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 l...

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Autores principales:	Haider Mahdi, Amy Joehlin‐Price, Esther Elishaev, Afshin Dowlati, Ata Abbas
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	CDK4/6 inhibitors gynecologic neuroendocrine carcinoma immunotherapy targets PARP inhibitors RB1 YAP1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/ffae59a46950433a8f22dbd047b6eba3
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spelling	oai:doaj.org-article:ffae59a46950433a8f22dbd047b6eba32021-12-02T10:31:06ZGenomic analyses of high‐grade neuroendocrine gynecological malignancies reveal a unique mutational landscape and therapeutic vulnerabilities1878-02611574-789110.1002/1878-0261.13057https://doaj.org/article/ffae59a46950433a8f22dbd047b6eba32021-12-01T00:00:00Zhttps://doi.org/10.1002/1878-0261.13057https://doaj.org/toc/1574-7891https://doaj.org/toc/1878-0261High‐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 YAP1high molecular subtype. Our study identifies several potential therapeutic targets and suggests an urgent need to re‐evaluate the treatment options for NEC‐GYN.Haider MahdiAmy Joehlin‐PriceEsther ElishaevAfshin DowlatiAta AbbasWileyarticleCDK4/6 inhibitorsgynecologic neuroendocrine carcinomaimmunotherapy targetsPARP inhibitorsRB1YAP1Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENMolecular Oncology, Vol 15, Iss 12, Pp 3545-3558 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	CDK4/6 inhibitors gynecologic neuroendocrine carcinoma immunotherapy targets PARP inhibitors RB1 YAP1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	CDK4/6 inhibitors gynecologic neuroendocrine carcinoma immunotherapy targets PARP inhibitors RB1 YAP1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Haider Mahdi Amy Joehlin‐Price Esther Elishaev Afshin Dowlati Ata Abbas Genomic analyses of high‐grade neuroendocrine gynecological malignancies reveal a unique mutational landscape and therapeutic vulnerabilities
description	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 YAP1high molecular subtype. Our study identifies several potential therapeutic targets and suggests an urgent need to re‐evaluate the treatment options for NEC‐GYN.
format	article
author	Haider Mahdi Amy Joehlin‐Price Esther Elishaev Afshin Dowlati Ata Abbas
author_facet	Haider Mahdi Amy Joehlin‐Price Esther Elishaev Afshin Dowlati Ata Abbas
author_sort	Haider Mahdi
title	Genomic analyses of high‐grade neuroendocrine gynecological malignancies reveal a unique mutational landscape and therapeutic vulnerabilities
title_short	Genomic analyses of high‐grade neuroendocrine gynecological malignancies reveal a unique mutational landscape and therapeutic vulnerabilities
title_full	Genomic analyses of high‐grade neuroendocrine gynecological malignancies reveal a unique mutational landscape and therapeutic vulnerabilities
title_fullStr	Genomic analyses of high‐grade neuroendocrine gynecological malignancies reveal a unique mutational landscape and therapeutic vulnerabilities
title_full_unstemmed	Genomic analyses of high‐grade neuroendocrine gynecological malignancies reveal a unique mutational landscape and therapeutic vulnerabilities
title_sort	genomic analyses of high‐grade neuroendocrine gynecological malignancies reveal a unique mutational landscape and therapeutic vulnerabilities
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/ffae59a46950433a8f22dbd047b6eba3
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Genomic analyses of high‐grade neuroendocrine gynecological malignancies reveal a unique mutational landscape and therapeutic vulnerabilities

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