Germline variants of homology-directed repair or mismatch repair genes in cervical cancer.

Autor: Kokemüller L; Department of Gynaecology, Hannover Medical School, Hannover, Germany., Ramachandran D; Department of Gynaecology, Hannover Medical School, Hannover, Germany., Schürmann P; Department of Gynaecology, Hannover Medical School, Hannover, Germany., Geffers R; Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany., Jentschke M; Department of Gynaecology, Hannover Medical School, Hannover, Germany., Böhmer G; IZD Ärztliche Partnerschaft Böhmer & Partner, Hannover, Germany., Strauß HG; Gynaecology Department, Martin-Luther-University Halle-Wittenberg, Halle Saale, Germany., Hirchenhain C; Gynaecology Department, University Hospital Carl Gustav Carus Dresden, Dresden, Germany., Schmidmayr M; Gynaecology Department, Technical University of Munich, Munich, Germany., Müller F; Gynaecology Department, Martin Luther Hospital, Berlin, Germany., Fasching PA; Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany., Luyten A; Department of Gynaecology and Obstetrics, MARE Klinikum, Dysplasia Unit, Kronshagen, Germany.; Clinics of Gynaecology and Obstetrics, Wolfsburg Hospital, Wolfsburg, Germany., Häfner N; Department of Gynaecology, Friedrich Schiller University Jena, Jena, Germany., Hillemanns P; Department of Gynaecology, Hannover Medical School, Hannover, Germany., Dörk T; Department of Gynaecology, Hannover Medical School, Hannover, Germany.
Jazyk: angličtina
Zdroj: International journal of cancer [Int J Cancer] 2024 Oct 23. Date of Electronic Publication: 2024 Oct 23.
DOI: 10.1002/ijc.35221
Abstrakt: While cervical cancer is associated with a persistent human papillomavirus (HPV) infection, the progression to cancer is influenced by genomic risk factors that have remained largely obscure. Pathogenic variants in genes of the homology-directed repair (HDR) or mismatch repair (MMR) are known to predispose to diverse tumour entities including breast and ovarian cancer (HDR) or colon and endometrial cancer (MMR). We here investigate the spectrum of HDR and MMR germline variants in cervical cancer, with particular focus on the HPV status and histological subgroups. We performed targeted next-generation sequencing for 5 MMR genes and 12 HDR genes on 728 German patients with cervical dysplasia or invasive cancer. In total, 4% of our patients carried a pathogenic germline variant, based on ClinVar classifications and additional ESM1b and AlphaMissense predictions. These included 15 patients with truncating variants in HDR genes (BARD1, BRCA1, BRCA2, BRIP1, FANCM, RAD51D and SLX4). MMR-related gene variants were less prevalent and mainly of the missense type. While MMR-related gene variants tended to associate with adenocarcinomas, HDR gene variants were commonly observed in squamous cancers. While one patient with HPV-negative cancer carried a pathogenic MMR gene variant (in MSH6), the HDR germline variants were found in patients with HPV-positive cancers and tended to associate with HPV18. Taken together, our study supports a potentially risk-modifying role of MMR and HDR germline variants in cervical cancer but no association with HPV-negative status. These variants may be exploitable in future therapeutic managements.
(© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
Databáze: MEDLINE
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