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

Mahdi, Haider; Joehlin‐Price, Amy; Elishaev, Esther; Dowlati, Afshin; Abbas, Ata

doi:10.1002/1878-0261.13057

Cited by 7 publications

(4 citation statements)

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“…Nevertheless, their part in treating gynecologic tract NENs is limited due to low incidence or insufficient clinical trials data. A comprehensive study by Mahdi et al reported that gynecological NEC demonstrated frequent mutations in KMT2C and KMT2D genes involved in gene enhancers regulation [ 113 ]. They also found that DDR (DNA damage response) gene mutations are high in gynecological NEC, making them susceptible to PARP inhibitors.…”

Section: Future Perspectivementioning

confidence: 99%

“…They also found that DDR (DNA damage response) gene mutations are high in gynecological NEC, making them susceptible to PARP inhibitors. In addition, mutations in CCDC6 suggest promising benefits from PARP inhibitors [ 113 ]. Further studies are required to evaluate the efficacy of targeted immunotherapy against HMGB1/TIM-3 and CD47/SIRPα.…”

Section: Future Perspectivementioning

confidence: 99%

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Neuroendocrine Neoplasms of the Gynecologic Tract

Virarkar

Vulasala

Morani

et al. 2022

Cancers

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Gynecological tract neuroendocrine neoplasms (NEN) are rare, aggressive tumors from endocrine cells derived from the neuroectoderm, neural crest, and endoderm. The primary gynecologic NENs constitute 2% of gynecologic malignancies, and the cervix is the most common site of NEN in the gynecologic tract. The updated WHO classification of gynecologic NEN is based on the Ki-67 index, mitotic index, and tumor characteristics such as necrosis, and brings more uniformity in the terminology of NENs like other disease sites. Imaging plays a crucial role in the staging, triaging, restaging, and surveillance of NENs. The expression of the somatostatin receptors on the surface of neuroendocrine cells forms the basis of increasing evaluation with functional imaging modalities using traditional and new tracers, including 68Ga-DOTA-Somatostatin Analog-PET/CT. Management of NENs involves a multidisciplinary approach. New targeted therapies could improve the paradigm of care for these rare malignancies. This article focuses on the updated staging classifications, clinicopathological characteristics, imaging, and management of gynecologic NENs of the cervix, ovary, endometrium, vagina, and vulva, emphasizing the relatively common cervical neuroendocrine carcinomas among these entities.

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Section: Future Perspectivementioning

confidence: 99%

Section: Future Perspectivementioning

confidence: 99%

Neuroendocrine Neoplasms of the Gynecologic Tract

Virarkar

Vulasala

Morani

et al. 2022

Cancers

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“…Microphthalmia-associated transcription factor (MITF/MiT) family translocation renal cell carcinoma and other types of tumors, such as perivascular epithelioid cell neoplasm and alveolar soft part sarcoma, are known to harbor MALAT1 fusion with TFE3 , TFEB , TFEC , and MITF . MALAT1 fusions, including MALAT1::SMG , EEF1A1::MALAT1 , and ASH1L::YY1AP1 , have been detected in nearly 20% of all fusion gene events in gynecologic high-grade neuroendocrine carcinomas [ 34 ]. Together with the results presented in this study, these findings suggest that MALAT1 can be highly available for gene rearrangement to form oncogenic fusions; however, the biological and clinical significance of these MALAT1 fusions has not been fully investigated.…”

Section: Resultsmentioning

confidence: 99%

MALAT1 functions as a transcriptional promoter of MALAT1::GLI1 fusion for truncated GLI1 protein expression in cancer

et al. 2023

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Background The long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a cancer biomarker. Furthermore, fusion of the MALAT1 gene with glioma-associated oncogene 1 (GLI1) is a diagnostic marker of plexiform fibromyxoma and gastroblastoma; however, the function of this fusion gene remains unexplored. Method In this study, we elucidate the structure and function of the MALAT1::GLI1 fusion gene. To this end, we determined a transcriptional start site (TSS) and promoter region for truncated GLI1 expression using rapid amplification of the 5' cDNA end and a luciferase reporter assay in cultured cells transfected with a plasmid harboring the MALAT1::GLI1 fusion gene. Results We found that the TATA box, ETS1 motif, and TSS were located in MALAT1 and that MALAT1 exhibited transcriptional activity and induced expression of GLI1 from the MALAT1::GLI1 fusion gene. Truncated GLI1, lacking SUMOylation and SUFU binding sites and located in the nucleus, upregulated mRNA expression of GLI1 target genes in the hedgehog signaling pathway. Conclusions We demonstrate a distinct and alternative function of MALAT1 as a transcriptional promoter for expression of the MALAT1::GLI1 fusion gene. Our findings will aid future research on MALAT1 and its fusion gene partners.

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“…Nevertheless, in a series of forty pathologic specimens from patients with NECs of the cervix, PD-L1 was positive (considered as a composite proportion score ≥ 1) in only 8% of samples, while all were microsatellite-stable by IHC [92]. However, mutations in DNA damage response (DDR) genes, which can be commonly observed in GY-NECs, also induce the accumulation of DNA mutations, which cause high TMB [93], which is a predictive factor of the activity of ICIs in several malignancies [94,95]. Indeed, a cohort of the DART SWOG 1609 phase II study investigated the activity of the combination of ipilimumab and nivolumab in non-pancreatic neuroendocrine neoplasms [96].…”

Section: Necs Of the Cervixmentioning

confidence: 99%

Extrapulmonary Neuroendocrine Carcinomas: Current Management and Future Perspectives

Stumpo,

Formelli,

Persano

et al. 2023

JCM

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Neuroendocrine carcinomas (NECs) are poorly differentiated and highly aggressive epithelial neuroendocrine neoplasms. The most common primary site is the lung, but they may arise in every organ. Approximately 37% of extrapulmonary NECs (EP-NECs) occur in the gastroenteropancreatic (GEP) tract, followed by the genitourinary (GU) system and gynecological tract. As a result of their rarity, there is scant evidence to guide treatment recommendations, and a multidisciplinary approach is essential for the management of such patients. Platinum-based chemotherapy currently represents the standard of care for EP-NECs of any site, mirroring the management of small-cell lung cancer (SCLC), but further approaches are still under investigation. Indeed, ongoing trials evaluating targeted therapies, immune checkpoint inhibitors (ICIs), and radionuclide therapy could provide potentially breakthrough therapeutic options. Given the relative dearth of evidence-based literature on these orphan diseases, the aim of this review is to provide an overview of the pathology and current treatment options, as well as to shed light on the most pressing unmet needs in the field.

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

Cited by 7 publications

References 50 publications

Neuroendocrine Neoplasms of the Gynecologic Tract

Neuroendocrine Neoplasms of the Gynecologic Tract

MALAT1 functions as a transcriptional promoter of MALAT1::GLI1 fusion for truncated GLI1 protein expression in cancer

Extrapulmonary Neuroendocrine Carcinomas: Current Management and Future Perspectives

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