Truncating mutation in CHEK2 increases the risk of breast cancer

 

Currently, active genetic testing for inherited mutations in BRCA1 and BRCA2 in women with a family history of breast or ovarian cancer is recommended, but other potential breast cancer genes are not frequently evaluated. Prior to performing invasive and expensive procedures, risk-reduction strategies by accurate assessment of genetic risk has increased the demand for genetic testing. Inherited mutations in BRCA1, BRCA2, CHEK2, and TP53 in families with Li-Fraumeni syndrome, or PTEN in families with Cowden syndrome, are all associated with a high risk of early onset breast cancer. The U.S. Preventive Services Task Force recommends genetic testing for women whose family histories suggest inherited BRCA1 or BRCA2 mutations.

Localized on the 22q12.1 human chromosome, the checkpoint kinase 2 (CHEK2) protein functions to maintain genome integrity. The benefits of detecting a clinically meaningful risk of breast cancer via CHEK2 mutation testing was studied in 7494 BRCA1 mutation–negative patients with breast cancer. Women with a positive history of breast cancer and a truncating CHEK2 mutation could have a 25% increased risk of breast cancer and are candidates for tamoxifen chemoprevention and magnetic resonance imaging screening. The CHEK2 Breast Cancer Case-Control Consortium showed that the 1100delC allele confers a twofold elevated breast cancer risk, even in women with no family history of breast cancer. The 1100delC carriers have an increased risk of bilateral breast cancer. Women with a positive breast cancer family history may benefit from regular genetic testing of a truncating CHEK2 mutation.

Suggested reading:

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