The CHEK2 gene and its encoded protein Chk2 have a well-known role in cancers, especially those related to breast cancer mediated through the BRCA1 gene.
In total, 120 germline CHEK2 missense variants, distributed along the protein sequence, and two large in-frame deletions were tested, originating from genetic test results in breast cancer families, or selected from the ClinVar database.
As part of the CAGI-5 challenge, we evaluated the performance of 18 submissions and three additional methods in predicting the pathogenicity of single nucleotide variants (SNVs) in checkpoint kinase 2 (CHEK2) for cases of breast cancer in Hispanic females.
Next-generation-sequencing-based targeted cancer-related gene assay confirmed <i>SMARCB1</i> loss and revealed other mutations in breast cancer 1 gene and checkpoint kinase 2 gene, which may have impacted her clinical course.
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).
The most important cause of developing hereditary breast cancer is germline mutations occurring in breast cancer (BCs) susceptibility genes, for example, BRCA1, BRCA2, TP53, CHEK2, PTEN, ATM, and PPM1D.
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.
Patients with CHEK2 mutations are significantly more likely to have family histories of cancer, and to develop lymph node-positive and/or PR-positive breast cancers.
However, the impact of screening and preventative interventions and spectrum of cancer risk beyond breast cancer associated with ATM and/or CHEK2 variants remain less well characterized.
In vivo Chk2 and antitumor activities of 8d as a single-agent, and in combination with doxorubicin, were evaluated in breast cancer bearing animals induced by N-methylnitrosourea.
ART can inhibit cell proliferation and promote G2/M arrest in MCF7 cells through ATM activation and the ensuing "ATM-Chk2-Cdc25C" pathway, thus implicating ART as a novel candidate for breast cancer chemotherapy.
PVs were identified in 9.3% of women tested; 51.5% of PVs were identified in genes other than breast cancer 1 (BRCA1) and BRCA2, including checkpoint kinase 2 (CHEK2) (11.7%), ataxia telangiectasia mutated (ATM; ATM serine/threonine kinase) (9.7%), and partner and localizer of BRCA2 (PALB2) (9.3%).
Of the 1007 probands in the study, 903 probands had no founder mutations in BRCA1 or BRCA2; of these probands, 7 (0.8%) carried another pathogenic mutation in BRCA1 or BRCA2, and 31 (3.4%) carried a pathogenic mutation in another breast cancer gene (29 in CHEK2, and 1 each in BRIP1 and NBN).
After exclusion of BRCA1, BRCA2, and syndromic breast cancer genes (CDH1, PTEN, and TP53), observed pathogenic variants in 5 of 16 genes were associated with high or moderately increased risks of breast cancer: ATM (OR, 2.78; 95% CI, 2.22-3.62), BARD1 (OR, 2.16; 95% CI, 1.31-3.63), CHEK2 (OR, 1.48; 95% CI, 1.31-1.67), PALB2 (OR, 7.46; 95% CI, 5.12-11.19), and RAD51D (OR, 3.07; 95% CI, 1.21-7.88).