Proteasome Subunit Beta Type 1 P11A Polymorphism Is a New Prognostic Marker in Multiple Myeloma

Gergely Varga, G. Mikala, Katalin Piroska Kiss, Éva Kosóczki, Edit Szabó, Nóra Meggyesi, Katalin Balassa, Petra Kövy, Bálint Tegze, Gergely Szombath, A. Tordai, H. Andrikovics, L. Homolya, T. Masszi

Research output: Article

1 Citation (Scopus)

Abstract

We retrospectively analyzed the prognostic impact of proteasome subunit beta type 1 rs12717 polymorphism in 211 consecutively diagnosed multiple myeloma cases. Patients carrying the variant G allele showed significantly shorter progression-free survival. In proteasomes of individuals with G/G genotype, we found significantly reduced protease activity and lower inhibitory capacity of bortezomib on the caspase- and trypsin-like activity. Background Proteasome subunit beta type 1 (PSMB1) rs12717 polymorphism, a single nucleotide polymorphism with unknown functional effect, was recently reported to influence response to bortezomib-based therapy in follicular lymphoma. Patients and Methods We retrospectively analyzed the prognostic impact of this polymorphism in 211 consecutively diagnosed multiple myeloma cases, and performed in vitro experiments to look into its functional consequences. Results On univariate analysis, patients carrying the variant G allele showed significantly shorter progression-free survival (PFS) with a pattern suggestive of a gene-dose effect (PFS 26.4, 22.3, and 16.4 months in C/C, C/G, and G/G patients, respectively, P =.002). On multivariate analysis, carrying the G/G genotype was a significant independent risk factor for relapse (hazard ratio [HR] 2.29, P <.001) with a similar trend in C/G carriers (HR 1.33, P =.097) when compared with the major allele carrier C/C cohort. Our subsequent in vitro analyses demonstrated significantly reduced protease activity in proteasomes of individuals with G/G genotype compared with that of C/C carriers, despite that PSMB1 expression and proteasome assembly remained unaltered. Bortezomib exhibited a lower inhibitory capacity on the caspase- and trypsin-like activity of proteasomes from G/G individuals. Conclusion Our results show that carriership of PSMB1 rs12717 minor allele is predictive for suboptimal response with bortezomib treatment, which could be explained by less active proteasomes that are less sensitive to bortezomib, and myeloma cells consequently relying on other escape mechanisms to cope with the abundance of misfolded proteins.

Original languageEnglish
Pages (from-to)734-742
Number of pages9
JournalClinical Lymphoma, Myeloma and Leukemia
Volume17
Issue number11
DOIs
Publication statusPublished - nov. 1 2017

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Proteasome Endopeptidase Complex
Multiple Myeloma
Alleles
Disease-Free Survival
Genotype
Caspases
Trypsin
Peptide Hydrolases
Follicular Lymphoma
Single Nucleotide Polymorphism
Multivariate Analysis
Bortezomib
Recurrence
Therapeutics

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Proteasome Subunit Beta Type 1 P11A Polymorphism Is a New Prognostic Marker in Multiple Myeloma. / Varga, Gergely; Mikala, G.; Kiss, Katalin Piroska; Kosóczki, Éva; Szabó, Edit; Meggyesi, Nóra; Balassa, Katalin; Kövy, Petra; Tegze, Bálint; Szombath, Gergely; Tordai, A.; Andrikovics, H.; Homolya, L.; Masszi, T.

In: Clinical Lymphoma, Myeloma and Leukemia, Vol. 17, No. 11, 01.11.2017, p. 734-742.

Research output: Article

Varga, Gergely ; Mikala, G. ; Kiss, Katalin Piroska ; Kosóczki, Éva ; Szabó, Edit ; Meggyesi, Nóra ; Balassa, Katalin ; Kövy, Petra ; Tegze, Bálint ; Szombath, Gergely ; Tordai, A. ; Andrikovics, H. ; Homolya, L. ; Masszi, T. / Proteasome Subunit Beta Type 1 P11A Polymorphism Is a New Prognostic Marker in Multiple Myeloma. In: Clinical Lymphoma, Myeloma and Leukemia. 2017 ; Vol. 17, No. 11. pp. 734-742.
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abstract = "We retrospectively analyzed the prognostic impact of proteasome subunit beta type 1 rs12717 polymorphism in 211 consecutively diagnosed multiple myeloma cases. Patients carrying the variant G allele showed significantly shorter progression-free survival. In proteasomes of individuals with G/G genotype, we found significantly reduced protease activity and lower inhibitory capacity of bortezomib on the caspase- and trypsin-like activity. Background Proteasome subunit beta type 1 (PSMB1) rs12717 polymorphism, a single nucleotide polymorphism with unknown functional effect, was recently reported to influence response to bortezomib-based therapy in follicular lymphoma. Patients and Methods We retrospectively analyzed the prognostic impact of this polymorphism in 211 consecutively diagnosed multiple myeloma cases, and performed in vitro experiments to look into its functional consequences. Results On univariate analysis, patients carrying the variant G allele showed significantly shorter progression-free survival (PFS) with a pattern suggestive of a gene-dose effect (PFS 26.4, 22.3, and 16.4 months in C/C, C/G, and G/G patients, respectively, P =.002). On multivariate analysis, carrying the G/G genotype was a significant independent risk factor for relapse (hazard ratio [HR] 2.29, P <.001) with a similar trend in C/G carriers (HR 1.33, P =.097) when compared with the major allele carrier C/C cohort. Our subsequent in vitro analyses demonstrated significantly reduced protease activity in proteasomes of individuals with G/G genotype compared with that of C/C carriers, despite that PSMB1 expression and proteasome assembly remained unaltered. Bortezomib exhibited a lower inhibitory capacity on the caspase- and trypsin-like activity of proteasomes from G/G individuals. Conclusion Our results show that carriership of PSMB1 rs12717 minor allele is predictive for suboptimal response with bortezomib treatment, which could be explained by less active proteasomes that are less sensitive to bortezomib, and myeloma cells consequently relying on other escape mechanisms to cope with the abundance of misfolded proteins.",
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AU - Varga, Gergely

