Low Risk Breast Cancer Genes

A growing list of genes is associated with more moderate risks of breast cancer. The first such gene to be identified was ATM. Mutations in this gene cause the recessive condition Ataxia-Telangiectasia (A-T) (62). Studies dating back over 30 years have suggested that relatives of A-T patients were at increased risk of breast (and perhaps other) cancer (63). This was long regarded as controversial because the studies were small. However, more recent national cohort studies, and direct studies of ATM mutations in breast cancer families and controls, have confirmed that ATM mutations confer an approximately twofold risk of breast cancer (with perhaps a higher relative risk at young ages) (64-67).

Another important low-risk susceptibility gene is CHEK2, another DNA repair gene that acts downstream of ATM. Mutations in this gene were first identified in patients with a family history reminiscent of Li-Fraumeni syndrome, and it was therefore suspected that this was another high-risk susceptibility gene (68). It was subsequently shown, however, that a single mutation in CHEK2,1100delC, that is present at frequencies of /% to 1% in European populations, confers an approximately twofold risk of breast cancer (69,70). There is no evidence of any high-risk mutations in this gene. CHEK21100delC appears to be the predominant disease-causing mutation in Western Europe, but other mutations in Poland and in Ashkenazi Jews, conferring similar risks, have been found. More recently, it has been shown that rare mutations in two other DNA repair genes, BRIP1 and PALB2, also confer similar risks of breast cancer (71-73).

Only one common variant identified through candidate gene studies has been unequivocally linked to breast cancer risk. An amino acid substitution D302H in the CASP8 gene, with an allele frequency of 13% in Europeans, has been estimated to confer a relative risk of 0.89 in heterozygotes and 0.74 in homozygotes (74). Recently, gene wide association studies have identified six further breast cancer loci (75,76). Many other associations between common genetic variants and breast cancer risk have been reported but most have been refuted (75). However, several genome-wide association studies are currently in progress, and it seems likely that further susceptibility loci will be identified soon.

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