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

Genet Med. 2024 May;26(5):101101. doi: 10.1016/j.gim.2024.101101. Epub 2024 Feb 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Checkpoint Kinase 2* / genetics
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • Exome Sequencing / methods
  • Female
  • Genetic Predisposition to Disease*
  • Germ-Line Mutation* / genetics
  • Humans
  • Male
  • Middle Aged
  • Neoplasms* / genetics
  • Phenotype
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology

Substances

  • Checkpoint Kinase 2
  • CHEK2 protein, human