Two studies have suggested that the risk associated with a CHEK2 1100delC mutation was stronger in the families of probands ascertained because of bilateral breast cancer.[22,23] Furthermore, a meta-analysis of 1100delC mutation carriers estimated the risk of breast cancer to be 42% by age 70 years in women with a family history of breast cancer. Similarly, a Polish study reported that CHEK2 truncating mutations confer breast cancer risks based on a family history of breast cancer as follows: no family history: 20%; one second-degree relative: 28%; one first-degree relative: 34%; and both first- and second-degree relatives: 44%. Moreover, a Dutch study suggested that female homozygotes for the CHEK2 1100delC mutation have a greater-than-twofold increased breast cancer risk compared to heterozygotes. Although there have been conflicting reports regarding cancers other than breast cancer associated with CHEK2 mutations, this may be dependent on mutation type (i.e., missense vs. truncating) or population studied and is not currently of clinical utility.[13,18,27,28,29,30,31,32] The contribution of CHEK2 mutations to breast cancer may depend on the population studied, with a potentially higher mutation prevalence in Poland.CHEK2 mutation carriers in Poland may be more susceptible to ER-positive breast cancer.
Currently, the clinical applicability of CHEK mutations remains uncertain because of low mutation prevalence and lack of guidelines for clinical management.
Ataxia telangiectasia (AT) (OMIM) is an autosomal recessive disorder characterized by neurologic deterioration, telangiectasias, immunodeficiency states, and hypersensitivity to ionizing radiation. It is estimated that 1% of the general population may be heterozygote carriers of ATM mutations (OMIM). More than 300 mutations in the gene have been identified to date, most of which are truncating mutations. ATM proteins have been shown to play a role in cell cycle control.[38,39,40] In vitro, AT-deficient cells are sensitive to ionizing radiation and radiomimetic drugs, and lack cell cycle regulatory properties after exposure to radiation.
Initial studies searching for an excess of ATM mutations among breast cancer patients provided conflicting results, perhaps due to study design and mutation testing strategies.[42,43,44,45,46,47,48,49,50,51,52] However, two large epidemiologic studies have demonstrated a statistically increased risk of breast cancer among female heterozygote carriers, with an estimated RR of approximately 2.0.[52,53] Despite this convincing epidemiologic association, the clinical application of testing for ATM mutations is unclear due to the wide mutational spectrum and the logistics of testing. Because the presence of a mutation could pose a risk in screening-related radiation exposure, further investigation is needed.