p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies.
p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies.
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DOI：
10.1182/blood.v84.9.3148.bloodjournal8493148
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发表时间：
1994
期刊：
影响因子：
20.3
通讯作者：
E. Wattel;C. Preudhomme;B. Hecquet;M. Vanrumbeke;B. Quesnel;I. Dervite;P. Morel;P. Fenaux
中科院分区：
文献类型：
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作者：
E. Wattel;C. Preudhomme;B. Hecquet;M. Vanrumbeke;B. Quesnel;I. Dervite;P. Morel;P. Fenaux
我们分析了p53突变对急性髓性白血病（AML）、骨髓增生异常综合征（MDS）和慢性淋巴细胞白血病（CLL）患者化疗反应和生存的预后价值。通过对P53基因外显子4 ~ 10的单链构象多态性（SSCP）分析检测突变，并通过直接测序证实突变。107例AML患者中有16例（15%），182例MDS患者中有20例（11%），81例CLL患者中有9例（11%）发现p53突变。在AML中，接受强化化疗的9例突变患者中有3例（33%）和81例非突变患者中有66例（81%）达到完全缓解（CR） （P = 0.005），而接受低剂量Ara C治疗的5例突变患者和6例非突变患者中有3例（P = 0.06）没有达到CR或部分缓解（PR） （P = 0.06）。突变病例中位精算生存期为2.5个月，非突变病例中位精算生存期为15个月（P < 10(-5)）。在接受化疗（强化化疗或低剂量Ara C）的MDS患者中，13例突变患者中有1例（8%）达到CR或PR， 38例非突变患者中有23例（60%）达到CR或PR (P = 0.004)，中位精算生存期分别为2.5个月和13.5个月（P < 10(-5)）。在所有MDS病例（治疗和未治疗）中，突变病例和非突变病例之间的生存差异也非常显著。在CLL中，8例突变患者中有1例（12.5%）接受化疗（氯苯和/或CHOP和/或氟达拉滨），而36例非突变患者中有29例（80%）有反应（P = 0.02）。在所有CLL病例中，p53分析中突变病例的生存期（中位7个月）明显短于非突变病例（中位未达到）（P < 10(-5)）。在45例AML、MDS和CLL突变病例中，有35例的细胞遗传学分析或SSCP和序列结果显示未突变的P53等位基因缺失。我们的研究结果表明，p53突变是AML、MDS和CLL患者化疗反应和生存的一个强有力的预后指标。在这些疾病中，p53突变通常与非突变p53等位基因的缺失有关，即肿瘤细胞中缺乏正常p53，这表明p53突变可以通过干扰肿瘤细胞中正常的凋亡途径，至少部分地诱导耐药性。
We analyzed the prognostic value of p53 mutations for response to chemotherapy and survival in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic lymphocytic leukemia (CLL). Mutations were detected by single-stranded conformation polymorphism (SSCP) analysis of exons 4 to 10 of the P53 gene, and confirmed by direct sequencing. A p53 mutation was found in 16 of 107 (15%) AML, 20 of 182 (11%) MDS, and 9 of 81 (11%) CLL tested. In AML, three of nine (33%) mutated cases and 66 of 81 (81%) nonmutated cases treated with intensive chemotherapy achieved complete remission (CR) (P = .005) and none of five mutated cases and three of six nonmutated cases treated by low-dose Ara C achieved CR or partial remission (PR) (P = .06). Median actuarial survival was 2.5 months in mutated cases, and 15 months in nonmutated cases (P < 10(-5)). In the MDS patients who received chemotherapy (intensive chemotherapy or low-dose Ara C), 1 of 13 (8%) mutated cases and 23 of 38 (60%) nonmutated cases achieved CR or PR (P = .004), and median actuarial survival was 2.5 and 13.5 months, respectively (P < 10(-5)). In all MDS cases (treated and untreated), the survival difference between mutated cases and nonmutated cases was also highly significant. In CLL, 1 of 8 (12.5%) mutated cases treated by chemotherapy (chlorambucil and/or CHOP and/or fludarabine) responded, as compared with 29 of 36 (80%) nonmutated cases (P = .02). In all CLL cases, survival from p53 analysis was significantly shorter in mutated cases (median 7 months) than in nonmutated cases (median not reached) (P < 10(-5)). In 35 of the 45 mutated cases of AML, MDS, and CLL, cytogenetic analysis or SSCP and sequence findings showed loss of the nonmutated P53 allele. Our findings show that p53 mutations are a strong prognostic indicator of response to chemotherapy and survival in AML, MDS, and CLL. The usual association of p53 mutations to loss of the nonmutated P53 allele, in those disorders, ie, to absence of normal p53 in tumor cells, suggests that p53 mutations could induce drug resistance, at least in part, by interfering with normal apoptotic pathways in tumor cells.