Genomic analyses of high-grade neuroendocrine gynecological malignancies reveal a unique mutational landscape and therapeutic vulnerabilities.

High-grade neuroendocrine carcinoma of gynecologic origin (NEC-GYN) is a highly aggressive cancer that often affects young women. The clinical management of NEC-GYN is typically extrapolated from its counterpart, small cell carcinoma of the lung (SCLC), but, unfortunately, available therapies have limited benefit. In our NEC-GYN cohort, median progression-free survival (PFS) and overall survival (OS) were 1 and 12 months, respectively, indicating the highly lethal nature of this cancer. Our comprehensive genomic analyses unveiled that NEC-GYN harbors a higher mutational burden with distinct mutational landscapes from SCLC. We identified 14 cancer driver genes, including the most frequently altered KMT2C (100%), KNL1 (100%), NCOR2 (100%), and CCDC6 (93%) genes. Transcriptomic analysis identified several novel gene fusions; astonishingly, the MALAT1 lincRNA gene was found in ˜ 20% of all fusion events in NEC-GYN. Furthermore, NEC-GYN exhibited a highly immunosuppressive state, intact RB1 expression, and was uniquely enriched with the YAP1 molecular subtype. Our study identifies several potential therapeutic targets and suggests an urgent need to re-evaluate the treatment options for NEC-GYN.