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

Snežana Hinić; Cezary Cybulski; Rachel S Van der Post; Janet R Vos; Janneke Schuurs-Hoeijmakers; Fulvia Brugnoletti; Saskia Koene; Lilian Vreede; Wendy A G van Zelst-Stams; C Marleen Kets; Maaike Haadsma; Liesbeth Spruijt; Marijke R Wevers; D Gareth Evans; Katharina Wimmer; Simon Schnaiter; Alexander E Volk; Anna Möllring; Robin de Putter; Leila Soikkonen; Tiina Kahre; Mikk Tooming; Mirjam M de Jong; Fátima Vaz; Arjen R Mensenkamp; Maurizio Genuardi; Jan Lubinski; Marjolijn Ligtenberg; Nicoline Hoogerbrugge; Richarda M de Voer

doi:10.1016/j.gim.2024.101101

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

Genet Med. 2024 Feb 13;26(5):101101. doi: 10.1016/j.gim.2024.101101. Online ahead of print.

Authors

Snežana Hinić¹, Cezary Cybulski², Rachel S Van der Post³, Janet R Vos⁴, Janneke Schuurs-Hoeijmakers¹, Fulvia Brugnoletti⁵, Saskia Koene⁶, Lilian Vreede¹, Wendy A G van Zelst-Stams¹, C Marleen Kets¹, Maaike Haadsma¹, Liesbeth Spruijt¹, Marijke R Wevers¹, D Gareth Evans⁷, Katharina Wimmer⁸, Simon Schnaiter⁸, Alexander E Volk⁹, Anna Möllring⁹, Robin de Putter¹⁰, Leila Soikkonen¹¹, Tiina Kahre¹², Mikk Tooming¹², Mirjam M de Jong¹³, Fátima Vaz¹⁴, Arjen R Mensenkamp¹, Maurizio Genuardi¹⁵, Jan Lubinski², Marjolijn Ligtenberg¹⁶, Nicoline Hoogerbrugge⁴, Richarda M de Voer¹⁷

Affiliations

¹ Radboud University Medical Center, Research Institute for Medical Innovation, Department of Human Genetics, Nijmegen, The Netherlands.
² International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland; European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, The Netherlands.
³ European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, The Netherlands; Radboud University Medical Center, Research Institute for Medical Innovation, Department of Pathology, Nijmegen, The Netherlands.
⁴ Radboud University Medical Center, Research Institute for Medical Innovation, Department of Human Genetics, Nijmegen, The Netherlands; European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, The Netherlands.
⁵ Radboud University Medical Center, Research Institute for Medical Innovation, Department of Human Genetics, Nijmegen, The Netherlands; Genomic Medicine, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy.
⁶ Leiden University Medical Center, Department of Clinical Genetics, Leiden, The Netherlands.
⁷ European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, The Netherlands; The University of Manchester, Genomic Medicine, Division of Evolution, Infection and Genomic Sciences, Manchester, United Kingdom.
⁸ European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, The Netherlands; Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
⁹ European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, The Netherlands; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁰ European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, The Netherlands; Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
¹¹ European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, The Netherlands; Oulu University Hospital, Department of Clinical Genetics, Oulu, Finland.
¹² European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, The Netherlands; 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.
¹³ European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, The Netherlands; Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.
¹⁴ European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, The Netherlands; Instituto Português Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal.
¹⁵ European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, The Netherlands; 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.
¹⁶ Radboud University Medical Center, Research Institute for Medical Innovation, Department of Human Genetics, Nijmegen, The Netherlands; European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, The Netherlands; Radboud University Medical Center, Research Institute for Medical Innovation, Department of Pathology, Nijmegen, The Netherlands.
¹⁷ Radboud University Medical Center, Research Institute for Medical Innovation, Department of Human Genetics, Nijmegen, The Netherlands; European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, The Netherlands. Electronic address: richarda.devoer@radboudumc.nl.

PMID: 38362852
DOI: 10.1016/j.gim.2024.101101

Abstract

Purpose: 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.

Methods: Exome sequencing of individuals who developed multiple primary malignancies identified 3 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).

Results: 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 with 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.

Conclusion: 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.

Keywords: Breast cancer; CHEK2; Genetic tumor risk syndrome; Multiple primary malignancies.