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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Lara Kokemüller - , Medizinische Hochschule Hannover (MHH) (Autor:in)
  • Dhanya Ramachandran - , Medizinische Hochschule Hannover (MHH) (Autor:in)
  • Peter Schürmann - , Helmholtz-Zentrum für Infektionsforschung (HZI) (Autor:in)
  • Robert Geffers - , Helmholtz-Zentrum für Infektionsforschung (HZI) (Autor:in)
  • Matthias Jentschke - , Medizinische Hochschule Hannover (MHH) (Autor:in)
  • Gerd Böhmer - , Institut für Zytologie und Dysplasie (IZD) (Autor:in)
  • Hans-Georg Strauß - , Martin-Luther-Universität Halle-Wittenberg (Autor:in)
  • Christine Hirchenhain - , Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe (Autor:in)
  • Monika Schmidmayr - , Technische Universität München (Autor:in)
  • Florian Müller - , Martin Luther Krankenhaus Berlin (Autor:in)
  • Peter A. Fasching - , Friedrich-Alexander-Universität Erlangen-Nürnberg (Autor:in)
  • Alexander Luyten - , Klinikum Wolfsburg (Autor:in)
  • Norman Häfner - , Universitätsklinikum Jena (Autor:in)
  • P. Hillemanns - , Medizinische Hochschule Hannover (MHH) (Autor:in)
  • T. Dörk - , Medizinische Hochschule Hannover (MHH) (Autor:in)

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

OriginalspracheEnglisch
Seiten (von - bis)700-710
Seitenumfang11
FachzeitschriftInternational Journal of Cancer
Jahrgang156
Ausgabenummer4
Frühes Online-Datum23 Okt. 2024
PublikationsstatusVeröffentlicht - 15 Feb. 2025
Peer-Review-StatusJa

Externe IDs

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

Schlagworte

Ziele für nachhaltige Entwicklung