Leone Paola E, Walker Brian A, Jenner Matthew W, Chiecchio Laura, Dagrada Gianpaolo, Protheroe Rebecca K M, Johnson David C, Dickens Nicholas J, Brito Jose Luis, Else Monica, Gonzalez David, Ross Fiona M, Chen-Kiang Selina, Davies Faith E, Morgan Gareth J
Section of Haemato-Oncology, The Institute of Cancer Research, 15 Cotswold Road, London, United Kingdom.
Clin Cancer Res. 2008 Oct 1;14(19):6033-41. doi: 10.1158/1078-0432.CCR-08-0347.
Deletions of chromosome 1 have been described in 7% to 40% of cases of myeloma with inconsistent clinical consequences. CDKN2C at 1p32.3 has been identified in myeloma cell lines as the potential target of the deletion. We tested the clinical impact of 1p deletion and used high-resolution techniques to define the role of CDKN2C in primary patient material.
We analyzed 515 cases of monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and newly diagnosed multiple myeloma using fluorescence in situ hybridization (FISH) for deletions of CDKN2C. In 78 myeloma cases, we carried out Affymetrix single nucleotide polymorphism mapping and U133 Plus 2.0 expression arrays. In addition, we did mutation, methylation, and Western blotting analysis.
By FISH we identified deletion of 1p32.3 (CDKN2C) in 3 of 66 MGUS (4.5%), 4 of 39 SMM (10.3%), and 55 of 369 multiple myeloma cases (15%). We examined the impact of copy number change at CDKN2C on overall survival (OS), and found that the cases with either hemizygous or homozygous deletion of CDKN2C had a worse OS compared with cases that were intact at this region (22 months versus 38 months; P = 0.003). Using gene mapping we identified three homozygous deletions at 1p32.3, containing CDKN2C, all of which lacked expression of CDKN2C. Cases with homozygous deletions of CDKN2C were the most proliferative myelomas, defined by an expression-based proliferation index, consistent with its biological function as a cyclin-dependent kinase inhibitor.
Our results suggest that deletions of CDKN2C are important in the progression and clinical outcome of myeloma.
在7%至40%的骨髓瘤病例中发现了1号染色体缺失，但其临床后果并不一致。位于1p32.3的CDKN2C已在骨髓瘤细胞系中被确定为该缺失的潜在靶点。我们测试了1p缺失的临床影响，并使用高分辨率技术来确定CDKN2C在原发性患者材料中的作用。
我们使用荧光原位杂交（FISH）技术分析了515例意义未明的单克隆丙种球蛋白病（MGUS）、冒烟型多发性骨髓瘤（SMM）和新诊断的多发性骨髓瘤病例，以检测CDKN2C的缺失情况。在78例骨髓瘤病例中，我们进行了Affymetrix单核苷酸多态性图谱分析和U133 Plus 2.0表达芯片分析。此外，我们还进行了突变、甲基化和蛋白质印迹分析。
通过FISH，我们在66例MGUS中的3例（4.5%）、39例SMM中的4例（10.3%）以及369例多发性骨髓瘤病例中的55例（15%）中发现了1p32.3（CDKN2C）缺失。我们检查了CDKN2C拷贝数变化对总生存期（OS）的影响，发现CDKN2C半合子或纯合子缺失的病例与该区域完整的病例相比，OS更差（22个月对38个月；P = 0.003）。通过基因图谱分析，我们在1p32.3发现了三个包含CDKN2C的纯合子缺失，所有这些缺失均缺乏CDKN2C的表达。根据基于表达的增殖指数定义，CDKN2C纯合子缺失的病例是增殖性最强的骨髓瘤，这与其作为细胞周期蛋白依赖性激酶抑制剂的生物学功能一致。
我们的结果表明，CDKN2C缺失在骨髓瘤的进展和临床结局中具有重要意义。
