子宫内膜癌与错配修复（MMR）基因的致病性变异有关，特别是在遗传性林奇综合征的背景下。最近，同源定向修复（HDR）基因的致病性变异也被认为与子宫内膜癌的一个子集有关。在目前以医院为基础的研究中，我们调查了来自哈萨克斯坦阿拉木图肿瘤诊所的 342 名子宫内膜癌患者中致病性 MMR 或 HDR 基因变异的相对分布。相比之下，我们还对来自同一人群、具有相同基因组的 178 名乳腺癌患者进行了测序。根据 ClinVar、ESM1b 和 AlphaMissense 预测工具对识别出的变异进行分类。我们发现 10 名子宫内膜癌患者 (2.9%) 携带 MMR 基因致病性或可能致病性变异 (7 MSH6、1 MSH2、2 MUTYH)，而 14 名子宫内膜癌患者 (4.1%) 携带 HDR 基因致病性变异 (4 BRCA2、3 BRCA1、3 FANCM、2 SLX4、1 BARD1、1 BRIP1)。在乳腺癌系列中，我们发现 8 名患者 (4.5%) 携带 MMR 基因致病性或可能致病性变异 (2 MSH2、2 MSH6、4 MUTYH)，而 12 名患者 (6.7%) 携带致病性或可能致病性 HDR 基因变异 (5 BRCA1、3 BRCA2、1 BRIP1、1 ERRC4、1 FANCM、1 SLX4)。一名先患乳腺癌、后来患子宫内膜癌的患者携带 MSH6 中的一种新型移码变异体。我们的结果表明，具有预测致病性的 MMR 和 HDR 基因变异在哈萨克人群的乳腺癌和子宫内膜癌患者中以相当高的频率出现。© 2024 作者。约翰·威利出版的《国际癌症杂志》

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.© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.