Sequence analysis of β-subunit genes of the 20S proteasome in patients with relapsed multiple myeloma treated with bortezomib or dexamethasone
Sequence analysis of β-subunit genes of the 20S proteasome in patients with relapsed multiple myeloma treated with bortezomib or dexamethasone
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DOI：
10.1182/blood-2012-05-426924
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发表时间：
2012-11-29
期刊：
影响因子：
20.3
通讯作者：
Anderson, Kenneth C.
中科院分区：
文献类型：
--
作者：
Lichter, David I.;Danaee, Hadi;Anderson, Kenneth C.
编码20 S蛋白酶体β亚基的蛋白酶体β（PSMB）基因内的变异可能影响蛋白酶体功能、组装和/或蛋白酶体抑制剂的结合。为了研究PSMB基因变异与硼替佐米治疗后出现的耐药性和/或长期结局之间的潜在相关性，在本研究中，在参与硼替佐米与高剂量地塞米松治疗复发性多发性骨髓瘤的3期蛋白酶体抑制延长缓解（APEX）研究的患者的肿瘤DNA样本中表征了PSMB基因序列变异。鉴定了12种新的PSMB变体。未发现PSMB单核苷酸多态性基因型频率与硼替佐米或地塞米松治疗的临床反应之间或PSMB单核苷酸多态性等位基因频率与汇总总生存期或进展时间之间存在关联。尽管之前在硼替佐米耐药的临床前模型中已经鉴定出特定的PSMB 5变体，但在硼替佐米临床复发后收集的患者肿瘤样本中未检测到这些变体，这表明硼替佐米不敏感性的替代机制。本研究在www.clinicaltrials.gov注册为NCT 00048230。（血。2012;120（23）：4513-4516）
Variations within proteasome beta (PSMB) genes, which encode the beta subunits of the 20S proteasome, may affect proteasome function, assembly, and/or binding of proteasome inhibitors. To investigate the potential association between PSMB gene variants and treatment-emergent resistance to bortezomib and/or long-term outcomes, in the present study, PSMB gene sequence variation was characterized in tumor DNA samples from patients who participated in the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib versus high-dose dexamethasone for treatment of relapsed multiple myeloma. Twelve new PSMB variants were identified. No associations were found between PSMB single nucleotide polymorphism genotype frequency and clinical response to bortezomib or dexamethasone treatment or between PSMB single nucleotide polymorphism allelic frequency and pooled overall survival or time to progression. Although specific PSMB5 variants have been identified previously in preclinical models of bortezomib resistance, these variants were not detected in patient tumor samples collected after clinical relapse from bortezomib, which suggests that alternative mechanisms underlie bortezomib insensitivity. This study is registered at www.clinicaltrials.gov as NCT00048230. (Blood. 2012;120(23):4513-4516)