IsCHEK2a moderate-risk breast cancer gene or the younger sister of Li-Fraumeni?

Abstract

The CHEK2 gene is mostly considered as a moderate breast cancer gene with the result that many clinicians have a narrow focus. We present the 10-year journey of a man who had five different cancers and had iterative genetic testing including for Li-Fraumeni syndrome, eventually to discover a pathogenic variant in the CHEK2 gene, possibly explaining his numerous cancers. This diagnosis offered him closure which he had desperately sought for well over a decade. A pathogenic variant in the CHEK2 gene can potentially explain these cancers because of its function as a tumour suppressor gene. Consideration is warranted of what this means for individuals with CHEK2 variants who may develop multiple cancers, their prognosis and whether different treatment modalities such as chemotherapy, radiotherapy or target agents would need modification. We encourage more research into the many faces of the CHEK2 gene and the potential for predisposition to multiple cancers.

Rare coding variants in DNA damage repair genes associated with timing of natural menopause

“… 32 After TP53 , CHEK2 was identified as a second causal gene for Li-Fraumeni syndrome (MIM: 609265 ), which involves risk for many cancers. 38 , 39 A common feature of the non-cancer diseases we find associated with CHEK2 is that they all involve benign hyperproliferation of tissue. Although CHEK2 acts as a brake on proliferation in response to DNA damage, it may serve as a more general negative regulator of mitosis in somatic cells even in the absence of DNA damage.…”

Genomic Breakpoints’ Characterization of a Large CHEK2 Duplication in an Italian Family with Hereditary Breast Cancer

“…The identification of the c.1110del in cases of Li-Fraumeni syndrome with no TP53 pathogenic variant led researchers to suspect CHEK2 as the possible cause of Li-Fraumeni syndrome 2 (MIM#609265) [ 18 ]. Subsequent studies questioned the evidence [ 19 , 20 ], but recent reports still imply that a possible contribution of CHEK2 variants to Li-Fraumeni-like phenotypes cannot be excluded [ 21 ]. Genotype–phenotype correlations seem to suggest that damaging variants resulting in a marked loss-of-function are associated with a higher risk of neoplasms, usually with early onset when compared to variants with a milder effect [ 5 ].…”

Population-based estimates of the age-specific cumulative risk of breast cancer for pathogenic variants in CHEK2: Findings from the Australian Breast Cancer Family Registry.

“…This has firmly consolidated CHEK2 as a bona fide breast cancer predisposition gene but information suitable for estimating agespecific cumulative risk (penetrance) has been lacking. Our population-based case-controlfamily study provides such information and estimated penetrance of CHEK2 pathogenic variants to be 26% (95% CI, 16-40%) and 33% (95% CI, [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] to 70 and 80 years respectively. There is no directly comparable data (generated with similar study design and methodology) from previous literature.…”

“…It is also important to further understand the risk of other cancers (in addition to breast cancer) that are associated with pathogenic variants in CHEK2 that include cancers in the Li-Fraumeni syndrome spectrum [35] and prostate cancer [36] and the associated penetrance of CHEK2 pathogenic variants for these cancers. Furthermore, it is likely that the presence of pathogenic variants in the CHEK2 gene will impact management options for those in whom detection coincides with the diagnosis of breast cancer, in consideration of targeted chemotherapy and the safety of radiotherapy.…”