Fast track — ArticlesGenetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence
Introduction
Breast cancer is a multifactorial disease caused by complex inherited and environmental factors.1 So far, genetic studies have identified and confirmed four rare high-penetrance genes (BRCA1, BRCA2, TP53, and PTEN), four rare moderate-penetrance genes (CHEK2, ATM, BRIP1, and PALB2), and around 20 common low-penetrance variants in 19 genes or loci that contribute to a woman's risk of breast cancer (Table 1, Table 2).2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 Common genetic risk variants have mainly been identified by genome-wide association studies (GWAS). Although the list in the Table 1, Table 2 represents the culmination of our current understanding of the genetic architecture of breast cancer, these genes and loci are estimated to account for only 28% of the inherited causes of the disease.11
Despite the prominence and growing body of results from GWAS, candidate-gene association studies remain the most prevalent type of investigation to identify common breast-cancer susceptibility alleles. More than 1000 candidate-gene breast-cancer association studies have been published in the past two decades, which have evaluated more than 7000 genetic variants (webappendix p 1). Although some of these variants could have true associations with breast-cancer risk, many false-positive associations are identified that do not replicate in additional study populations. Determining if associations are real has generally been done by examining all the epidemiological evidence in conjunction with biological plausibility, in the form of a meta-analysis. Previous meta-analyses mainly focused on one variant, or variants within one gene; however, recent meta-analyses have begun to increase in size and scope.13, 14 Guidelines for the assessment of cumulative evidence for genetic associations, which have become known as the Venice criteria, have been set forth by the Human Genome Epidemiology Network Working Group.15, 16
This study was undertaken in view of the plethora of candidate-gene association studies, the necessity for replication across studies to identify markers truly associated with disease risk,17, 18, 19 and the criteria provided to evaluate genetic associations with disease. We attempted to evaluate all candidate-gene association studies of breast cancer, perform meta-analyses for variants with sufficient data available, and provide a synopsis of our current understanding of the genetic architecture of breast-cancer risk.
Section snippets
Methods
All methods were based on guidelines proposed by the Human Genome Epidemiology Network for systematic review of genetic-association studies and follow PRISMA guidelines.15, 16, 20, 21
Results
A total of 1059 publications including 521 genes or chromosomal loci and 2790 variants were eligible to be included in our analysis (figure). Most of these reports (n=961, 91%) were published since 2000, with the highest number published in 2008 (n=154; webappendix p 1). The mean number of variants analysed per publication was consistently less than five until 2005, and then increased to a maximum of 15·6 in 2008. The median sample size of cases included in the 1059 publications was 461 (range
Discussion
This study is, to the best of our knowledge, the largest and most comprehensive assessment of literature on the genetic architecture of breast-cancer susceptibility done so far. Using methods based on the guidelines for systematic reviews of genetic-association studies, proposed by the Human Genome Epidemiology Network,15, 16, 20, 21 we did a comprehensive research synopsis and meta-analysis of genetic variants and breast-cancer risk. Significant associations with breast-cancer risk were found
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