TP53 in gastric cancer: Mutations in the L3 loop and LSH motif DNA‐binding domains of TP53 predict poor outcome

Abstract

The aim of this study was to clarify whether specific p53 mutations may have biological relevance in terms of disease relapse or death in gastric carcinomas (GC). Resected specimens from a consecutive series of 62 patients with GC undergoing potentially curative surgery were prospectively studied. The mutational status of exons 5-8 of the p53 gene was investigated in 62 cases using the PCR-SSCP and sequencing. Presence of microsatellite instability (MSI) was evaluated in 56 cases by analyzing loci highly sensitive of MSI. Twenty mutations of p53 were detected in 17 of the 62 cases analyzed (27%). Ten mutations (50%) occurred in highly conserved domains. According to the p53 specific functional domains: 4/20 mutations (20%) were in the L3 loop and 3/20 (15%) in LSH motif. Eight of the 56 GC resulted MSI-H, 5 (9%) MSI-L, and 43 (77%) MSI stable (MSS). None of the 8 (14%) MSI-H GC showed p53 mutations. p53 mutations were associated with intestinal histotype. Moreover, specific mutations in functional domain (L3 and LSH), together with advanced TNM stage, node involvement, depth of invasion, diffuse histotype, proved to be significantly related to quicker relapse and to shorter overall survival. Specific mutations in p53 functional domains, rather than any mutations in this gene, may be biologically more significant in terms of patients outcome, indicating that these mutations might have biological relevance to identify subgroups of patients at higher risk of relapse or death who might benefit from a more aggressive therapeutic approach. J. Cell. Physiol. 200: 476-485, 2004. Despite a decreasing trend in incidence and mortality in most developed countries, gastric carcinomas (GC) was still recently estimated to represent the fourth most common cancer in the world and the second leading cause of cancer death . Moreover, this neoplasia still leads to an unfavorable prognosis, with a relative 5-year survival rate varying from 5% to 15% in the Western world. In adenocarcinomas, which represent over 95% of GCs, distinct morphological, histological, and biomolecular features have been observed, with the result that a great many classification systems for GC have been devised in the attempt to identify patient subgroups with different prognostic features. The authorship is shared equally by Manuela Migliavacca and Laura Ottini, and their names are listed in alphabetical order.

Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study

“…Similarly, mutations affecting the Loop-L3 and LSH motifs have been reported to predict a poor outcome, with doxorubicin resistance, in breast and ovarian tumors. [17][18][19][20][21][22]55 Colorectal cancers with TP53 mutations in conserved regions or affecting Loop-L3 are poorly differentiated and more aggressive than those with other mutations. 18,21 In head and neck squamous cell carcinoma, TP53 mutations in direct DNA contact areas resulted in accelerated tumor progression and reduced therapeutic responsiveness.…”

“…56,57 Mutations in the Loop-L2 motif do not appear to be prognostically important in DLBCL; however, this observation has not been reported in other human cancers. [17][18][19][20][21][22] This finding may not be representative of DLBCL because of the low number cases with the Loop-L2 mutations in this series. Therefore, further study is needed to evaluate the role and the predictive value of Loop-L2 mutations in DLBCL.…”

“…A poor prognosis was found to be associated with specific mutations in the DNA-binding domain of TP53 in various cancers, [17][18][19][20][21][22] and recently in DLBCL. 23 In vitro studies have also shown that missense mutations in TP53 have different functional consequences and exhibit great variability in transactivation activity, with mutations in the DNAbinding domain usually resulting in loss of specific transactivation activity.…”

Loss of RUNX3 Expression Significantly Affects the Clinical Outcome of Gastric Cancer Patients and Its Restoration Causes Drastic Suppression of Tumor Growth and Metastasis

“…Specifically, they confer a tremendous survival and growth advantage to gastric cancer cells. Previous studies indicated the role of several tumor suppressor genes in gastric cancer development and progression, including the E-cadherin/ CDH1 gene, TP53, and p16 (3,6,(8)(9)(10)(11) and, most recently, runtrelated (RUNX) genes (12).…”

Reduction of TIP30 correlates with poor prognosis of gastric cancer patients and its restoration drastically inhibits tumor growth and metastasis

“…Previous studies indicated the role of several tumor suppressor genes in gastric cancer development and progression, including the E-cadherin/CDH1 gene, TP53 and p16. 3,6,[8][9][10][11] Although gastric cancer may harbor multiple molecular alterations, they may not be specific for gastric cancers.5-10 Thus, the identified abnormalities may represent only the pathogenesis of gastric cancer, and they have not been identified as a specific sequence of changes leading to gastric carcinoma.11,12 Therefore, the role of genetic changes such as altered tumor suppressor genes in gastric cancer development and progression remains unclear.Cancer gene therapies can be broadly classified into 2 groups: (i) those that modify the host responses to a tumor; or (ii) those that induce direct antitumor action by introducing genetic material that directly affects the cancer cell and halts its growth.13 Replacement therapies involving tumor suppressor genes are the prototypes of gene therapies with direct antitumor action. Although TIP30 has been implicated as a tumor suppressor in several tumors, 12,14,15 the effect of its alterations on patient outcome and the use of this pathway for targeted gastric cancer therapy have not been examined.…”