Genetic polymorphisms and breast cancer risk: evidence from meta-analyses, pooled analyses, and genome-wide association studies

Abstract

To address the association between variants and breast cancer, an increasing number of articles on genetic association studies, genome-wide association studies (GWASs), and related meta- and pooled analyses have been published. Such studies have prompted an updated assessment of the associations between gene variants and breast cancer risk. We searched PubMed, Medline, and Web of Science and retrieved a total of 87 meta- and pooled analyses, which addressed the associations between 145 gene variants and breast cancer. Analyses met the following criteria: (1) breast cancer was the outcome, (2) the articles were all published in English, and (3) in the recent published meta- and pooled analyses, the analyses with more subjects were selected. Among the 145 variants, 46 were significantly associated with breast cancer and the other 99 (in 62 genes) were not significantly associated with breast cancer. The summary ORs for the 46 significant associations (P < 0.05) were further assessed by the method of false-positive report probability (FPRP). Our results demonstrated that 10 associations were noteworthy: CASP8 (D302H), CHEK2 (*1100delC), CTLA4 (+49G>A), FGFR2 (rs2981582, rs1219648, and rs2420946), HRAS (rare alleles), IL1B (rs1143627), LSP1 (rs3817198), and MAP3K1 (rs889312). In addition, eight GWASs were identified, in which 25 loci were obtained (14 in nine genes, six near a gene or genes, and five intergenic loci). Of the 25 SNPs, 20 were noteworthy: C6orf97 (rs2046210 and rs3757318), FGFR2 (rs2981579, rs1219648, and rs2981582), LSP1 (rs909116), RNF146 (rs2180341), SLC4A7 (rs4973768), MRPS30 (rs7716600), TOX3 (rs3803662 and rs4784227), ZNF365 (rs10995190), rs889312, rs614367, rs13281615, rs13387042, rs11249433, rs1011970, rs614367, and rs1562430. In summary, in this review of genetic association studies, 31.7% of the gene-variant breast cancer associations were significant, and 21.7% of these significant associations were noteworthy. However, in GWASs, 80% of the significant associations were noteworthy.

1236 C/T and 3435 C/T polymorphisms of the ABCB1 gene in Mexican breast cancer patients

“…Breast cancer oncogenesis implies complex interactions between genes and epigenetic alterations, including susceptibility genes such as BRCA1, BRCA2, PTEN, and p53, and somatic genetic alterations such as DNA methylation, chromatin remodeling, and regulation by noncoding RNA (Bièche and Lidereau, 2011). Genetic polymorphism studies are useful for identifying susceptibility genes as well as predictive biomarkers (Peng et al, 2011). The ABCB1 gene located at 7q21.1 (OMIM: 171050, Gene ID: 5243) codes for the MDR1 protein, which is a member of the superfamily of ATP-binding cassette (ABC) transporters (Couture et al, 2006).…”

TP53 Gene Polymorphisms in Cancer Risk: The Modulating Effect of Ageing, Ethnicity and TP53 Somatic Abnormalities

“…In this aspect, it is of note that some contradictions in the abovementioned meta-analyses could be due to age-related effects of TP53 germline variations. For example, breast cancer is one of a few diseases for which TP53 rs1042522 polymorphism raises many questions Hu et al, 2010b;Lu et al, 2011b;Ma et al, 2011;Peng et al, 2011;Sergentanis and Economopoulos, 2010b;The Breast Cancer Association Consortium, 2006;Zhang et al, 2010b;Zhuo et al, 2009a). According to our data, the C allele contributes to high breast cancer risk in the premenopausal period , whereas a combination of rs1042522, rs17878362, and rs1625895 major genotypes often occurs in postmenopausal BC (Perel'muter et al, 2008).…”

“…No significant contribution of TP53 rs1042522 polymorphism to oral cancer has been reported (Zhuo et al, 2009c). A high heterogeneity of results was observed in breast Hu et al, 2010b;Lu et al, 2011b;Ma et al, 2011;Peng et al, 2011;Sergentanis and Economopoulos, 2010b;The Breast Cancer Association Consortium, 2006;Zhang et al, 2010b;Zhuo et al, 2009a), colon and rectum (Dahabreh et al, 2010;Liu et al, 2011;Tang et al, 2010;Wang et al, 2010b) cancers. Though still not quite clear, cancer of the ovary (Schildkraut et al, 2009;Zhang et al, 2008), endometrium (Francisco et al, 2010;Jiang et al, 2010b), stomach (Francisco et al, 2010;Gao et al, 2009;Liu et al, 2011), bladder (Jiang et al, 2010a;Li et al, 2010), prostate Zhang et al, 2011b;Zhu et al, 2011), and skin (Francisco et al, 2010;Jiang et al, 2011) appear to be affected.…”

A new paradigm of genetic testing for hereditary breast/ovarian cancers

“…Other genes such as TP53 and PTEN have also been identified to be associated with an increased risk of breast cancer. 7 High-risk women are likely to benefit from genetic testing as there are now emerging targeted therapies and interventions that have been shown to improve outcome in mutation carriers.…”