来自哈萨克斯坦的子宫内膜癌和乳腺癌患者的不匹配修复和同源指导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
影响因子:4.70000
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
摘要
子宫内膜癌与不匹配修复（MMR）基因的致病变异有关，尤其是在遗传林奇综合征的背景下。最近，还建议在同源指导修复基因（HDR）中的致病变异，从而有助于子宫内膜癌的一部分。在目前的基于医院的研究中，我们研究了来自哈萨克斯坦Almaty肿瘤学诊所的一系列342例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，我们还通过相同的基因组对来自同一人群的178名乳腺癌患者进行了测序。根据Clinvar，ESM1B和Alphamissense预测工具对已识别的变体进行了分类。 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).一名首先患上乳腺癌和子宫内膜癌的患者随后在MSH6中携带了一种新型的移疗变体。我们的结果表明，来自哈萨克H人群的乳腺癌和子宫内膜癌患者的MMR和HDR基因变异具有预测的致病性。
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.