TP53 DNA contact mutations are selectively associated with allelic loss and have a strong clinical impact in head and neck cancer

Abstract

Recent studies have suggested that di erent mutation types within the core domain of the tumour suppressor protein p53, i.e. DNA contact mutations and structural mutations, confer di erent biological properties. We have analysed in 86 head and neck squamous cell carcinomas (HNSCC), whether these p53 mutation types have a di erential clinical impact. Thirty-seven missense mutations were identi®ed. Thirteen of these (36%) were DNA contact mutations, occurring in the L3 loop, in the H2 loop sheet helix motif, in the S10 b strand and in Zinc binding residues. Microsatellite marker analysis revealed a selective association between these mutations and the loss of wild-type alleles (100% LOH vs 50% LOH in tumours with structural mutations; P=0.0034, Fisher's exact, 2-tailed). In comparison to structural mutations or to the absence of mutations in the core domain, DNA contact mutations were associated with higher tumour stages (84.6% vs 62%), a higher incidence of lymph node metastasis (91.7% vs 56%; P=0.014, Fisher's exact, 2-tailed), a shortened recurrence-free survival (8.1 months vs 23.7 months, P=0.047, log rank test) and overall survival (11 months vs 29.2 months; P=0.003, log rank test). The latter was also the case when only stage IV tumours were analysed (P=0.0055, log rank test). These data indicate that in HNSCC, TP53 DNA contact mutations confer a strong selection pressure to eliminate wild-type alleles, and that they result in an accelerated tumour progression and reduced therapeutic responsiveness.

Genome-wide DNA copy number alterations in head and neck squamous cell carcinomas with or without oncogene-expressing human papillomavirus

“…The viral oncogene E6 binds and inactivates p53, while in tumors without HPV involvement TP53 gene is mostly inactivated by mutation, often accompanied by allelic loss (Ahomadegbe et al, 1995;Erber et al, 1998;Tabor et al, 2001;Braakhuis et al, 2004b). In a previous study, we showed that a significant difference in allelic loss frequency at 17p was observed between HPV-positive and -negative tumors, as determined by microsatellite markers (Braakhuis et al, 2004b).…”

A novel natural killer cell line (KHYG-1) from a patient with aggressive natural killer cell leukemia carrying a p53 point mutation

“…Therefore, mutations in these codons are now regarded as contact mutations which might acquire stronger carcinogenic ability. [45][46][47] In the present case, a point mutation was found at one of the CpG hot spots, codon 248 in exon 7 which is located in the L3-loop of the p53 protein. The establishment of an NK leukemia cell line with a contact mutation may serve as a good model for further study of p53-associated leukemogenesis.…”

p53 Transgenic Mice Are Highly Susceptible to 4-Nitroquinoline-1-Oxide-Induced Oral Cancer

“…We have shown previously that p53 transgenic mice with a dominant-negative p53 mutation are highly susceptible to carcinogen-induced lung adenoma/adenocarcinoma, uterine sarcoma, and colon adenocarcinoma (9)(10)(11)(12). Mutation in the p53 gene is also commonly seen in SCCs of oral mucosa (13)(14)(15)(16). Abnormal staining of p53 protein is a frequent finding (17)(18)(19).…”