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 language | English |
|---|---|
| Pages (from-to) | 734-742 |
| Number of pages | 9 |
| Journal | Clinical Lymphoma, Myeloma and Leukemia |
| Volume | 17 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - nov. 1 2017 |
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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
}
TY - JOUR
T1 - Proteasome Subunit Beta Type 1 P11A Polymorphism Is a New Prognostic Marker in Multiple Myeloma
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.
PY - 2017/11/1
Y1 - 2017/11/1
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.
KW - Bortezomib
KW - Multiple myeloma
KW - Proteasome activity
KW - PSMB1
KW - SNP
UR - http://www.scopus.com/inward/record.url?scp=85024873677&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85024873677&partnerID=8YFLogxK
U2 - 10.1016/j.clml.2017.06.034
DO - 10.1016/j.clml.2017.06.034
M3 - Article
C2 - 28733196
AN - SCOPUS:85024873677
VL - 17
SP - 734
EP - 742
JO - Clinical Lymphoma, Myeloma and Leukemia
JF - Clinical Lymphoma, Myeloma and Leukemia
SN - 2152-2650
IS - 11
ER -