Polymorphisms of the Transforming Growth Factor Beta 1 (TGFB1) Gene Define a Subgroup of Patients with Late Onset of Disease and Poor Outcome in Multiple Myeloma.

Common genetic variants in immune and inflammatory genes can affect the risk of developing multiple myeloma. The aim of this study was to determine the effect of polymorphic variants in the interleukin 10 (IL10), transforming growth factor beta (TGFB1) and tumor necrosis factor alpha (TNFa) genes on the predisposition to multiple myeloma and the effect of these polymorphisms on survival after treatment with chemotherapy. Genotype data of 7 single-nucleotide polymorphisms and clinical follow-up information were available for 239 consecutive patients with multiple myeloma who presented at our outpatient department. All patients were treated with chemotherapy, including high-dose chemotherapy and peripheral blood stem cell transplantation in 191 patients. In particular, there were 155 males and 84 females with a median age of 55 years (range, 30 – 84). The median follow-up period for the entire cohort was 75 months (range, 3 – 190 months). The TGFB1 low producer genotype 10Leu/Leu (n=78) was associated with a 3.5 years older age at start of treatment (57.5 versus 54 years, p=0.005), a higher level of beta2-microglobulin (3.4 versus 2.5 mg/l, p=0.01), a higher frequency of ISS-scores II and III versus I (OR=0.50, p=0.01) and an inferior median survival rate of 71.8 versus 91.6 months (p=0.02) as compared to other genotypes, respectively. In a multivariate analysis, the TGFB1 low producer genotype 10Leu/Leu was identified as an independent factor for survival (p=0.03), indicating that the poor prognosis of these patients is not due to the older age at the start of treatment. All other gene polymorphisms analyzed (IL10–1082A>G, IL10–819C>T, IL10–592C>A, TGFB1 Arg25Pro, TNFa -308G>A, TNFa -238G>A) showed no statistically significant effect on overall survival. Our findings suggest that patients carrying the TGFB1 low producer polymorphism show a later onset of disease and need for chemotherapy treatment as compared to other genotypes. In addition, our findings indicate that TGFB1 genetic variants influence prognosis in patients with multiple myeloma who received chemotherapy and suggest that genetically determined cytokine production affects the clinical course of the disease possibly through regulation of immune surveillance.