Functional analysis of p53 gene and the prognostic impact of dominant‐negative p53 mutation in endometrial cancer

Abstract

In addition to the loss of function, mutant p53 can possess a dominant-negative effect on wild-type p53 and may also exert gain-offunction activity. It is not clear whether the functional status of p53 mutation contributes to differences in outcome in endometrial cancer. We collected a total of 92 RNA samples of high quality from endometrial cancer tissues, and the samples were subjected to yeast functional assay and sequencing for p53 mutations. The detected mutant p53 genes were further investigated for their dominant-negative activity using a yeast-based transdominance assay. p53 mutation was found in 24 out of 92 (26.1%) tumors, of which 10 exhibited no dominant-negative activity (recessive mutation) and 14 showed dominant-negative activity. Dominant-negative p53 mutation was related to advanced stages (p 5 0.01), nonendometrioid type tumors (p 5 0.01) and grade 3 tumors (p 5 0.04). The patients with dominant-negative mutation had significantly shorter survival than patients with no mutation (p < 0.0001) and those with a recessive mutation (p 5 0.01) in the p53 gene. No difference in survival was found between the patients with tumors harboring a recessive p53 mutation and those with tumors harboring a wild-type p53. Multivariate analysis revealed that dominantnegative p53 mutation (p 5 0.019), FIGO stage (p 5 0.0037) and histologic subtype (p 5 0.014) were independently related to patient survival. Dominant-negative p53 mutation was the most important prognostic factor for stage III/IV endometrial cancer (p 5 0.0023). In conclusion, dominant-negative p53 mutation is often found in advanced stages and aggressive histologic subtypes of endometrial cancer and it is a strong predictor of survival of patients with advanced endometrial cancer. To elucidate further the role of p53 mutation in endometrial cancer, it is necessary to investigate gain-of-function activity involving dominant-negative p53 mutant proteins. ' 2005 Wiley-Liss, Inc.Key words: endometrial cancer; p53; mutation; dominant negative; survival; serous adenocarcinoma The p53 tumor suppressor gene is mutated in about 50% of all tumors, 1-3 and more than 19,000 different somatic mutations have been identified. 4 Mutation of the p53 gene plays a key role in the carcinogenesis and progression of many different malignancies, including endometrial cancer. p53 overexpression has been shown to predict patient survival in endometrial cancer. 5-7 p53 overexpression, as determined by immunohistochemistry (IHC), is a surrogate marker of missense mutation of p53 protein. Because MDM2 is a transcriptional target of p53, loss of p53 function reduces the production of MDM2. MDM2 degrades p53 protein through ubiquitination of the protein, and reduced MDM2 production will lead to an accumulation of p53 protein in the nucleus, which is detected as overexpression by IHC. 8 IHC is a convenient method for the investigation of p53 status. However, it can be affected by many factors, such as antibody used, antigen retrieval technique and subjectivity of criteria for p53 ...

p53 Mutation and Multiple Primary Oral Squamous Cell Carcinomas

“…We have found that oral SCC patients with DNp53 mutations have a significantly worse outcome than patients with recessive mutations, in terms of recurrence free survival [Hassan et al, 2008]. This has also been noted in other cancers (Marutani et al, 1999;Sakuragi et al, 2005). The overrepresentation of DN mutants, accounting for about 27% of all p53 mutations (6414 of all 23,544 in the IARC database R11), suggests an advantage for tumour development of the cancer cell harbouring a DN mutation.…”

p53 dominant-negative mutant R273H promotes invasion and migration of human endometrial cancer HHUA cells

“…In our previous study [12], we demonstrated a strong link between DN mutant TP53 and the progression of endometrial cancer. In the present work, we focused on the precise role of DN mutant TP53 R273H in the cell invasion and migration of the endometrial cancer cell HHUA, and showed for the first time that DN mutant TP53 R273H, a TP53 missense mutation commonly found in endometrial cancer, strongly induces the invasive and migratory activities of the endometrial cancer cell HHUA.…”

“…Taken together, our findings suggested that the invasive phenotype in HHUA endometrial cancer cells was mostly given by a balance between the transdominant canceling effect of R273H and wt p53 transcriptional activity rather than a gain-of-function effect induced solely by R273H mutant p53. This may, at least in part, afford a possible molecular basis by which DN mutant p53 promotes tumor progression in patients with the advanced stages and nonendometrioid subtype of endometrial cancer [12].…”

“…In our previous study, mutant TP53 was found in 24 out of 92 (26.1%) endometrial cancers, of which 14 cases showed dominant-negative activity that was associated with advanced stages, non-endometrioidtype tumors and grade 3 tumors. The presence of a DN mutant p53 was related to poor outcomes as the most important, independent prognostic factor for patients with stage III/IV endometrial cancer [12], suggesting that DN mutant TP53 may play an important role in the progression of endometrial cancer.…”

Death or survival – progesterone-dependent cell fate decisions in the human endometrial stroma

“…In addition to lower FOXO1 expression, the majority of oestrogen-related type I (endometrioid) endometrial cancers are characterised by loss or mutation of the tumour-suppressor gene PTEN, leading to enhanced activity of the PI3K/Akt signalling pathway, and further inactivation of FOXO proteins (Kong et al 1997, Risinger et al 1998. Conversely, dominant-negative TP53 mutations are often found in advanced and histological subtypes of endometrial cancer and are a strong predictor of survival (Sakuragi et al 2005). These clinico-pathological observations should accelerate research into the mechanisms that govern life and death decisions in the human endometrium.…”