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

Abstract

To understand the biology of low-risk breast cancer alleles, and to investigate whether these loci also contribute to disease progression that was once established, we examined the association of SNPs tagging the low-risk breast cancer loci in or near FGFR2, LSP1, MAP3K1, H19, TOX3, POU5F1P1, MYC, and 2q35, with clinical, pathological characteristics, prognosis, and mRNA expression of the nearest genes. Tumor DNA samples of 2,480 breast cancer patients were available. Out of this cohort, 1,290 patients with lymph-node negative disease who did not receive adjuvant systemic therapy, the SNP status was associated with metastasis-free survival (MFS). In 1,401 patients, the mRNA expression levels of FGFR2, LSP1, MAP3K1, H19, TOX3, POU5F1P1, and MYC were determined and correlated with SNP genotypes. The SNP rs2981582 in FGFR2 was significantly associated with positive ER and PgR status (P < 0.001 and P = 0.003, respectively). No other significant associations with patient or tumor characteristics were observed. Only rs2107425 near H19 was significantly associated with shorter MFS in uni- and multi-variate analysis (HR: 1.53, CI: 1.12-2.08, P = 0.006 and HR: 1.59, CI: 1.16-2.20, P = 0.004, respectively), with the more aggressive minor allele displaying a recessive trait. The minor allele of SNP rs3803662 located near the TOX3 gene was associated with lower mRNA expression of this gene. In conclusion, except for the association of rs13283662 with TOX3 gene expression indicating a tumor suppressor role of TOX3, our findings suggest that breast cancer low-risk loci generally do not affect expression of the nearest gene in breast tumor tissue. Also the prognosis of patients is largely not affected by low-risk breast cancer loci except for the SNP near H19. How, this SNP affects prognosis warrants further study as it does not operate through altering H19 mRNA expression.

Integrative eQTL-Based Analyses Reveal the Biology of Breast Cancer Risk Loci

“…In the cis- analysis, we observed 3 transcripts associated with 3 risk loci at an FDR<0.1 (2q35/ IGFBP5 , 5q11/ C5orf35 , and 16q12/ TOX3 ). Interestingly, the association with TOX3 (in the same direction) has been previously observed further demonstrating the utility of publicly available data (Riaz et al, 2012). IGFBP5 is a strong candidate gene for mediating the effect of the 2q35 risk locus.…”

Increased risk of breast cancer in individuals carrying the TNRC9 rs3803662 C>T polymorphism: a meta-analysis of case-control studies

“…CITED1 is a transcription coregulator that enhances the activity of transcription factors such as ERs (Yahata et al, 2001). A correlation between the rs3803662 genotype and decreased TNRC9 mRNA has been observed in breast tumors, in which transcription of this gene decreases in an allele-dependent manner (Riaz et al, 2012). To date, one study has shown an effect of TNRC9 expression on BC, showing that increased levels of TNRC9 mRNA predict bone metastasis in this disease (Smid et al, 2006).…”

Unbiased analysis of potential targets of breast cancer susceptibility loci by Capture Hi-C

“…Many of the risk SNPs map to non-protein-coding regions and are thought to influence transcriptional regulation (Hindorff et al 2009;Freedman et al 2011). In some instances the proximity of the SNP to a plausible candidate gene has provided a potential mechanism (Meyer et al 2008;Riaz et al 2012;Bojesen et al 2013), but several of the breast cancer risk SNPs map to gene deserts with the nearest known gene mapping several hundred kilobases (kb) away.…”