FGFR3 and Tp53 mutations in T1G3 transitional bladder carcinomas:: Independent distribution and lack of association with prognosis
FGFR3 and Tp53 mutations in T1G3 transitional bladder carcinomas:: Independent distribution and lack of association with prognosis
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DOI：
10.1158/1078-0432.ccr-05-0122
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发表时间：
2005-08-01
影响因子：
11.5
通讯作者：
Real, FX
中科院分区：
文献类型：
--
作者：
Hernández, S;López-Knowles, E;Real, FX
FGFR 3和Tp 53突变被认为是膀胱移行细胞癌发病机制中的两种替代途径。FGFR 3突变与低级别肿瘤和良好的预后相关。TP 53改变与晚期肿瘤相关，并且可能与不良预后相关。我们在这里集中在T1 G3浅表肿瘤的亚组，因为他们是一个主要的临床挑战。患者（n = 119）是从1,356例病例的前瞻性研究中确定的。使用PCR和直接测序分析FGFR 3（外显子7、10和15）和Tp 53（外显子4-9）中的突变。所有病例均随访复发和死亡。采用Kaplan-Meier曲线和多变量考克斯回归分析生存率。在20例（16.8%）肿瘤中检测到FGFR 3突变;在78例（65.5%）肿瘤中发现100个Tp 53突变。19例（16%）肿瘤中存在Tp 53的多重改变。失活突变存在于58%的肿瘤中。组合突变分布（FGFR 3/Tp 53）为：wt/wt（34.5%）、mut/wt（7.6%）、wt/mut（48.7%）和mut/mut（9.2%），表明任一突变的存在不依赖于另一突变（P值= 0.767）。FGFR 3和Tp 53突变与患者的临床病理学特征无关，单独或联合使用不能预测复发或生存。以wt/wt组为参照，突变相关的癌症特异性死亡风险分别为：mut/wt 1.42（0.15-13.75），wt/mut 0.67（0.19-2.31），mut/mut 1.62（0.27-9.59）。这些分子特征支持了T1 G3肿瘤处于膀胱癌发生和进展的两种主要分子途径的交叉点的观点。
FGFR3 and Tp53 mutations have been proposed as defining two alternative pathways in the pathogenesis of transitional bladder cancer. FGFR3 mutations are associated with low-grade tumors and a favorable prognosis. Tp53 alterations are associated with advanced tumors and, possibly, with a poor prognosis. We focus here on the subgroup of T1G3 superficial tumors because they are a major clinical challenge. Patients (n = 119) were identified from a prospective study of 1,356 cases. Mutations in FGFR3 (exons 7, 10, and 15) and Tp53 (exons 4-9) were analyzed using PCR and direct sequencing. All cases were followed for recurrence and death. Survival was analyzed using Kaplan-Meier curves and multivariable Cox regression. FGFR3 mutations were detected in 20 (16.8%) tumors; 100 mutations in Tp53 were found in tumors from 78 (65.5%) cases. Multiple alterations in Tp53 were present in 19 tumors (16%). Inactivating mutations were present in 58% of tumors. The combined mutation distribution (FGFR3/Tp53) was: wt/wt (34.5%), mut/wt (7.6%), wt/mut (48.7%), and mut/mut (9.2%), indicating that the presence of either mutation did not depend on the other (P value = 0.767). FGFR3 and Tp53 mutations were not associated with clinicopathologic characteristics of patients and did not predict, alone or in combination, recurrence or survival. Taking the risk of the wt/wt group as reference, the mutation-associated risks of cancer-specific mortality were: mut/wt 1.42 (0.15-13.75), wt/mut 0.67 (0.19-2.31), mut/mut 1.62 (0.27-9.59). These molecular features support the notion that T1G3 tumors are at the crossroads of the two main molecular pathways proposed for bladder cancer development and progression.