High prevalence of p53 exon 4 mutations in soft tissue sarcoma

Abstract

BACKGROUND p53 is the most commonly mutated gene in cancer, including soft tissue sarcoma (STS). The authors characterized p53 alterations (protein accumulation and gene mutation) in STS to evaluate possible associations with patient outcomes. METHODS Thirty-one STS specimens (multiple histologies) were analyzed by p53 immunohistochemistry (IHC) and direct DNA sequencing of p53 exons 2–11 and then correlated with outcomes. RESULTS Direct p53 sequencing detected mutations in 10 of 31 STSs; 7 of 10 were missense mutations, whereas 3 of 10 were either insertions or frameshift mutations, leading to nonfunctional truncated p53; 7 of these p53 mutations have not been previously described. Four p53 exon 4 mutations were identified, a p53 region previously unknown to be mutation prone. Eighteen of the 31 specimens expressed p53 when the authors used the clinical IHC assay of their institution. Interassay concordance of 48% was observed; only 6 of 10 sequencing-identified p53 mutated specimens exhibited nuclear p53 protein expression by IHC, whereas 12 of 18 specimens exhibiting p53 protein expression by IHC harbored sequencing-identified wild-type p53. Decreased survival was observed in STS patients bearing sequencing-identified mutated p53 versus wild-type p53, as was a correlation between IHC-determined nuclear p53 protein expression and decreased survival. CONCLUSIONS p53 protein stabilization and p53 mutation frequently occur in STS, and both suggest worse outcomes for patients so affected. However, increased p53 protein expression does not necessarily indicate p53 gene mutation. The high incidence of exon 4 mutations found in STS suggests that p53 sequencing should not be limited to the core DNA binding domain. Cancer 2007. © 2007 American Cancer Society.