Liu P, Leong T, Quam L, Billadeau D, Kay N E, Greipp P, Kyle R A, Oken M M, Van Ness B
University of Minnesota, Minneapolis, USA.
Blood. 1996 Oct 1;88(7):2699-706.
Mutations of members of the ras family are among the most common oncogene mutations found in multiple myeloma (MM). We have examined the mutational status of the N- and K-ras genes at codons 12, 13, and 61 in 160 newly diagnosed MM patients enrolled on the Eastern Cooperative Oncology Group (ECOG) phase III clinical trial E9486. The total incidence of ras mutations was found to be 39% of the samples analyzed. Five patients showed evidence of more than one mutation. We obtained 22 marrow samples from patients at the time of disease progression or relapse, for whom a ras mutation was identified at diagnosis. In all cases, the ras mutation of the disease progression sample was identical to that found at diagnosis. In contrast, three of 25 patients who did not show any ras mutation at diagnosis acquired a ras mutation at the time of disease progression. No significant association was observed between any ras mutation and stage of disease, beta 2-microglobulin levels, labelling index, or protein type. The mean tumor burden and median survival for patients with mutations of N-ras was indistinguishable from patients with no ras mutations. However, patients with K-ras mutations had a significantly higher mean bone marrow tumor burden at diagnosis than patients with no ras mutations (57% v 36%, P < .02); and the median survival of patients with a K-ras mutation was significantly shorter (2.0 v 3.7 years, P < .02). To determine if the status of ras mutations could affect treatment response, we examined patient survival on the three treatment arms of E9486. Although the presence of a ras mutation in the multidrug treatment, VBMCP alone, showed a marginal significance, neither the VBMCP, nor the addition of interferon-alpha showed statistically significant survival differences between mutant and wildtype ras status. Interestingly, there appeared to be a statistically significant difference in survival of patients treated with VBMCP and alternating high doses of cyclophosphamide + prednisone. Patients with ras mutations had a median survival of 2.1 years; patients with wild-type ras had a median survival of 4.0 years (P < .01).
Ras家族成员的突变是多发性骨髓瘤（MM）中最常见的癌基因突变之一。我们检测了160例新诊断的MM患者N-和K-ras基因第12、13和61密码子的突变状态，这些患者参加了东部肿瘤协作组（ECOG）的III期临床试验E9486。在分析的样本中，ras突变的总发生率为39%。5例患者显示有不止一种突变的证据。我们在疾病进展或复发时从患者处获得了22份骨髓样本，这些患者在诊断时被鉴定出有ras突变。在所有病例中，疾病进展样本的ras突变与诊断时发现的相同。相比之下，25例在诊断时未显示任何ras突变的患者中有3例在疾病进展时获得了ras突变。在任何ras突变与疾病分期、β2-微球蛋白水平、标记指数或蛋白类型之间未观察到显著关联。N-ras突变患者的平均肿瘤负荷和中位生存期与无ras突变的患者无差异。然而，K-ras突变患者在诊断时的平均骨髓肿瘤负荷显著高于无ras突变的患者（57%对36%，P<.02）；K-ras突变患者的中位生存期显著缩短（2.0年对3.7年，P<.02）。为了确定ras突变状态是否会影响治疗反应，我们检查了E9486三个治疗组患者的生存期。尽管在多药治疗（单独使用VBMCP）中ras突变的存在显示出边缘显著性，但无论是VBMCP组，还是加用α-干扰素组，在突变型和野生型ras状态之间均未显示出统计学上显著的生存差异。有趣的是，在接受VBMCP和交替高剂量环磷酰胺+泼尼松治疗的患者生存期中似乎存在统计学上的显著差异。ras突变患者的中位生存期为2.1年；野生型ras患者的中位生存期为4.0年（P<.01）。
