Abstract
RAD50 is commonly depleted in basal-like breast cancer with concomitant absence of INPP4B and several tumor suppressors such as BRCA1 and TP53. Our previous study revealed that INPP4B and RAD50 interact and such an interaction is associated with breast cancer survival at the transcriptional, translational and genomic levels. In the present study, we explored single nucleotide polymorphisms (SNPs) of these two genes that have synergistic effects on breast cancer survival to decipher mechanisms driving their interactions at the genetic level. The Cox’s proportional hazards model was used to test whether SNPs of these two genes are interactively associated with breast cancer survival, following expression quantitative trait loci (eQTL) analysis and functional investigations. Our study revealed two disease-associating blocks, each encompassing five and two non-linkage disequilibrium linked SNPs of INPP4B and RAD50, respectively. Concomitant presence of any rare homozygote from each disease-associating block is synergistically prognostic of poor breast cancer survival. Such synergy is mediated via bypassing pathways controlling cell proliferation and DNA damage repair, which are represented by INPP4B and RAD50. Our study provided genetic evidence of interactions between INPP4B and RAD50, and deepened our understandings on the orchestrated genetic machinery governing tumor progression.
Highlights
As the second leading cause of deaths worldwide, great attention has been paid in order to reveal the underlying factors that drive the genesis of cancer [1]
The results of the block-wise overall survival (OS) analysis using recessive model indicated that concomitant presence of the rare homozygote of any single nucleotide polymorphism (SNP) from each disease-associating block is associated with significantly reduced breast cancer OS (Figure 2E)
We found from GeneMania that BCKDHB had genetic interactions with INPP4B and RAD50, respectively, which were previously reported by [32], and RMND5A and PWP2 had known genetic interactions with RAD50, which were in agreement with what we observed in the present study and supported our findings
Summary
As the second leading cause of deaths worldwide, great attention has been paid in order to reveal the underlying factors that drive the genesis of cancer [1]. Breast cancer is the leading cause of deaths among women with the annual mortality rate being estimated over 570000 worldwide [8,9]. As one of the most common types of genetic variations in human genome, single nucleotide polymorphisms (SNPs) in genes involved in DNA damage repair, metabolism, carcinogen metabolism, cell-cycle control, apoptosis and immunity are likely to be associated with genetic susceptibility to various cancer types including breast cancer [11,12]. Common SNPs can account for 18% of breast cancer familial risk among women [13]
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