Presence of dominant negative mutation of TP53 is a risk of early recurrence in oral cancer

p53 Mutation and Multiple Primary Oral Squamous Cell Carcinomas

“…Such "gain of function" activities include the ability to transform cells, increase tumorigenicity, and modulate the sensitivity of cancer cells to drugs (Sigal & Rotter, 2000;. 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).…”

“…In this study we found R273H mutant, which is the most common hotspot DN mutations to the IARC TP53 database (release 11, containing a total of 1093 oral SCC). Studies using mouse models of Li-Fraumeni syndromes have reported gain of functions in R175H and R273H mutants (Lang et al, 2004), which were identified as DN mutants in our study (Hassan et al, 2008). R248W and R273 H mutants interfere with recruiting MRE11-RAD50-NBS1 (MRN) complex to the site of DNA damage, leading to inactivation of ATM .…”

“…Using laser capture microdissection of tumour cells, p53 mutations were found in 100% of SCC (Agar et al, 2004). The p53 gene is mutated in more than 70% of oral SCC (Kashiwazaki et al, 1997, Hassan et al, 2008. In this article, we demonstrate that p53 statuses were diverse in the oral SCCs and leukoplakias, which indicated independent origins of the tumors in the multiple cancers.…”

“…Immunohistochemical positivity or various mutation analyses of the DNA-binding domain of p53 are known to be useful markers for predicting prognosis of patients with oral SCC (Hassan et al, 2008, Yamazaki et al, 2003, De Vicente et al, Marx et al, 2007. Mutation most often occurs at a 'hot spot' region from codon 238 to codon 248 (Somers et al, 1992;Hainaut et al, 1998;Kropveld et al, 1999) and causes defects in the binding of specific DNA sequences and the transactivation of genes whose expression is up-regulated by the wildtype protein (Vogelstein et al, 2001).…”

DNA Repair, Cancer and Cancer Therapy

“…If the TP53 gene is mutated, tumor suppression will be severely reduced. High levels of mutant p53 protein are often observed in tumors (Bartek et al, 1991;Hassan et al, 2008;Iggo et al, 1990;Jonason et al, 1996;Lee et al, 2007;Rotter, 1983). Accumulation of mutant p53 has no correlation with tumor progression, however, it correlates well with increased metastasis (Morton et al, 2010).…”