Breast cancer genome-wide association studies: there is strength in numbers

Abstract

Breast cancer (BC) is a heterogeneous disease that exhibits familial aggregation. Family linkage studies have identified high-penetrance genes, BRCA1, BRCA2, PTEN and TP53, that are responsible for inherited BC syndromes. Moreover, a combination of family-based and population-based approaches indicated that genes involved in DNA repair, such as CHEK2, ATM, BRIP and PALB2, are associated with moderate risk. Therefore, all of these known genes account for only 25% of the familial aggregation cases. Recently, genome wide association studies (GWAS) in BC revealed single nucleotide polymorphisms (SNPs) in five novel genes associated to susceptibility: TNRC9, FGFR2, MAP3K1, H19 and lymphocyte-specific protein 1 (LSP1). The most strongly associated SNP was in intron 2 of the FGFR2 gene that is amplified and overexpressed in 5-10% of BC. rs3803662 of TNRC9 gene has been shown to be the SNP with the strongest association with BC, in particular, this polymorphism seems to be correlated with bone metastases and estrogen receptor positivity. Relevant data indicate that SNP rs889312 in MAP3K1 is correlated with BC susceptibility only in BRCA2 mutation carriers, but is not associated with an increased risk in BRCA1 carriers. Finally, different SNPs in LSP1 and H19 and in minor genes probably were associated with BC risk. New susceptibility allelic variants associated with BC risk were recently discovered including potential causative genes involved in regulation of cell cycle, apoptosis, metabolism and mitochondrial functions. In conclusion, the identification of disease susceptibility loci may lead to a better understanding of the biological mechanism for BC to improve prevention, early detection and treatment.

Association of low-penetrance alleles with male breast cancer risk and clinicopathological characteristics: results from a multicenter study in Italy

“…At present, there are no data on possible correlations between clinicopathological characteristics and common low-penetrance BC susceptibility alleles in MBC. On the other hand, in FBC, there is increasing evidence that associations between common variants and BC risk could vary by clinically important tumor characteristics, mainly by ER expression [25][26][27][28][29][30][31]. We found that ESR1 was significantly associated with the risk of ER-BCs in males.…”

“…In addition, there is evidence that the increased risk associated with several of the loci identified to date shows BC subtype specificity in FBC [25][26][27][28]. Notably, associations with most of the susceptibility loci appear to be stronger for estrogen receptor-positive (ER?)…”

Preimplantation genetic diagnosis using combined strategies on a breast cancer patient with a novel genomic deletion in BRCA2

“…Many other high or moderate risk genes such as PTEN, TP53, CHEK2, ATM, BRIP, PALB2, etc. have also been identified [19] to be associated with breast cancer. In addition, more than 40 novel breast cancer susceptibility loci have been found in a most recent meta-analysis of nine GWAS studies [20,21].…”

Identification of genetic markers with synergistic survival effect in cancer

“…For instance, inherited breast cancer predisposition is currently thought to result from rare high penetrance mutations in high risk families, or multiplicative effects of moderate penetrance variants or common low risk variants in the population [1,2]. So far, over 20 low penetrance variants, such as single nucleotide polymorphisms (SNPs), have been identified but they only explain approximately 8% of the familial risk of breast cancer, with the high and moderate penetrance genes explaining roughly 25% [3,4]. Combinatorial effects of large numbers of putative risk alleles are likely to be important in further explaining the genetic risk for breast cancer [5].…”