Fine scale mapping of the breast cancer 16q12 locus

Abstract

Recent genome-wide association studies have identified a breast cancer susceptibility locus on 16q12 with an unknown biological basis. We used a set of single nucleotide polymorphism (SNP) markers to generate a fine-scale map and narrowed the region of association to a 133 kb DNA segment containing the largely uncharacterized hypothetical gene LOC643714, a short intergenic region and the 5' end of TOX3. Re-sequencing this segment in European subjects identified 293 common polymorphisms, including a set of 26 highly correlated candidate causal variants. By evaluation of these SNPs in five breast cancer case-control studies involving more than 23 000 subjects from populations of European and Southeast Asian ancestry, all but 14 variants could be excluded at odds of <1:100. Most of the remaining variants lie in the intergenic region, which exhibits evolutionary conservation and open chromatin conformation, consistent with a regulatory function. African-American case-control studies exhibit a different pattern of association suggestive of an additional causative variant.

A Genome-wide Breast Cancer Scan in African Americans

“…At 11q13, rs609275 lies 74 kb telomeric of the index signal and in closer proximity to a number of candidate genes, including CCND1 (encoding cyclin D1, a protein crucial for cell-cycle control), ORAOV1 (encoding oral cancer overexpressed 1) and FGF19 (encoding fibroblast growth factor 19). The association at 16q12 confirms the findings of a previous, smaller study of African Americans (16), and is consistent with a previous fine-mapping study suggesting that African Americans may harbor a separate causal variant in this region (42). Whether this variant is influencing the same genes/pathways as the index variant rs3803662 is not known; however, the stronger associations noted for both variants with ER+ disease (2,18) suggest that they may affect the same biological process.…”

Correlation of breast cancer susceptibility loci with patient characteristics, metastasis-free survival, and mRNA expression of the nearest genes

“…A recent fine mapping of the LD block has further narrowed this risk-associated locus down to a region of 133 kb spanning the entire coding part of LOC643714 and a small intergenic region. Moreover, this region exhibits evolutionary conservation and open chromatin conformation suggesting a regulatory function [27]. Our study shows that the alleles in this locus that have strongest association with risk (rs3803662 and rs12443621) were significantly related with a lower expression of TOX3 mRNA.…”

“…The lower expression of the TOX3 gene, which encodes a high mobility group box nuclear protein involved in calcium dependent transcription and structural modification of chromatin, in tumors with risk alleles of rs3803662, suggests that TOX3 might act as a tumor suppressor gene. It is important to note that although the risk alleles of rs3803662 are significantly associated with lower expression of TOX3, yet another recent study showed an association of the rs3803662 SNP with an increased expression of the RBL2 gene, which is also located nearby this risk allele [27]. Although this study including only 77 breast tumors is underpowered compared with our analysis, it might however, be possible that this locus differentially regulates more than one distant gene in cis or in trans.…”

A family-based, genome-wide association study of young-onset breast cancer: inherited variants and maternally mediated effects

“…The SNP in TOX3 (rs4784227:C4T) that was ranked fourth in the main analysis and second in the analysis that excluded the known BRCA-positive families, is a known susceptibility locus first identified in a breast cancer GWAS by Long et al 28 It has since been replicated in investigations among women of many ethnicities. [29][30][31][32][33] Presence of the variant allele (T) increases the chromatin's affinity for FOXA1, 34 a pioneer factor that can bind to chromatin and recruit the ER, thereby facilitating estrogen-driven transcription and cellular changes. 35 The other highly ranked TOX3 SNP, rs3803662:G4A, was also originally identified in a GWAS study 36 and the association was successfully replicated.…”