Previous studies of families with multiple cases of breast cancer have indicated that a frameshift alteration in the CHEK2 gene, 1100delC, is associated with an elevated frequency of breast cancer in such families, but the risk associated with the variant in other situations is uncertain.
Germline DNA from 1054 BRCA-mutation-negative Hispanic women with hereditary BC (BC diagnosed at age <51 years, bilateral BC, breast and ovarian cancer, or BC diagnosed at ages 51-70 years with ≥2 first-degree or second-degree relatives who had BC diagnosed at age <70 years), 312 local controls, and 887 multiethnic cohort controls was sequenced and analyzed for 12 known and suspected, high-penetrance and moderate-penetrance cancer susceptibility genes (ataxia telangiectasia mutated [ATM], breast cancer 1 interacting protein C-terminal helicase 1 [BRIP1], cadherin 1 [CDH1], checkpoint kinase 2 [CHEK2], nibrin [NBN], neurofibromatosis type 1 [NF1], partner and localizer of BRCA2 [PALB2], phosphatase and tensin homolog [PTEN], RAD51 paralog 3 [RAD51C], RAD51D, serine/threonine kinase 11 [STK11], and TP53).
A 1100delC mutation in CHEK2 (previously known as CHK2), a cell-cycle checkpoint kinase, has been implicated in predisposition of Li-Fraumeni syndrome (LFS) and breast cancer in families suggestive of LFS.
The CHEK21100delC-associated breast cancer is associated with a higher contralateral breast cancer rate as well as worse survival measures beyond 6 years after diagnosis.
On the basis of the experience of mothers, sisters and daughters of probands, breast cancer risk due to CHEK2.S428F was estimated as 0.17 (+/-0.08) by age 60.
Consequently, new genes have emerged as breast cancer susceptibility genes, including rare germline mutations in high penetrant genes, such as TP53 and PTEN, and more frequent mutations in moderate penetrant genes, such as CHEK2, ATM and PALB2.
This case provides insight into the role of the CHEK2 gene in causing breast cancer susceptibility in families and supports the use of multigene panel testing in cases with hereditary predisposition to breast cancer.
Our study suggests that the risk of breast cancer in carriers of a deleterious CHEK2 mutation is increased if the second allele is the I157T missense variant.
Eleven mutations were found in other breast cancer susceptibility genes including CHEK2 (n = 5), PALB2 (n = 2), BLM (n = 2), ATM (n = 1) and TP53 (n = 1).
Modest increases of breast cancer risk were observed for the four analysed CHEK2 variants (I157T, 1100delC, IVS2 + 1G > A and del5395) (OR = 2.2; 95% 1.7-2.8; P = 0.0001).
The main goal of this study was to evaluate and to compare the role of truncating mutations, splice junction mutations and rare missense substitutions in breast cancer susceptibility gene CHEK2.
Our research indicates that the CHEK2I157T variant may be another important genetic mutation which increases risk of breast cancer, especially the lobular type.
Our work indicates that a variety of deleterious CHEK2 alleles make an appreciable contribution to breast cancer susceptibility, and their identification could help in the clinical management of patients carrying a CHEK2 mutation.
Comparing the prevalence of CHEK2 mutations in BC with controls revealed that carriers of an I157T variant had OR of 1.80 for luminal A subtype and carriers of truncating mutations had OR of 6.26 for luminal B subtype of BC.
The CHEK2 gene mutations I157T (c.470T>C) and IVS2+1G>A affecting the forkhead-associated domain (FHA) have been shown to increase the risk of breast cancer development in several populations.