The mutational repertoire of uterine sarcomas and carcinosarcomas in a Brazilian cohort: A preliminary study

Autor(es)

Leonardo Tomiatti da Costa ^[1] ; Laura Gonzalez dos Anjos ^[2] ; Luciane Tsukamoto Kagohara ^[3] ; Giovana Tardin Torrezan ^[4] ; Claudia A. Andrade De Paula ^[5] ; Edmund Chada Baracat ^[6] ; Dirce Maria Carraro ^[7] ; Katia Candido Carvalho ^[8]

Afiliação do(s) autor(es)

^[1] Universidade de Sao Paulo. Hospital das Clinicas (HCFMUSP), Faculdade de Medicina. Laboratorio de Ginecologia Estrutural e Molecular, Disciplina de Ginecologia - Brasil

^[2] Universidade de Sao Paulo. Hospital das Clinicas (HCFMUSP), Faculdade de Medicina. Laboratorio de Ginecologia Estrutural e Molecular, Disciplina de Ginecologia - Brasil

^[3] Johns Hopkins University. Sidney Kimmel Comprehensive Cancer Center. School of Medicine - Estados Unidos

^[4] Centro A.C.Camargo. Grupo de Biologia Molecular e Genomica - Brasil

^[5] Centro A.C.Camargo. Grupo de Biologia Molecular e Genomica - Brasil

^[6] Universidade de Sao Paulo. Hospital das Clinicas (HCFMUSP), Faculdade de Medicina. Laboratorio de Ginecologia Estrutural e Molecular, Disciplina de Ginecologia - Brasil

^[7] Centro A.C.Camargo. Grupo de Biologia Molecular e Genomica - Brasil

^[8] Universidade de Sao Paulo. Hospital das Clinicas (HCFMUSP), Faculdade de Medicina. Laboratorio de Ginecologia Estrutural e Molecular, Disciplina de Ginecologia - Brasil

• Tipo de documento: Artigo Científico
• Fonte: Clinics; v. 76, 2021-01-20.

Resumo

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. (AU)

• Processo FAPESP: 19/01109-2 - Aspectos genéticos e epigenéticos dos tumores de musculatura lisa do útero: identificação de marcadores moleculares
• Beneficiário: Kátia Cândido Carvalho
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/03163-6 - Estudo de alterações gênicas em amostras de sarcomas uterinos e carcinossarcomas uterinos: Identificação de marcadores para diagnóstico diferencial e tratamento
• Beneficiário: Leonardo Tomiatti da Costa
• Modalidade de apoio: Bolsas no Brasil - Mestrado