结直肠癌中TP53突变的功能类别：一项国际合作研究的结果

Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study.

作者信息

Iacopetta B, Russo A, Bazan V, Dardanoni G, Gebbia N, Soussi T, Kerr D, Elsaleh H, Soong R, Kandioler D, Janschek E, Kappel S, Lung M, Leung C-S S, Ko J M, Yuen S, Ho J, Leung S Y, Crapez E, Duffour J, Ychou M, Leahy D T, O'Donoghue D P, Agnese V, Cascio S, Di Fede G, Chieco-Bianchi L, Bertorelle R, Belluco C, Giaretti W, Castagnola P, Ricevuto E, Ficorella C, Bosari S, Arizzi C D, Miyaki M, Onda M, Kampman E, Diergaarde B, Royds J, Lothe R A, Diep C B, Meling G I, Ostrowski J, Trzeciak L, Guzinska-Ustymowicz K, Zalewski B, Capellá G M, Moreno V, Peinado M A, Lönnroth C, Lundholm K, Sun X F, Jansson A, Bouzourene H, Hsieh L-L, Tang R, Smith D R, Allen-Mersh T G, Khan Z A J, Shorthouse A J, Silverman M L, Kato S, Ishioka C

机构信息

Università di Palermo, Department of Oncology, Palermo, Italy.

出版信息

Ann Oncol. 2006 May;17(5):842-7. doi: 10.1093/annonc/mdl035. Epub 2006 Mar 8.

DOI:10.1093/annonc/mdl035

PMID:16524972

Abstract

BACKGROUND

Loss of TP53 function through gene mutation is a critical event in the development and progression of many tumour types including colorectal cancer (CRC). In vitro studies have found considerable heterogeneity amongst different TP53 mutants in terms of their transactivating abilities. The aim of this work was to evaluate whether TP53 mutations classified as functionally inactive (< or=20% of wildtype transactivation ability) had different prognostic and predictive values in CRC compared with mutations that retained significant activity.

MATERIALS AND METHODS

TP53 mutations within a large, international database of CRC (n = 3583) were classified according to functional status for transactivation.

RESULTS

Inactive TP53 mutations were found in 29% of all CRCs and were more frequent in rectal (32%) than proximal colon (22%) tumours (P < 0.001). Higher frequencies of inactive TP53 mutations were also seen in advanced stage tumours (P = 0.0003) and in tumours with the poor prognostic features of vascular (P = 0.006) and lymphatic invasion (P = 0.002). Inactive TP53 mutations were associated with significantly worse outcome only in patients with Dukes' stage D tumours (RR = 1.71, 95%CI 1.25-2.33, P < 0.001). Patients with Dukes' C stage tumours appeared to gain a survival benefit from 5-fluorouracil-based chemotherapy regardless of TP53 functional status for transactivation ability.

CONCLUSIONS

Mutations that inactivate the transactivational ability of TP53 are more frequent in advanced CRC and are associated with worse prognosis in this stage of disease.

摘要

背景

通过基因突变导致TP53功能丧失是包括结直肠癌（CRC）在内的多种肿瘤类型发生和发展的关键事件。体外研究发现，不同的TP53突变体在反式激活能力方面存在相当大的异质性。本研究的目的是评估在CRC中，被分类为功能失活（野生型反式激活能力的≤20%）的TP53突变与保留显著活性的突变相比，是否具有不同的预后和预测价值。

材料与方法

在一个大型国际CRC数据库（n = 3583）中，根据反式激活的功能状态对TP53突变进行分类。

结果

在所有CRC中，29%发现有失活的TP53突变，在直肠肿瘤（32%）中比近端结肠肿瘤（22%）更常见（P < 0.001）。在晚期肿瘤（P = 0.0003）以及具有血管侵犯（P = 0.006）和淋巴侵犯（P = 0.002）等不良预后特征的肿瘤中，失活的TP53突变频率也更高。仅在Dukes D期肿瘤患者中，失活的TP53突变与显著更差的预后相关（RR = 1.71，95%CI 1.25 - 2.33，P < 0.001）。无论TP53反式激活能力的功能状态如何，Dukes C期肿瘤患者似乎都能从基于5-氟尿嘧啶的化疗中获得生存益处。