The CHK2 kinase is recurrently mutated and functionally impaired in the germline of pediatric cancer patients

Abstract

Predisposing CHEK2 germline variants are associated with various adult‐type malignancies, whereas their impact on cancer susceptibility in childhood cancer is unclear. To understand the frequency of germline variants in the CHEK2 gene and their impact on pediatric malignancies, we used whole‐exome sequencing to search for CHEK2 variants in the germlines of 418 children diagnosed with cancer in our clinics. Moreover, we performed functional analysis of the pathogenic CHEK2 variants to analyze the effect of the alterations on CHK2 protein function. We detected a CHEK2 germline variant in 32/418 (7.7%) pediatric cancer patients and 46.8% of them had leukemia. Functional analysis of the pathogenic variants revealed that 5 pathogenic variants impaired CHK2 protein function. 6/32 patients carried one of these clearly damaging CHEK2 variants and two of them harbored a matching family history of cancer. In conclusion, we detected germline CHEK2 variants in 7.7% of all pediatric cancer patients, of which a minority but still relevant fraction of approximately 20% had a profound impact on protein expression or its phosphorylation after irradiation‐induced DNA damage. Accordingly, we conclude that CHEK2 variants increase the risk for not only adult‐onset but also pediatric cancer.

Germline Variants in Cancer Predisposition Genes in Pediatric Patients with Central Nervous System Tumors

“…Germline CHEK2 variants in general, as well as specific variant p.Ile157Thr, have been associated with Li-Fraumeni syndrome especially in TP53-negative patients, as was the case in our patient with supporting cancer family history [48,49]. Regarding pediatric brain tumors, the same missense variant was reported in patients with medulloblastoma, neuroblastoma and pilocytic astrocytoma [46,50]. The p.Ile157Thr CHEK2 variant has been defined as a common variant of this CPG [51].…”

“…Given that there are conflicting data about the clinical relevance that this p.Ile157Thr variant has, with the help of the bioinformatic tools, we created protein models for both wild-type and mutated CHEK2 protein, with the intention of contributing to the characterization of this variant (Figure 2). Although in silico prediction indicates a potentially damaging effect of this variant, the latest functional analyses do not support this, suggesting that the protein remains functional to the greatest extent [46,60]. Still, according to the current ACMG guidelines, CHEK2 p.Ile157Thr is characterized as likely pathogenic.…”

“…Therefore, the presence of germline variants in the CHEK2 gene disrupting the normal function of this protein could result in an increased predisposition to cancer. The CHEK2 gene is one of the well-known CPGs, with variants associated with the occurrence of different types of pediatric tumors [46,47].…”

Comprehensive analysis of the functional impact of single nucleotide variants of humanCHEK2

“…This deletion mutation has also been associated with increased risk for male breast cancer, gastric, testicular, prostate, and thyroid cancers [15][16][17][18][19][20] . Additional CHEK2 variants that impair protein function have been identified in cancer patient samples and are associated with the development of cancer [21][22][23][24][25][26][27] . Most variants detected in patient screening, however, lack supporting evidence by statistically significant population data to classify them as either pathogenic (cancer-causing) or benign, resulting in their classification as variants of uncertain significance (VUS) 28 .…”

Reply to: Comments on “The CHK2 kinase is recurrently mutated and functionally impaired in the germline of pediatric cancer patients”

“…1,2 In agreement with many sequencing studies of pediatric cancer patients, as listed in our publication, we also advocate for functional testing for the individual variants, as demonstrated in figure 2 of our report. 3 Nevertheless, there is no doubt that even a germline-encoded functional alteration of a single protein (like CHEK2) does not automatically result in the development of a such complex disease like cancer, a fact that relates to children and adults likewise.…”