Laboratorio de Ginecologia Estrutural e Molecular, Disciplina de Ginecologia, Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR.
School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
Clinics (Sao Paulo). 2021 Jan 20;76:e2324. doi: 10.6061/clinics/2021/e2324. eCollection 2021.
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.
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.
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.
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.
本研究旨在为涉及子宫肉瘤（US）和癌肉瘤（UCS）致癌过程的遗传突变目录做出贡献，这可能有助于这些疾病的准确诊断和治疗方案的选择。
我们对 15 个 US（7 个子宫平滑肌肉瘤 [ULMS]、7 个子宫内膜间质肉瘤 [ESS]、1 个腺肉瘤 [ADS]）、5 个 UCS 和 3 个子宫平滑肌瘤（ULM）样本进行了 409 个癌症相关基因的靶向基因下一代测序（NGS）。应用质量、频率和功能过滤器选择假定的体细胞变异。
在本研究评估的 23 个样本中，检测到 42 个失活功能（LOF）突变和 111 个错义突变，共 153 个突变。其中，66 个突变在癌症体细胞突变目录（COSMIC）数据库中观察到。TP53（48%）、ATM（22%）和 PIK3CA（17%）是突变最频繁的基因。就特定的肿瘤亚型而言，ESS 显示 PDE4DIP、IGTA10 和 DST 基因的突变，UCS 显示 ERBB4 突变，ULMS 显示 NOTCH2 和 HER2 的独特改变。KMT2A 基因的突变仅在 ULM 和 ULMS 中观察到。计算机通路分析表明，ULMS 和 ESS 中许多突变的基因具有与细胞对缺氧的反应和细胞对肽激素刺激的反应相关的功能。在 UCS 和 ADS 中，改变最多的基因具有与磷脂酰肌醇激酶活性和甘油磷脂代谢过程相关的功能。
本初步研究观察到 US 和 UCS 样本中的致病性突变。进一步的研究将扩大队列并进行功能分析，为 US 和 UCS 的精准医学治疗方法的发展提供助力。
