The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2.

CHEK2 breast cancer genetic tumor risk syndrome multiple primary malignancies

Journal

Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831

Informations de publication

Date de publication:
12 Feb 2024
Historique:
received: 30 08 2023
revised: 08 02 2024
accepted: 09 02 2024
medline: 16 2 2024
pubmed: 16 2 2024
entrez: 16 2 2024
Statut: aheadofprint

Résumé

Females with biallelic CHEK2 germline pathogenic variants (gPVs) more often develop multiple breast cancers than individuals with monoallelic CHEK2 gPVs. This study is aimed at expanding the knowledge on the occurrence of other malignancies. Exome sequencing of individuals who developed multiple primary malignancies identified three individuals with the CHEK2 (NM_007194.4) c.1100del p.(Thr367MetfsTer15) loss-of-function gPV in a biallelic state. We collected the phenotypes of an additional cohort of individuals with CHEK2 biallelic gPVs (n=291). In total, 157 individuals (53.4%; 157/294 individuals) developed ≥1 (pre)malignancy. The most common (pre)malignancies next to breast cancer were colorectal- (n=19), thyroid- (n=19) and prostate (pre)malignancies (n=12). Females with biallelic CHEK2 loss-of-function gPVs more frequently developed ≥2 (pre)malignancies and at an earlier age compared to females biallelic for the CHEK2 c.470T>C p.(Ile157Thr) missense variant. Furthermore, 26 males (31%; 26/84 males) with CHEK2 biallelic gPVs developed ≥1 (pre)malignancies of 15 origins. Our study suggests that CHEK2 biallelic gPVs likely increase the susceptibility to develop multiple malignancies in various tissues, both in females and males. However, it is possible that a substantial proportion of individuals with CHEK2 biallelic gPVs is missed as diagnostic testing for CHEK2 often is limited to individuals who developed breast cancer.

Identifiants

DOI: 10.1016/j.gim.2024.101101 PMID: 38362852
pubmed: 38362852
pii: S1098-3600(24)00034-0
doi: 10.1016/j.gim.2024.101101
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

101101

Informations de copyright

Copyright © 2024. Published by Elsevier Inc.

Auteurs

Snežana Hinić (S)

Radboud university medical center, Research Institute for Medical Innovation, Department of Human Genetics, Nijmegen, Netherlands.

Cezary Cybulski (C)

International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland; European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS).

Rachel S Van der Post (RS)

European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS); Radboud university medical center, Research Institute for Medical Innovation, Department of Pathology, Nijmegen, Netherlands.

Janet R Vos (JR)

Radboud university medical center, Research Institute for Medical Innovation, Department of Human Genetics, Nijmegen, Netherlands; European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS).

Janneke Schuurs-Hoeijmakers (J)

Radboud university medical center, Research Institute for Medical Innovation, Department of Human Genetics, Nijmegen, Netherlands.

Fulvia Brugnoletti (F)

Radboud university medical center, Research Institute for Medical Innovation, Department of Human Genetics, Nijmegen, Netherlands; Genomic Medicine, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy.

Saskia Koene (S)

Leiden University Medical Center, Department of Clinical Genetics, Leiden, Netherlands.

Lilian Vreede (L)

Radboud university medical center, Research Institute for Medical Innovation, Department of Human Genetics, Nijmegen, Netherlands.

Wendy A G van Zelst-Stams (WAG)

Radboud university medical center, Research Institute for Medical Innovation, Department of Human Genetics, Nijmegen, Netherlands.

C Marleen Kets (CM)

Radboud university medical center, Research Institute for Medical Innovation, Department of Human Genetics, Nijmegen, Netherlands.

Maaike Haadsma (M)

Radboud university medical center, Research Institute for Medical Innovation, Department of Human Genetics, Nijmegen, Netherlands.

Liesbeth Spruijt (L)

Radboud university medical center, Research Institute for Medical Innovation, Department of Human Genetics, Nijmegen, Netherlands.

Marijke R Wevers (MR)

Radboud university medical center, Research Institute for Medical Innovation, Department of Human Genetics, Nijmegen, Netherlands.

D Gareth Evans (DG)

European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS); The University of Manchester, Genomic Medicine, Division of Evolution, Infection and Genomic Sciences, Manchester, United Kingdom.

Katharina Wimmer (K)

European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS); Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.

Simon Schnaiter (S)

European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS); Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.

Alexander E Volk (AE)

European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Anna Möllring (A)

European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Robin de Putter (R)

European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS); Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.

Leila Soikkonen (L)

European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS); Oulu University Hospital, Department of Clinical Genetics, Oulu, Finland.

Tiina Kahre (T)

European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS); Genetics and Personalized Medicine Clinic, Department of Laboratory Genetics, Tartu University Hospital, Tartu, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.

Mikk Tooming (M)

European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS); Genetics and Personalized Medicine Clinic, Department of Laboratory Genetics, Tartu University Hospital, Tartu, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.

Mirjam M de Jong (MM)

European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS); Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands.

Fátima Vaz (F)

European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS); Instituto Português Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal.

Arjen R Mensenkamp (AR)

Radboud university medical center, Research Institute for Medical Innovation, Department of Human Genetics, Nijmegen, Netherlands.

Maurizio Genuardi (M)

European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS); Genomic Medicine, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy; Medical Genetics Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Jan Lubinski (J)

International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland; European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS).

Marjolijn Ligtenberg (M)

Radboud university medical center, Research Institute for Medical Innovation, Department of Human Genetics, Nijmegen, Netherlands; European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS); Radboud university medical center, Research Institute for Medical Innovation, Department of Pathology, Nijmegen, Netherlands.

Nicoline Hoogerbrugge (N)

Radboud university medical center, Research Institute for Medical Innovation, Department of Human Genetics, Nijmegen, Netherlands; European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS).

Richarda M de Voer (RM)

Radboud university medical center, Research Institute for Medical Innovation, Department of Human Genetics, Nijmegen, Netherlands; European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS). Electronic address: richarda.devoer@radboudumc.nl.

Classifications MeSH