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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Lara Kokemüller - , Hannover Medical School (MHH) (Author)
  • Dhanya Ramachandran - , Hannover Medical School (MHH) (Author)
  • Peter Schürmann - , Helmholtz Centre for Infection Research (Author)
  • Robert Geffers - , Helmholtz Centre for Infection Research (Author)
  • Matthias Jentschke - , Hannover Medical School (MHH) (Author)
  • Gerd Böhmer - , Institute for Cytology and Dysplasia Hannover (IZD) (Author)
  • Hans-Georg Strauß - , Martin Luther University Halle-Wittenberg (Author)
  • Christine Hirchenhain - , Department of Gynecology and Obstetrics (Author)
  • Monika Schmidmayr - , Technical University of Munich (Author)
  • Florian Müller - , Martin Luther Hospital Berlin (Author)
  • Peter A. Fasching - , Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Alexander Luyten - , Wolfsburg Hospital (Author)
  • Norman Häfner - , Jena University Hospital (Author)
  • P. Hillemanns - , Hannover Medical School (MHH) (Author)
  • T. Dörk - , Hannover Medical School (MHH) (Author)

Abstract

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.

Details

Original languageEnglish
Pages (from-to)700-710
Number of pages11
JournalInternational Journal of Cancer
Volume156
Issue number4
Early online date23 Oct 2024
Publication statusPublished - 15 Feb 2025
Peer-reviewedYes

External IDs

Scopus 85207246051
PubMed 39440754
Mendeley 9ea36961-1a09-3147-83dd-ef4cebe03815

Keywords

Sustainable Development Goals