Geographical Variations in TP53 Mutational Spectrum in Ovarian Carcinomas

Abstract

SummaryThe TP53 gene mutational spectrum in human tumours shows variations related to tissue of origin, carcinogen exposure or molecular background. We have compared TP53 mutations in ovarian carcinomas from different geographical regions; this study was based on data extracted and verified from the IARC database (R10, 2005), and on our results from 127 carcinomas. In total 873 mutations were evaluated. Tumours from Japan and Korea had a higher frequency of exon 7 mutations (38% vs 25%, p = 0.011) and lower frequency of exon 8 mutations (11% vs 29%, p = 0.0003) than those from Western countries; they were particularly different from Norwegian tumours which showed the lowest proportion of exon 7 (19%, p = 0.001) and highest proportion of exon 8 (37%, p < 0.0001) mutations. There were also differences in the profile of TP53 hotspots. The third hotspot in tumours from Poland was amino acid (AA) 176 (8.2% of substitutions vs 1.7% in other countries, p < 0.001), while in tumours from the UK it was AA 220 (8.9% vs 2.3%, p < 0.001). Codon 273 was the only apparent hotspot in the Norwegian tumours, while it was rarely mutated in Polish and Asian tumours. In contrast to other data tumours from Norway presented with 273 HIS codon (82% of mutations at AA 273, p = 0.002), while tumours from the UK shared the 273 CYS codon (80%, p < 0.001). Further analysis of TP53 gene mutations in ovarian cancer by geography could provide greater insights.

Analysis of DNA Copy Number Alterations in Ovarian Serous Tumors Identifies New Molecular Genetic Changes in Low-Grade and High-Grade Carcinomas

“…In contrast, HG serous carcinomas often present in advanced stages (stages III-IV) and rarely harbor mutations in KRAS/BRAF/ERBB2 . HG serous carcinomas grow rapidly and are highly aggressive and over than 75% of these tumors harbor TP53 mutations (14–18). …”

Nuclear survivin expression is a positive prognostic factor in taxane-platinum-treated ovarian cancer patients

“…This has been shown in ovarian (high nuclear survivin in the TP53 mutant tumours), pancreatic, breast and gastric carcinomas [54-57]. We have failed to observe this correlation in our large group of 435 tumours; however, we evaluated TP53 accumulation only and it occurs with a frequency approximately 30% lower than TP53 mutations, thus the rate of TP53 dysfunctional tumours in our group may be much higher [33]. …”

“…Biotinylated secondary goat anti-rabbit IgG (for survivin) (1/1500) and anti-mouse IgG (for TP53) (1/1500), peroxidase-conjugated streptavidin (1/500) (all from Immunotech, Marseille, France), and DAB were used as a detection system. As a positive control for TP53 accumulation, we used a tumour with a defined TP53 gene missense mutation [33]. Normal rabbit IgG or normal mouse IgG of the same subclasses and at the concentrations of the relevant primary antibodies served as negative controls.…”

The significance of c.690G>T polymorphism (rs34529039) and expression of the CEBPA gene in ovarian cancer outcome

“…Thus, abnormalities within TP53 (which are common in ovarian cancer [36]) may disturb the normal physiological function of CEBPA and change the way it affects ovarian cancer development and prognosis. As a confirmation of this hypothesis, Seipel et al [37] have recently shown that restoring the TP53 function after treatment with cytotoxic chemotherapy compounds and TP53 restoring non-genotoxic agents induced CEBPA gene expression, myeloid differentiation, and cell-cycle arrest in AML cells.…”