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Frequent alteration of p16 INK4a /p14 ARF and p53 pathways in the round cell component of myxoid/round cell liposarcoma: p53 gene alterations and reduced p14 ARF expression both correlate with poor prognosis
Author(s) -
Oda Yoshinao,
Yamamoto Hidetaka,
Takahira Tomonari,
Kobayashi Chikashi,
Kawaguchi Kenichi,
Tateishi Naomi,
Nozuka Yoko,
Tamiya Sadafumi,
Tanaka Kazuhiro,
Matsuda Shuichi,
Yokoyama Ryohei,
Iwamoto Yukihide,
Tsuneyoshi Masazumi
Publication year - 2005
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.1848
Subject(s) - biology , p14arf , cancer research , immunohistochemistry , gene , gene expression , microbiology and biotechnology , point mutation , carcinogenesis , gene mutation , tumor suppressor gene , mutation , pathology , genetics , medicine , immunology
In myxoid/round cell liposarcoma (MLS/RCLS), the presence of a round cell (RC) component has been reported to correlate with a worse prognosis for the patients. However, little is known about the molecular genetic differences between conventional myxoid (MX) components and RC components in this tumour. The aim of this study was to investigate the possible implications of molecular alterations of G 1 to S‐phase check‐point genes, especially in the RC component. We evaluated the immunohistochemical expression of p53, MDM2, p14 and p16 protein and assessed proliferative activities using MIB‐1 in 29 RC components and 81 MX components from 90 cases. Mutation of the p53 gene, amplification of the MDM2 gene, homozygous deletion, methylation status and mutation of the p16 INK4a /p14 ARF genes were also investigated, using concordant paraffin‐embedded and frozen material. The data were analysed together with clinicopathological factors to assess their prognostic implications in MLS/RCLS. Immunohistochemically, the over‐expression of p53 protein ( p = 0.01366) and the reduced expression of p14 ( p < 0.0001) and p16 ( p < 0.0001) proteins were significantly more frequently observed in RC components than in MX components. Reduced expression of p14 protein correlated significantly with hypermethylation of the p14 ARF gene promoter ( p = 0.0176) and over‐expression of p53 protein ( p = 0.00837). By univariate analysis, reduced expression of p14 and p53 missense mutation were found to reduce the rate of survival significantly ( p < 0.05). Multivariate analysis, including clinicopathological factors, revealed that tumour site ( p = 0.0251), the presence of an RC component ( p = 0.0113), high MIB‐1 labelling index ( p = 0.0005) and p53 missense mutation ( p = 0.0036) were adverse prognostic factors. In MLS/RCLS, reduction of p14 protein expression and p53 mutation were related to poor prognosis. Accordingly, the p14 ARF /p53 pathway may contribute to the presence of an RC component and malignant progression in this tumour. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.