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

The high-grade neuroendocrine carcinoma of gynecologic origin (NEC-GYN) is a highly aggressive cancer affecting young women. The clinical management of NEC-GYN is often extrapolated from their counterpart, small cell carcinoma of the lung (SCLC), but, unfortunately, they have limited effect. In our NEC-GYN cohort, median progression-free survival (PFS) and overall survival (OS) were 1 and 12 months, respectively, indicating their highly lethal nature. 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 (FDR <0.01) including the most frequently altered KMT2C (100%), KNL1 (100%), NCOR2 (100%), and CCDC6 (93%) genes. Transcriptomic analyses identified several novel gene fusions in NEC-GYN. Furthermore, NEC-GYN exhibited a highly immunosuppressive state and uniquely belonged to the YAP1 high molecular subtype that promotes multidrug resistance. Our study suggests an urgent need to reevaluate the therapeutic options and targets for NEC-GYN.