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

Abstract

Adaptive response to hypoxia is regulated by several mechanisms and transcription factors, including 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). 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. 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 developing 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 overall 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. 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.