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Abstract
OBJECTIVES:The present study aimed to contribute to the catalog of genetic mutations involved in the carcinogenic processes of uterine sarcomas (USs) and carcinosarcomas (UCSs), which may assist in the accurate diagnosis of, and selection of treatment regimens for, these conditions.METHODS:We performed gene-targeted next-generation sequencing (NGS) of 409 cancer-related genes in 15 US (7 uterine leiomyosarcoma [ULMS], 7 endometrial stromal sarcoma [ESS], 1 adenosarcoma [ADS]), 5 UCS, and 3 uterine leiomyoma (ULM) samples. Quality, frequency, and functional filters were applied to select putative somatic variants.RESULTS:Among the 23 samples evaluated in this study, 42 loss-of-function (LOF) mutations and 111 missense mutations were detected, with a total of 153 mutations. Among them, 66 mutations were observed in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. TP53 (48%), ATM (22%), and PIK3CA (17%) were the most frequently mutated genes. With respect to specific tumor subtypes, ESS showed mutations in the PDE4DIP, IGTA10, and DST genes, UCS exhibited mutations in ERBB4, and ULMS showed exclusive alterations in NOTCH2 and HER2. Mutations in the KMT2A gene were observed exclusively in ULM and ULMS. In silico pathway analyses demonstrated that many genes mutated in ULMS and ESS have functions associated with the cellular response to hypoxia and cellular response to peptide hormone stimulus. In UCS and ADS, genes with most alterations have functions associated with phosphatidylinositol kinase activity and glycerophospholipid metabolic process.CONCLUSION:This preliminary study observed pathogenic mutations in US and UCS samples. Further studies with a larger cohort and functional analyses will foster the development of a precision medicine-based approach for the treatment of US and UCS.
Highlights
Sarcomas are rare heterogeneous tumors that affect the female genital tract and originate from tissues such as muscle, fat, bones, and fibrous tissue
40 Uterine sarcomas (USs) and Uterine carcinosarcoma (UCS) (14 Uterine leiomyosarcoma (ULMS), 12 ESS, 2 ADS, and 12 UCS) and 3 Uterine leiomyoma (ULM) samples were selected from the pathology department files; only 23 (7 ULMS, 7 ESS, 1 ADS, 5 UCS, and 3 ULM) remained until the end of NextGeneration Sequencing (NGS) analyses
Some losses occurred while performing multiplex PCR reactions (AmpliSeqt), during which we observed a high degree of fragmented DNA and many genetic artifacts in several samples
Summary
Sarcomas are rare heterogeneous tumors that affect the female genital tract and originate from tissues such as muscle, fat, bones, and fibrous tissue. Uterine sarcomas (USs) are the most commonly occurring gynecological sarcomas, representing 90% of the total cases [1]. Received for publication on August 11, 2020. Accepted for publication on October 15, 2020
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