哈萨克斯坦子宫内膜癌与乳腺癌患者中错配修复与同源重组修复基因的比较测序研究

Comparative sequencing study of mismatch repair and homology-directed repair genes in endometrial cancer and breast cancer patients from Kazakhstan

INTERNATIONAL JOURNAL OF CANCER

影响因子:4.7

分区:医学2区 / 肿瘤学2区

发表日期:2025 Feb 15

作者: Ying Zheng, Natalia Vdovichenko, Peter Schürmann, Dhanya Ramachandran, Robert Geffers, Lisa-Marie Speith, Natalia Bogdanova, Julia Enßen, Natalia Dubrowinskaja, Tatyana Yugay, Zura Berkutovna Yessimsiitova, Nurzhan Turmanov, Peter Hillemanns, Thilo Dörk

DOI: 10.1002/ijc.35215

摘要

子宫内膜癌与错配修复（MMR）基因的致病变异密切相关，尤其在遗传性林奇综合征（Lynch Syndrome）背景下更为明显。近年来，也有研究表明同源重组修复（HDR）基因的致病变异可能对部分子宫内膜癌的发展具有贡献。本研究为医院基础研究，调查了来自哈萨克斯坦阿拉木图肿瘤科诊所的342名子宫内膜癌患者中致病或可能致病的MMR或HDR基因变异的相对分布。同时，比较分析了来自同一群体的178名乳腺癌患者的基因检测结果。变异通过ClinVar、ESM1b和AlphaMissense预测工具进行分类。结果显示，10名子宫内膜癌患者（2.9%）携带致病或疑似致病的MMR基因变异（7 MSH6，1 MSH2，2 MUTYH），而14名（4.1%）子宫内膜癌患者携带致病的HDR基因变异（4 BRCA2，3 BRCA1，3 FANCM，2 SLX4，1 BARD1，1 BRIP1）。乳腺癌组中，8名患者（4.5%）携带致病或疑似致病的MMR基因变异（2 MSH2，2 MSH6，4 MUTYH），12名（6.7%）患者携带致病或疑似致病的HDR基因变异（5 BRCA1，3 BRCA2，1 BRIP1，1 ERRC4，1 FANCM，1 SLX4）。一例患者先患乳腺癌，后诊断子宫内膜癌，伴有MSH6新型框移变异。结果表明，哈萨克族人群中，具有预测致病性的MMR和HDR基因变异的发生频率较高，提示这两类基因变异在乳腺癌和子宫内膜癌患者中均具有一定的遗传风险。

Abstract

Endometrial cancer has been associated with pathogenic variants in mismatch repair (MMR) genes, especially in the context of the hereditary Lynch Syndrome. More recently, pathogenic variants in genes of homology-directed repair (HDR) have also been suggested to contribute to a subset of endometrial cancers. In the present hospital-based study, we investigated the relative distribution of pathogenic MMR or HDR gene variants in a series of 342 endometrial cancer patients from the Oncology Clinic in Almaty, Kazakhstan. In comparison, we also sequenced 178 breast cancer patients from the same population with the same gene panel. Identified variants were classified according to ClinVar, ESM1b, and AlphaMissense prediction tools. We found 10 endometrial cancer patients (2.9%) carrying pathogenic or likely pathogenic variants in MMR genes (7 MSH6, 1 MSH2, 2 MUTYH), while 14 endometrial cancer patients (4.1%) carried pathogenic variants in HDR genes (4 BRCA2, 3 BRCA1, 3 FANCM, 2 SLX4, 1 BARD1, 1 BRIP1). In the breast cancer series, we found 8 carriers (4.5%) of pathogenic or likely pathogenic variants in MMR genes (2 MSH2, 2 MSH6, 4 MUTYH) while 12 patients (6.7%) harbored pathogenic or likely pathogenic HDR gene variants (5 BRCA1, 3 BRCA2, 1 BRIP1, 1 ERRC4, 1 FANCM, 1 SLX4). One patient who developed breast cancer first and endometrial cancer later carried a novel frameshift variant in MSH6. Our results indicate that MMR and HDR gene variants with predicted pathogenicity occur at substantial frequencies in both breast and endometrial cancer patients from the Kazakh population.