Single nucleotide variation in the TP53 3′ untranslated region in diffuse large B-cell lymphoma treated with rituximab-CHOP: a report from the International DLBCL Rituximab-CHOP Consortium Program
Single nucleotide variation in the TP53 3′ untranslated region in diffuse large B-cell lymphoma treated with rituximab-CHOP: a report from the International DLBCL Rituximab-CHOP Consortium Program
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DOI：
10.1182/blood-2012-12-471722
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发表时间：
2013-05-30
期刊：
影响因子：
20.3
通讯作者：
Young, Ken H.
中科院分区：
文献类型：
--
作者：
Li, Yong;Gordon, Michael W.;Young, Ken H.
我们在244例弥漫性大B细胞淋巴瘤（DLBCL）患者的肿瘤标本中鉴定了TP 53 3 3'非翻译区（3' UTR）的多个单核苷酸变异（SNV）。携带野生型TP 53编码序列（CDS）和1个或多个3 'UTR SNV的患者比携带野生型CDS和参考3' UTR的患者具有更好的5年生存率，但总生存率（OS）没有统计学显著差异。相反，3 'UTR变异预测具有突变型TP 53 CDS的患者的OS较差。然后，我们对另外247名DLBCL患者的TP 53 3 'UTR进行测序作为验证集。总共，我们确定了187个新的SNV; 36个至少发生了两次。大多数新鉴定的3 'UTR SNV位于与预测或实验已知靶向TP 53的microRNA（miRNA）的种子序列互补的位点。三个SNV破坏了miR-125 b和TP 53 3 'UTR之间的种子匹配，从而阻碍了该miRNA对p53的抑制。此外，位于TP 53多聚腺苷酸化信号中的种系SNV（rs78378222）导致p53信使RNA和蛋白质水平的下调以及细胞凋亡的减少。该研究首次证明了TP 53 3 'UTR在癌症中的预后价值。
We identified multiple single nucleotide variants (SNVs) in the TP53 3' untranslated region (3'UTR) in tumor specimens from 244 patients with diffuse large B-cell lymphoma (DLBCL). Patients carrying a wild-type TP53 coding sequence (CDS) and 1 or more 3'UTR SNVs had a better 5-year survival rate than patients carrying a wild-type CDS and the reference 3'UTR, yet there is no statistically significance difference in overall survival (OS). In contrast, 3'UTR variation predicted poorer OS for patients with a mutant TP53 CDS. We then sequenced TP53 3'UTR in 247 additional DLBCL patients as a validation set. Altogether, we identified 187 novel SNVs; 36 occurred at least twice. Most of the newly identified 3'UTR SNVs were located at sites that are complementary to seed sequences of microRNAs (miRNAs) that are predicted or experimentally known to target TP53. Three SNVs disrupt the seed match between miR-125b and the TP53 3'UTR, thereby impeding suppression of p53 by this miRNA. In addition, a germline SNV (rs78378222) located in the TP53 polyadenylation signal resulted in downregulation of both p53 messenger RNA and protein levels and reduction of cellular apoptosis. This study is the first to demonstrate the prognostic value of the TP53 3'UTR in cancer.