Dept. of Obstetrics and Gynecology, Carol Davila University of Medicine and Pharmacy, Bucharest; Dept. of Obstetrics and Gynecology, Alessandrescu-Rusescu National Institute of Mother and Child Health, Bucharest, Romania.
Dept. of Pathology, Carol Davila University of Medicine and Pharmacy, Bucharest; Dept. of Pathology, Alessandrescu-Rusescu National Institute of Mother and Child Health, Bucharest, Romania.
J Gastrointestin Liver Dis. 2024 Sep 29;33(3):339-347. doi: 10.15403/jgld-5856.
Lynch Syndrome, a hereditary disorder characterized by germline mutations in mismatch repair (MMR) genes, is a major contributor to colorectal cancers. It has also been identified in endometrial cancer. Despite the established role of MMR deficiency in tumorigenesis, the specific genomic alterations driving Lynch syndrome-associated endometrial cancer, and their overlap with colorectal cancer, remain incompletely understood. This study aims to fill this gap by performing a detailed comparative analysis of germline and somatic mutations in endometrial cancer within the context of Lynch syndrome.
We conducted whole exome sequencing on matched germline and somatic DNA from 13 patients diagnosed with Lynch syndrome-associated endometrial cancer. High-depth sequencing was performed, followed by rigorous bioinformatics analysis to identify and annotate variants, focusing on their potential pathogenicity and relevance to both endometrial and colorectal cancer.
Our analysis revealed 1,118 germline and 14,051 somatic variants, with 493 variants common to both. Recurrent pathogenic mutations in MLH1, MSH2, and MSH6 were confirmed, highlighting their critical role in Lynch syndrome. Notably, frequent somatic mutations in the PIK3CA and PTEN genes were identified, implicating the PI3K/AKT/mTOR pathway as a key oncogenic driver in these cancers. Additionally, novel somatic mutations in genes related to the extracellular matrix such as FBN1 and SPARC were uncovered, suggesting a possible unique role in endometrial tumor progression.
This study provides new insights into the molecular basis of Lynch syndrome-associated endometrial cancer, emphasizing the overlap in oncogenic pathways with colorectal cancer. The discovery of shared and unique genetic mutations highlights the importance of developing combined treatment strategies and suggests that targeting these specific mutations could improve therapy for patients with Lynch syndrome-associated cancers.
林奇综合征（Lynch syndrome）是一种遗传性疾病，其特征为错配修复（MMR）基因的种系突变，是结直肠癌的主要致病因素。它也存在于子宫内膜癌中。尽管 MMR 缺陷在肿瘤发生中具有重要作用，但导致林奇综合征相关子宫内膜癌的特定基因组改变及其与结直肠癌的重叠仍不完全清楚。本研究旨在通过在林奇综合征背景下对子宫内膜癌的种系和体细胞突变进行详细比较分析来填补这一空白。
我们对 13 例诊断为林奇综合征相关子宫内膜癌的患者的匹配种系和体细胞 DNA 进行了全外显子组测序。进行了深度测序，然后进行了严格的生物信息学分析，以鉴定和注释变体，重点关注其潜在的致病性和与子宫内膜癌和结直肠癌的相关性。
我们的分析揭示了 1118 种种系和 14051 种体细胞变体，其中 493 种变体在两者中均存在。证实了 MLH1、MSH2 和 MSH6 中反复出现的致病性突变，突出了它们在林奇综合征中的关键作用。值得注意的是，PI3K/AKT/mTOR 通路中的 PIK3CA 和 PTEN 基因频繁发生体细胞突变，表明其是这些癌症的关键致癌驱动因素。此外，还发现了与细胞外基质相关的基因如 FBN1 和 SPARC 的新的体细胞突变，表明其在子宫内膜肿瘤进展中可能具有独特作用。
本研究为林奇综合征相关子宫内膜癌的分子基础提供了新的见解，强调了与结直肠癌中致癌途径的重叠。共享和独特遗传突变的发现强调了开发联合治疗策略的重要性，并表明针对这些特定突变可能会改善林奇综合征相关癌症患者的治疗效果。
