p53 in head and neck cancer: Functional consequences and environmental implications of TP53mutations

Abstract

BackgroundAlthough TP53 mutations in human tumours generally have been extensively studied, the significance of p53 in the aetiology of head and neck cancers is still incompletely characterized. In recent years, considerable interest has been focused on mutant forms of p53, the abnormal protein product of TP53 alleles with missense mutation that often accumulate in cancer cells.MethodsWe compared the nature of TP53 mutations in primary 46 head and neck squamous cell carcinomas (HNSCC) analyzed by PCR-SSCP and sequencing, immunohistochemistry, and using structural information available at IARC p53 database.ResultsSequencing confirmed 36 TP53 mutations in 23 tumours of the 39 mutations in 26 tumours found by PCR-SSCP. Only half (17) putatively affect the function of p53 protein. Of these 8 were in the L2 domain, three affected the LSH motif and three the L3 domain. Three were in other domains. Codon 259 (GAC > GAA) which is a very rare mutation was found in 4 samples in our study. There were indications of p53 aberrations being associated with the combined effect of smoking, alcohol and work history. Patients with a negative family history of cancer had more often TP53 mutations than patients with a positive family history (71% vs. 46%).ConclusionsOur study contributes to the knowledge of cumulative chemical exposure and p53 aberrations in head and neck cancer, an area where literature is scarce.

The MDM2 309 T/G Polymorphism is Associated with Head and Neck Cancer Risk Especially in Nasopharyngeal Cancer: A Meta-Analysis

“…HNCisamultifactorialdiseaseforwhichepidemiological evidence suggests HPV infection to be an etiological factor. Severalotherenvironmentalfactors,suchastobaccosmoking andalcoholconsumption,havealsobeenshowntobeassociated with the development of HNC [14][15][16]. Although our overall meta-analysis provided some evidence of an associationbetweenMDM2SNP309T/GandHNCrisk(OR=0.82, 95%CI0.67-0.99forTGvs.GG),inconsiderationoftheresultsofthesubgroupanalysis,theMDM2309T/Ggenotype decreasedtheHNCriskmainlyintheNPCsubgroup.Therefore, the results of the overall meta-analysis must be interpretedcautiously.Onelimitationofourmeta-analysisisthe lack of detailed individual data such as lifestyle.…”

Association of Two Polymorphic Codons in P53 and ABCC1 Promoter with Prostate Cancer

“…In one study, the researchers found a concomitant reduction in ABCC1 mRNA levels with wtp53 expression (8). Previous reports suggested that a functional polymorphism in codon 72 of p53 gene, which encodes polyproline domain with a vital role in apoptosis induction, is in relation to the most cancers (18)(19)(20)(21)(22)(23) and prevalence of exon 5-8 mutations, which encodes the DNA binding domain of the TP53 molecule are found in many of human cancers (5,26). On the other hand, a report by Zhao et al, indicated that promoter polymorphism of ABCC1 gene too, is associated with cancer development (10).…”

Disruption of iron homeostasis and resultant health effects upon exposure to various environmental pollutants: A critical review

“…For example, previous studies have demonstrated that a variety of environmental pollutants could cause the genetic mutation or functional disability of p53 (Anetor, 2012;Besaratinia and Pfeifer, 2010;Peltonen et al, 2010), which is a most important tumor suppressor. Our preliminary data also identified a crucial role of iron in stabilizing p53 via an interaction with ferritin.…”