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

Zheng Y. Vdovichenko N. Schürmann P. Ramachandran D. Geffers R. Speith L.-M. Bogdanova N. Enßen J. Dubrowinskaja N. Yugay T. Yessimsiitova Z.B. Turmanov N. Hillemanns P. Dörk T.
15 February 2025 John Wiley and Sons Inc

International Journal of Cancer
2025 #156 Issue 4 764 - 775 pp.

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.

breast cancer , endometrial carcinoma , homologous recombination , mismatch repair , targeted sequencing

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Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
Genome Analytics, Helmholtz Center for Infection Research, Braunschweig, Germany
Rahat Clinics, Almaty, Kazakhstan
Department of Biodiversity and Bioresources, al-Farabi Kazakh National University, Almaty, Kazakhstan

Gynaecology Research Unit
Genome Analytics
Rahat Clinics
Department of Biodiversity and Bioresources

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