Two strategies have been taken to identify low-penetrance polymorphisms leading to breast cancer susceptibility: candidate gene and genome-wide searches. Both involve the epidemiologic case-control study design. The candidate gene approach involves selecting genes based on their known or presumed biological function, relevance to carcinogenesis or organ physiology, and searching for or testing known genetic variants for an association with cancer risk. This strategy relies on imperfect and incomplete biological knowledge, and, despite some confirmed associations (described below), has been relatively disappointing [6,7] The candidate gene approach has largely been replaced by the genome-wide association studies (GWAS) in which a very large number of single nucleotide polymorphisms (SNPs) (potentially 1 million or more) are chosen within the genome and tested, mostly without regard to their possible biological function, but instead to capture all genetic variation throughout the genome more uniformly.
Breast Cancer Susceptibility Genes Identified Through Candidate Gene Approaches
There is a very large literature of genetic epidemiology studies describing associations between various loci and breast cancer risk. Many of these studies suffer from significant design limitations. Perhaps as a consequence, most reported associations do not replicate in follow-up studies. This section is not a comprehensive review of all reported associations. This section describes associations that are believed by the editors to be clinically valid, in that they have been described in several different studies or are supported by robust meta-analyses. The clinical utility of these observations remains unclear, however, as the risks associated with these variations usually fall below a threshold that would justify a clinical response.
CHEK2 (OMIM) is a gene involved in the DNA damage repair response pathway. Based on numerous studies, a polymorphism, 1100delC, appears to be a rare, moderate-penetrance cancer susceptibility allele.[8,9,10,11,12,13] One study identified the mutation in 1.2% of the European controls, 4.2% of the European BRCA1/BRCA2-negative familial breast cancer cases, and 1.4% of unselected female breast cancer cases. In a group of 1,479 Dutch women younger than 50 years with invasive breast cancer, 3.7% were found to have the CHEK2 1100delC mutation. In additional European and U.S. (where the mutation appears to be slightly less common) studies, including a large prospective study, the frequency of CHEK2 mutations detected in familial breast or ovarian cancer cases has ranged from 0%  to 11%; overall, these studies have found an approximately 1.5-fold to 3-fold increased risk of female breast cancer.[15,17,18,19,20] A multicenter combined analysis and reanalysis of nearly 20,000 subjects from ten case-control studies, however, has verified a significant 2.3-fold excess of breast cancer among mutation carriers.
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.