Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence

Abstract

SUMMARY Background Over 1,000 reports have been published during the past two decades on associations between genetic variants in candidate genes and breast cancer risk. Results have been generally inconsistent. We conducted literature searches and meta-analyses to provide a field synopsis of the current understanding of the genetic architecture of breast cancer risk. Methods Systematic literature searches for candidate gene association studies of breast cancer risk were conducted in two stages using PubMed on or before February 28, 2010. A total of 24,500 publications were identified, of which, 1,059 were deemed eligible for inclusion. Meta-analyses were conducted for 279 genetic variants in 128 candidate genes or chromosomal loci that had a minimum of three data sources available. Variants with significant associations by meta-analysis were assessed using the Venice criteria and scored as having strong, moderate, or weak cumulative evidence for an association with breast cancer risk. Findings Fifty-one variants in 40 genes showed statistically significant associations with breast cancer risk. Cumulative epidemiologic evidence for an association with breast cancer risk was graded as strong for 10 variants in six genes (ATM, CASP8, CHEK2, CTLA4, NBN, and TP53), moderate for four variants in four genes (ATM, CYP19A1, TERT, and XRCC3), and weak for 37 additional variants. Additionally, in meta-analyses that included a minimum of 10,000 cases and 10,000 controls, convincing evidence of no association with breast cancer risk was identified for 45 variants in 37 genes. Interpretation While most genetic variants evaluated in previous candidate gene studies showed no association with breast cancer risk in meta-analyses, 14 variants in 9 genes were found to have moderate to strong evidence for an association with breast cancer risk. Further evaluation of these variants is warranted.

CHEK2 1100delC Variant and Breast Cancer Risk in Caucasians: A Meta-analysis Based on 25 Studies with 29,154 Cases and 37,064 Controls

“…It is estimated that 458,503 deaths were due to breast cancer in 2008 alone, which accounts for 13.7% of cancer deaths in women worldwide (World Cancer Report, 2008). Many candidate genes have been reported to be associated with breast cancer susceptibility, including CHEK2, BRCA1, BRCA2, TP53, CYP19, CASP8, XRCC3, PETN (Baig et al, 2011), and CTLA4 (Zhang et al, 2011). The CHEK2 gene, which encodes G2 checkpoint kinase, has been widely cited for its potential implications in breast cancer susceptibility.…”

Lack of any Association of the CTLA-4 +49 G/A Polymorphism with Breast Cancer Risk in a North Indian Population

“…The effect of SNPs on cancer susceptibility differs in different ethnic populations and there is no data till date with respect to the effect of this SNP on breast cancer susceptibility in our North Indian population. Breast cancer risk and pathogenesis can be influenced by single nucleotide polymorphisms and several studies in the past have identified different genetic variants in the human genome that showed strong or moderate evidence of associations with breast cancer (Zhang et al, 2011). Besides, breast cancer is the leading type of cancer among women of North India and its rate is expected to rise in the years to come (Takiar et al, 2010).…”

IL1RN (interleukin 1 receptor antagonist)

“…In the meta-analysis performed by Zhang and cols., which included 71 studies of multiple cancers, with 14854 cases and 19337 controls, the research group found a consistent association with gastric cancer. IL1RN polymorphisms frequency is significantly different across ethnicities; the frequency of allele 2 is significantly lower in Asian controls (11.14%) compared to Caucasian controls (26%) (Zhang et al, 2011).…”

“…Lee and cols, found a decreased breast cancer risk with the short allele (*2) and a higher risk of cancer in women with the long allele and higher body mass index (Lee et al, 2006). Zhang and cols, performed a meta-analysis study and found a similar trend with allele IL1RN*2 (Zhang et al, 2011), however, with this apparent diminish in risk for breast cancer, other studies have found an elevated risk of earlier recurrence of breast cancer in women with IL1RN*2 allele (Grimm et al, 2009). …”