence of germline pathogenic/likely-pathogenic (P/LP) mutations and actionable somatic mutations to understand the clinical utility of next-generation sequencing (NGS) in gynecological malignancies.

Methods: Genomic data was retrospectively analyzed for 1,610 women with various stages of gynecological malignancies including ovarian (OC, n=945), cervical (CC, n=358), and endometrial cancers (EC, n=307). Genomic data were derived from targeted NGS of paired white blood cell and other biological samples using a 520-gene panel that included 62 cancer predisposition genes. Genomic signatures including tissue-based tumor mutation burden (tTMB) and microsatellite instability (MSI) were also estimated from somatic mutation profiles.

Results: The prevalence of germline P/LP mutations in cancer predisposition genes was 20.6% for OC, 13.4% for EC, and 6.4% for CC. OC had the highest mutation rate in genes involved in the homologous recombination repair pathway (18.8%, 178/945), while EC had the highest mutation rate in genes involved in mismatch repair (MMR) pathway (5.5%, 17/307). The frequency of actionable germline P/LP mutations was 19.8% for OC, 11.7% for EC, and 5.0% for CC. The detection rate for actionable somatic mutations were comparable between carrier and non-carrier of germline mutations (OC, 80.5% vs 76.3%, p=0.2; EC, 73.2% vs 80.5%, p=0.4; and CC, 56.5% vs 63.0%, p=0.7). tTMB was also comparable and generally low among carrier and non-carrier of germline mutations (OC, 3.0 [range: 2.0-5.0] vs 3.0 [2.0-5.0], p=0.9; EC, 6.2 [4.8-45.1] vs. 4.8 [2.8-13.2], p=0.1; and CC, 4.8 [2.4-6.0] vs 4.0 [2.4-7.9], p=0.8). The proportion of MSI-H was comparable for OC patients with or without germline mutations (2.6% vs 1.2%, p=0.2); however, the proportion of MSI-H was significantly higher for EC (29.3% vs 11.7%, p=0.019) and CC (13.0% vs 1.2%, p&lt;0.001) who were carriers of germline mutations than non-carriers. The proportion of MSI-H was comparable between EC patients with germline (n=5) and somatic (n=29) MMR gene mutations (40.0%, 2/5 vs 48.3%, 14/29; p=1). EC patients with MSI-H were more likely to have high tTMB (cut-off ≥7 mutations/Mb) (p&lt;0.001).

Conclusions: The comparable frequency of actionable somatic mutations in women with or without germline mutations indicates that both populations could benefit from NGS testing. Our findings raise the importance of NGS-based genetic testing with a large gene panel as part of gynecological cancer screening and diagnosis to explore heritable and acquired mutation status for risk assessment and therapeutic decision-making.

Citation Format: Hao Wen, Qin Xu, Xiujie Sheng, Huawen Li, Xipeng Wang, Xiaohua Wu. Investigation on the prevalence of germline and somatic mutations in gynecological malignancies: Implications for risk assessment and therapeutic decision-making [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5872.