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Single nucleotide polymorphisms and breast cancer: not yet a success story

DOI: 10.1186/bcr1529

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There is considerable evidence that genetics plays a role in breast cancer. Women with a family history of breast cancer are at a near twofold increased risk for breast cancer. Identification of highly penetrant genes has supported the notion that breast cancer is a genetic disease. However, these genes (e.g. BRCA1 and BRCA2) account for a very small percentage of breast cancers in the population [1]. The common disease-common variant hypothesis has been one of the overarching suppositions driving many of the breast cancer association studies [2,3]. This hypothesis suggests that the risk attributable to genetics for common diseases will come from alleles that are not under severe negative selection and that are in the population at a relatively high frequency. This hypothesis is appealing from a public health perspective because common variants will have the greatest impact at the population level.The sequencing of the human genome and discovery of millions of single nucleotide polymorphisms (SNPs) [4] provided the opportunity to characterize human genetic variation and its impact on breast cancer systematically. Numerous studies have examined low penetrance susceptibility polymorphisms in candidate genes, with some reporting significant findings. However, for the most part these associations could not be replicated in subsequent studies, suggesting that the original observations were due to chance [5]. In a pooled analysis of 46 association studies examining polymorphisms in 18 different genes, only three polymorphisms were significantly associated with breast cancer [5]. Despite considerable efforts made during the past few years to study genetic variation and breast cancer, there has been little success in identifying important contributions to breast cancer. The lack of robust and consistent findings from single SNP association studies led to the explosion of haplotype studies, which promised to examine more comprehensively the association between common genetic


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