A common variant within the HNF1B gene is associated with overall survival of multiple myeloma patients: results from the IMMEnSE consortium and meta-analysis.

Rafael Ríos-Tamayo,Enrico Orciuolo,Niels Weinhold,Gabriele Buda,Federico Canzian,Kari Hemminki,Juan Sainz,Hartmut Goldschmidt,Andrés Jerez,Krzysztof Jamroziak,Federica Gemignani,Rui Manuel Reis,Daniele Campa,Artur Jurczyszyn,Asta Försti,Herlander Marques,Thomas Hielscher,Fabienne Lesueur,Stefano Landi,Ulla Vogel,Manuel Jurado,Charles Dumontet,Marzena Wątek,Mario Petrini,Ramón García‐Sanz ,Carmen Belén Lupiáñez ,Joaquín Martínez‐López ,Annette Juul Vangsted

doi:10.18632/oncotarget.10665

Abstract

Diabetogenic single nucleotide polymorphisms (SNPs) have recently been associated with multiple myeloma (MM) risk but their impact on overall survival (OS) of MM patients has not been analysed yet. In order to investigate the impact of 58 GWAS-identified variants for type 2 diabetes (T2D) on OS of patients with MM, we analysed genotyping data of 936 MM patients collected by the International Multiple Myeloma rESEarch (IMMENSE) consortium and an independent set of 700 MM patients recruited by the University Clinic of Heidelberg. A meta-analysis of the cox regression results of the two sets showed that rs7501939 located in the HNF1B gene negatively impacted OS (HRRec= 1.44, 95% CI = 1.18–1.76, P = 0.0001). The meta-analysis also showed a noteworthy gender-specific association of the SLC30A8rs13266634 SNP with OS. The presence of each additional copy of the minor allele at rs13266634 was associated with poor OS in men whereas no association was seen in women (HRMen-Add = 1.32, 95% CI 1.13–1.54, P = 0.0003). In conclusion, these data suggest that the HNF1Brs7501939 SNP confers poor OS in patients with MM and that a SNP in SLC30A8 affect OS in men.

Highlights

Multiple myeloma is an incurable and heterogeneous plasma cell neoplasm that affects about 6.3 per 100.000 people per year worldwide (i.e., 25.850 new cases only in 2015) and represents 1.6% of all cancers and 2% of all cancer deaths [1]
When we evaluated the effect of selected polymorphisms on MM overall survival (OS) in the International Multiple Myeloma rESEarch (IMMENSE) population, we found that 6 single nucleotide polymorphism (SNP) showed a noteworthy association with OS
The most relevant effect was observed for the HNF1Brs7501939 SNP that was associated with poor OS when recessive and log-additive models of inheritance were assumed (HRREC = 1.49, 95% confidence intervals (CI) 1.11–2.00, P = 0.008 and HRADD = 1.34 95% CI 1.13–1.59, P = 0.001, respectively; Table 2)

Summary

Introduction

Multiple myeloma is an incurable and heterogeneous plasma cell neoplasm that affects about 6.3 per 100.000 people per year worldwide (i.e., 25.850 new cases only in 2015) and represents 1.6% of all cancers and 2% of all cancer deaths [1]. Chiu et al (2006) reported that high level of postload glucose was associated with increased risk of mortality in hematological malignancies [24] whereas Chou et al (2012) reported that MM patients with preexisting T2D have 50% higher all-cause mortality compared with non-diabetic patients [25] These observations might be explained, at least in part, by the stimulatory effects of T2D-associated hyperglycaemia, insulin resistance and resulting hyperinsulinemia on MM cell growth [26, 27] and by the deregulation of tumour-suppressor genes linked to T2D (such as CDKN2A-2B, KCNQ1, HNF1B) [28,29,30] that might lead to uncontrolled cell proliferation, cell differentiation and disease progression and, to shorter survival periods. Emerging evidences suggest that the activation of certain T2D-related genes (such as NOTCH2) may induce MM cell migration from the infiltrated site to different bone marrow districts [35] and promote osteoclast formation [36], which is a process intimately related to proliferation and long-term survival of MM cells [37]

Methods

Results

Conclusion