文章：

TP53 R72P多态性与骨髓增生异常综合征疾病结局及TP53突变的关系

The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes

原文发布日期：2015-03-13

DOI: 10.1038/bcj.2015.11

类型: Original Article

开放获取: 是

英文摘要：

Nonsynonymous TP53 exon 4 single-nucleotide polymorphism (SNP), R72P, is linked to cancer and mutagen susceptibility. R72P associations with specific cancer risk, particularly hematological malignancies, have been conflicting. Myelodysplastic syndrome (MDS) with chromosome 5q deletion is characterized by erythroid hypoplasia arising from lineage-specific p53 accumulation resulting from ribosomal insufficiency. We hypothesized that apoptotically diminished R72P C-allele may influence predisposition to del(5q) MDS. Bone marrow and blood DNA was sequenced from 705 MDS cases (333 del(5q), 372 non-del(5q)) and 157 controls. Genotype distribution did not significantly differ between del(5q) cases (12.6% CC, 38.1% CG, 49.2% GG), non-del(5q) cases (9.7% CC, 44.6% CG, 45.7% GG) and controls (7.6% CC, 37.6% CG, 54.8% GG) (P=0.13). Allele frequency did not differ between non-del(5q) and del(5q) cases (P=0.91) but trended towards increased C-allele frequency comparing non-del(5q) (P=0.08) and del(5q) (P=0.10) cases with controls. Median lenalidomide response duration increased proportionate to C-allele dosage in del(5q) patients (2.2 (CC), 1.3 (CG) and 0.89 years (GG)). Furthermore, C-allele homozygosity in del(5q) was associated with prolonged overall and progression-free survival and non-terminal interstitial deletions that excluded 5q34, whereas G-allele homozygozity was associated with inferior outcome and terminal deletions involving 5q34 (P=0.05). These findings comprise the largest MDS R72P SNP analysis.

摘要翻译： 

TP53基因第4外显子的非同义单核苷酸多态性（SNP）R72P与癌症和致突变物易感性相关。R72P与特定癌症风险（尤其是血液系统恶性肿瘤）的关联性研究存在争议。伴随5号染色体长臂缺失（5q）的骨髓增生异常综合征（MDS）以红系造血功能不全为特征，其根源在于核糖体功能不足引发的谱系特异性p53蛋白积聚。我们假设促凋亡作用减弱的R72P C等位基因可能影响del(5q) MDS的易感性。通过对705例MDS患者（333例del(5q)，372例非del(5q)）和157例对照者的骨髓及血液DNA进行测序，发现基因型分布在del(5q)患者组（CC 12.6%、CG 38.1%、GG 49.2%）、非del(5q)患者组（CC 9.7%、CG 44.6%、GG 45.7%）与对照组（CC 7.6%、CG 37.6%、GG 54.8%）间无显著差异（P=0.13）。等位基因频率在非del(5q)与del(5q)组间无差异（P=0.91），但与非del(5q)组（P=0.08）和del(5q)组（P=0.10）相比，对照组C等位基因频率呈升高趋势。在del(5q)患者中，来那度胺治疗中位缓解持续时间随C等位基因剂量增加而延长（CC型2.2年、CG型1.3年、GG型0.89年）。此外，del(5q)患者中C等位基因纯合子与更长的总生存期和无进展生存期相关，且多表现为不涉及5q34的中间缺失；而G等位基因纯合子则预后较差，多伴涉及5q34的末端缺失（P=0.05）。本研究构成了目前规模最大的MDS R72P多态性分析。

原文链接：

The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes