Open AccessGenomic analyses of high‐grade neuroendocrine gynecological malignancies reveal a unique mutational landscape and therapeutic vulnerabilities
Author(s) -
Mahdi Haider,
JoehlinPrice Amy,
Elishaev Esther,
Dowlati Afshin,
Abbas Ata
Publication year - 2021
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.13057
Subject(s) - transcriptome , fusion gene , gene , biology , cancer , lung cancer , overall survival , medicine , bioinformatics , malat1 , oncology , cancer research , genetics , gene expression , rna , long non coding rna
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 high molecular subtype. Our study identifies several potential therapeutic targets and suggests an urgent need to re‐evaluate the treatment options for NEC‐GYN.