Christiansen D H, Andersen M K, Pedersen-Bjergaard J
Section of Hematology and Oncology, Cytogenetic Laboratory, and Department of Clinical Genetics, The Juliane Marie Center, Rigshospitalet, Copenhagen, Denmark.
J Clin Oncol. 2001 Mar 1;19(5):1405-13. doi: 10.1200/JCO.2001.19.5.1405.
To study mutations and loss of heterozygosity (LOH) of p53 in therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML).
Fifty-two unselected patients with t-MDS and 25 patients with t-AML were studied by polymerase chain reaction (PCR)-single-strand conformational polymorphism (SSCP) at the DNA level and by reverse transcriptase (RT)-PCR-SSCP at the mRNA level, and cases with aberrant SSCP patterns were sequenced.
Somatically acquired mutations of p53 were observed in 21 of 77 cases of t-MDS or t-AML, and 19 of these 21 patients had received alkylating agents. Single-base substitutions at A:T pairs were more common in t-MDS and t-AML, whereas single-base substitutions at G:C pairs are most common in MDS and AML de novo and in solid tumors. Six patients demonstrated a cytogenetic loss of 17p13, and these six and an additional nine patients with p53 mutations demonstrated LOH of p53 at the DNA or mRNA level. This suggests a cytogenetic loss of the normal p53 allele in these nine cases combined with duplication of the homologous chromosome 17 carrying the mutated p53 allele. Mutations of p53 were significantly associated with deletion or loss of 5q (P <.0001) and a complex karyotype (P =.0001), but surprisingly were not associated with deletion or loss of 7q (P =.73), and were infrequent in patients with balanced chromosome translocations (P =.03). Mutations of p53 were more common in older patients (P =.036) and were associated with an extremely poor prognosis (P =.014), apparently restricted to the 15 cases with LOH of p53 ( P =.046).
Mutations with loss of function of p53 are significantly associated with deletion or loss of 5q in t-MDS and t-AML after previous treatment with alkylating agents and are associated with genetic instability.
研究治疗相关骨髓增生异常综合征（t-MDS）和急性髓系白血病（t-AML）中p53基因的突变及杂合性缺失（LOH）情况。
对52例未经挑选的t-MDS患者和25例t-AML患者进行研究，在DNA水平采用聚合酶链反应（PCR）-单链构象多态性（SSCP）技术，在mRNA水平采用逆转录酶（RT）-PCR-SSCP技术，对SSCP图谱异常的病例进行测序。
在77例t-MDS或t-AML患者中，有21例观察到p53基因的体细胞获得性突变，这21例患者中有19例曾接受烷化剂治疗。在t-MDS和t-AML中，A:T碱基对的单碱基替换更为常见，而在原发性MDS和AML以及实体瘤中，G:C碱基对的单碱基替换最为常见。6例患者出现17p13的细胞遗传学缺失，这6例以及另外9例p53基因突变患者在DNA或mRNA水平表现出p53基因的杂合性缺失。这表明在这9例病例中正常p53等位基因发生细胞遗传学缺失，同时携带突变p53等位基因的同源染色体17发生复制。p53基因突变与5q缺失或丢失（P<.0001）以及复杂核型（P=.0001）显著相关，但令人惊讶的是与7q缺失或丢失无关（P=.73），在染色体平衡易位患者中也很少见（P=.03）。p53基因突变在老年患者中更常见（P=.036），且与预后极差相关（P=.014），显然仅限于15例p53基因杂合性缺失的患者（P=.046）。
p53功能缺失性突变与既往接受烷化剂治疗后的t-MDS和t-AML中的5q缺失或丢失显著相关，并与基因不稳定有关。
