Selected Genetic Polymorphisms Associated with Hypoxia and Multidrug Resistance in Monoclonal Gammopathies Patients

Abstract

Background: Adaptive response to hypoxia is regulated by several mechanisms and transcription factors, includ ing hypoxia-inducible factors (HIFs). Activation of HIF-1α is associated with increased expression of P-glycoprotein and multidrug resistance in cancer cells. In this retrospective study, we analyzed candidate single-nucleotide polymorphisms (SNPs) in HIF-1α and HIF-1β associated with risk of monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM). Patients and Methods: Genotypes of SNPs associated with hypoxia were determined in an independent cohort of monoclonal gammopathies (MG) (275 MM and 228 MGUS patients) and in 219 cancer-free controls by real time polymerase chain reaction allelic discrimination. Results: When MM patients were compared to controls, protective role of CG genotype compared to CC in HIF-1β (rs2228099) for MM development was observed (OR = 0.65; CI 0.45-0.95; p = 0.026). Even after adjustment for patients' age and body mass index (BMI), there were significantly lower odds (OR = 0.55; p = 0.045) of develop ing MM patients of CG genotype in comparison to CC genotype. Log-rank test confirmed association of GT haplotype (rs11549467, rs2057482) in HIF-1α with better over all survival (median 41.8 months; (CI 35.1-48.5)) for "none GT" and median 93.8 months (CI 31.3-156.4) for "at least one GT" haplotype (p = 0.0500). Further, significant associations between SNPs in MDR1 and outcome of MM were found in 110 MM patients that underwent bortezomib-based treatment. Conclusion: Our study showed a genetic predisposition for risk of MG development and/ or outcome of MM patients; nevertheless, further studies are needed to confirm our initial analysis.

Analysis of HIF-1α expression and genetic polymorphisms in human clear cell renal cell carcinoma

“…Rs2057482 is located in 3′UTR of HIF1A. There are several reports that hypothesized that the minor T allele in this polymorphism may decrease the HIF1A expression by creating a new microRNA binding site [ 22 , 51 – 54 ]. However, according to our data, neither the tumor nor the normal kidney HIF-1α tissue levels did not appear to be influenced by any of these two polymorphisms in HIF1A .…”

The association between hypoxia inducible factor 1 subunit alpha gene rs2057482 polymorphism and cancer risk: a meta-analysis

“…The HIF1A gene has many SNPs, but we focused on rs2057482 for the following reasons: First, the relationship between rs2057482 and cancer risk has been reported in previous epidemiology studies [12][13][14][15][16][17][18]. Second, in the 1000 Genomes Project Phase 3, minor allele frequencies of rs2057482 are greater than 10% in most populations (Additional file 1: Table S4).…”

“…The rs2057482 polymorphism is located in the 3'UTR of HIF1A. Many researchers have hypothesized that this polymorphism may be located near the microRNA binding site and that it affects the expression of HIF1A by binding HIF1A to the microRNA [13,[15][16][17][18]. Wang et al reported that rs2057482 may affect the expression of HIF1A by microRNA 199a [15].…”

“…The rs2057482 polymorphism is located in the 3′ untranslated region (3′-UTR) region of the HIF1A gene. The SNP has been widely explored for its relationship with cancer risk [12][13][14][15][16][17][18]. We performed this metaanalysis to provide a more accurate assessment and obtain a comprehensive understanding of the relationship between rs2057482 and cancer risk.…”