AU - Mikala, G.

AU - Kiss, Katalin Piroska

AU - Kosóczki, Éva

AU - Szabó, Edit

AU - Meggyesi, Nóra

AU - Balassa, Katalin

AU - Kövy, Petra

AU - Tegze, Bálint

AU - Szombath, Gergely

AU - Tordai, A.

AU - Andrikovics, H.

AU - Homolya, L.

AU - Masszi, T.

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N2 - We retrospectively analyzed the prognostic impact of proteasome subunit beta type 1 rs12717 polymorphism in 211 consecutively diagnosed multiple myeloma cases. Patients carrying the variant G allele showed significantly shorter progression-free survival. In proteasomes of individuals with G/G genotype, we found significantly reduced protease activity and lower inhibitory capacity of bortezomib on the caspase- and trypsin-like activity. Background Proteasome subunit beta type 1 (PSMB1) rs12717 polymorphism, a single nucleotide polymorphism with unknown functional effect, was recently reported to influence response to bortezomib-based therapy in follicular lymphoma. Patients and Methods We retrospectively analyzed the prognostic impact of this polymorphism in 211 consecutively diagnosed multiple myeloma cases, and performed in vitro experiments to look into its functional consequences. Results On univariate analysis, patients carrying the variant G allele showed significantly shorter progression-free survival (PFS) with a pattern suggestive of a gene-dose effect (PFS 26.4, 22.3, and 16.4 months in C/C, C/G, and G/G patients, respectively, P =.002). On multivariate analysis, carrying the G/G genotype was a significant independent risk factor for relapse (hazard ratio [HR] 2.29, P <.001) with a similar trend in C/G carriers (HR 1.33, P =.097) when compared with the major allele carrier C/C cohort. Our subsequent in vitro analyses demonstrated significantly reduced protease activity in proteasomes of individuals with G/G genotype compared with that of C/C carriers, despite that PSMB1 expression and proteasome assembly remained unaltered. Bortezomib exhibited a lower inhibitory capacity on the caspase- and trypsin-like activity of proteasomes from G/G individuals. Conclusion Our results show that carriership of PSMB1 rs12717 minor allele is predictive for suboptimal response with bortezomib treatment, which could be explained by less active proteasomes that are less sensitive to bortezomib, and myeloma cells consequently relying on other escape mechanisms to cope with the abundance of misfolded proteins.

AB - We retrospectively analyzed the prognostic impact of proteasome subunit beta type 1 rs12717 polymorphism in 211 consecutively diagnosed multiple myeloma cases. Patients carrying the variant G allele showed significantly shorter progression-free survival. In proteasomes of individuals with G/G genotype, we found significantly reduced protease activity and lower inhibitory capacity of bortezomib on the caspase- and trypsin-like activity. Background Proteasome subunit beta type 1 (PSMB1) rs12717 polymorphism, a single nucleotide polymorphism with unknown functional effect, was recently reported to influence response to bortezomib-based therapy in follicular lymphoma. Patients and Methods We retrospectively analyzed the prognostic impact of this polymorphism in 211 consecutively diagnosed multiple myeloma cases, and performed in vitro experiments to look into its functional consequences. Results On univariate analysis, patients carrying the variant G allele showed significantly shorter progression-free survival (PFS) with a pattern suggestive of a gene-dose effect (PFS 26.4, 22.3, and 16.4 months in C/C, C/G, and G/G patients, respectively, P =.002). On multivariate analysis, carrying the G/G genotype was a significant independent risk factor for relapse (hazard ratio [HR] 2.29, P <.001) with a similar trend in C/G carriers (HR 1.33, P =.097) when compared with the major allele carrier C/C cohort. Our subsequent in vitro analyses demonstrated significantly reduced protease activity in proteasomes of individuals with G/G genotype compared with that of C/C carriers, despite that PSMB1 expression and proteasome assembly remained unaltered. Bortezomib exhibited a lower inhibitory capacity on the caspase- and trypsin-like activity of proteasomes from G/G individuals. Conclusion Our results show that carriership of PSMB1 rs12717 minor allele is predictive for suboptimal response with bortezomib treatment, which could be explained by less active proteasomes that are less sensitive to bortezomib, and myeloma cells consequently relying on other escape mechanisms to cope with the abundance of misfolded proteins.

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KW - Multiple myeloma

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