p53 exon 5 mutations as a prognostic indicator of shortened survival in non-small-cell lung cancer

Abstract

Summary Inactivation of the tumour-suppressor gene p53 has been described as one of the most common molecular changes found in lung tumours. Our purpose was to study the prognostic value of p53 alterations and to determine whether some specific mutation type in the p53 gene could be associated with poor clinical evolution in non-small-cell lung cancer (NSCLC) patients. To this end, we studied 81 resected primary NSCLCs in order to detect p53 alterations. p53 protein accumulation was analysed using immunohistochemistry methods; p53 gene mutations in exons 5-9 were studied using polymerase chain reaction-single-strand conformation polymorphism and sequencing techniques. p53 protein was immunodetected in 46.9% of lung carcinomas and 44.7% of p53-immunopositive tumours showed p53 mutations. Survival analysis was performed on 62 patients. No survival differences were found for patients with or without p53 immunopositivity. A shorter survival was found in patients with underlying p53 gene mutations, mainly in patients with squamous cell lung tumours; the worst prognosis was found when mutations were located in exon 5 (P= 0.007). In conclusion, the location of p53 mutations might be considered as a prognostic indicator for the evaluation of poor clinical evolution in NSCLC patients.

Evolution of p53 in hypoxia-stressedSpalaxmimics human tumor mutation

“…The Spalax-specific modifications observed within the p53 DNAbinding domain replace arginine (R) with lysine (K) in the Spalax p53 protein (corresponding to codons 174 and 209 in humans). Arginine at codon 174 is reported to be affected in 57 different tumors of various types (www.iarc.fr͞p53͞index.html), with an identical arginine-to-lysine exchange in eight different human cancers, including medulloblastoma (32), squamous cell carcinomas of the head and neck (33), oral cancer (34), breast cancer (35), colon cancer (36), ovary adenocarcinoma (37), lung cancer (38,39), and liver cancer (40). Moreover, this specific mutation was reported in canine thyroid carcinoma (41).…”

Gain of Function of p53 Cancer Mutants in Disrupting Critical DNA Damage Response Pathways

“…29 For example, expression of p53 mutant but not the absence of WT p53 is correlated with the poor prognosis in soft tissue sarcomas, 38 and R175 mutation is correlated with poor prognosis with small-cell lung cancer. 39 Considering that cancer cells are under constant selection for growth advantage, these findings suggest that p53 mutants might promote tumorigenesis. In further support of this notion, p53 mutants collaborate with the Ras oncogene to transform primary rat cells.…”

Prognostic value of genomic damage in non-small-cell lung cancer

“…p53 gene mutations were detected as described by Vega et al (1997). Accumulation of the p53 protein in the tumour cell nuclei was detected as described by Vega et al (1997). C-myc overexpression was evaluated by Northern blot analysis (unpublished results).…”

“…Once these groups of tumours were established, we tried to correlate the incidence of genomic damage detected by AP-PCR with clinicopathological features of tumours, as well as with some prevalent genetic abnormalities previously investigated by us in these lung tumours, such as K-ras mutations (Vega et al, 1996), p53 alterations (Vega et al, 1997) and c-mvc overexpression (unpublished results). When we correlated the incidence of genomic damage with tumour stage, histology and differentiation, our results did not show significant differences.…”

“…In addition, we tried to establish a relationship between AP-PCR genomic alterations and other molecular changes considered to be most prevalent in lung tumours, such as K-ras and p53 mutations (Slebos et al, 1990;Rodenhuis and Slebos, 1992;Horio et al, 1993;Mitsudomi et al, 1993;Vega et al, 1996;1997), as well as c-myc overexpression, considered as a relatively late event in the lung cancer development (Bergh, 1990 (Mountain, 1986) …”