Padua R A, Guinn B A, Al-Sabah A I, Smith M, Taylor C, Pettersson T, Ridge S, Carter G, White D, Oscier D, Chevret S, West R
Department of Hematology, University of Wales College of Medicine, Cardiff, UK.
Leukemia. 1998 Jun;12(6):887-92. doi: 10.1038/sj.leu.2401044.
The molecular mechanisms underlying the development and evolution of myelodysplastic syndrome (MDS) are largely unknown. The increasing number of blast cells in the bone marrow correlate with poor prognosis and risk of developing acute leukemia. Such progression is frequently associated with increasing chromosomal abnormalities and genetic mutations. A cohort of 75 MDS patients were investigated for RAS, FMS and p53 mutations, and these molecular findings were related to cytogenetics, clinical status, transformation to acute leukemia, prognostic scores and survival. A mutation incidence of 57% (43/75) was found, with 48% (36/75) RAS mutations, 12% (9/75) FMS mutations and 8% (4/50) p53 mutations. The mutation status for RAS and FMS was related to MDS subgroup, increasing with poor-risk disease. The highest incidence was in the chronic myelomonocytic leukemia (CMML) subgroup. The most frequent RAS mutations were of codon 12 and a predominance of FMS codon 969 mutations was observed. A statistically significant increased frequency of transformation to AML was observed in MDS patients harboring RAS or FMS mutations (P < 0.02). Patients with oncogene mutations had a significantly poorer survival compared with those without mutations at 2 years and at the end of the period of follow-up (P < 0.02). Multivariate analysis including mutation, age, gender, diagnosis (FAB), cytogenetics and International score shows that the International score and mutation and age is the best predictive model of a poor outcome, (P < 0.0001). When the analysis was undertaken without the International score, mutation and gender was the best predictor of poor survival (P = 0.005). This study shows that oncogene mutation, indicative of genetic instability, is associated with disease progression and poor survival in MDS.
骨髓增生异常综合征（MDS）发生和演变的分子机制在很大程度上尚不清楚。骨髓中原始细胞数量的增加与预后不良及发展为急性白血病的风险相关。这种进展常与染色体异常和基因突变的增加有关。对75例MDS患者进行了RAS、FMS和p53基因突变检测，并将这些分子学发现与细胞遗传学、临床状态、向急性白血病的转化、预后评分和生存率相关联。发现突变发生率为57%（43/75），其中RAS突变占48%（36/75），FMS突变占12%（9/75），p53突变占8%（4/50）。RAS和FMS的突变状态与MDS亚组相关，随着疾病风险增加而升高。最高发生率出现在慢性粒单核细胞白血病（CMML）亚组中。最常见的RAS突变是密码子12突变，且观察到FMS密码子969突变占优势。在携带RAS或FMS突变的MDS患者中，观察到转化为急性髓系白血病（AML）的频率有统计学意义的增加（P < 0.02）。与无基因突变的患者相比，有癌基因突变的患者在2年及随访期末的生存率明显更差（P < 0.02）。包括突变、年龄、性别、诊断（FAB）、细胞遗传学和国际评分的多变量分析表明，国际评分、突变和年龄是预后不良的最佳预测模型（P < 0.0001）。当不考虑国际评分进行分析时，突变和性别是生存不良的最佳预测指标（P = 0.005）。本研究表明，指示遗传不稳定性的癌基因突变与MDS的疾病进展和不良生存相关。
