Association Between p53 Gene Mutations and Tobacco and Alcohol Exposure in Laryngeal Squamous Cell Carcinoma

Ronchetti, Domenica; Neglia, Cesare Bartolomeo; Cesana, Bruno Mario; Carboni, Nadia; Neri, Antonino; Pruneri, Giancarlo

doi:10.1001/archotol.130.3.303

Cited by 16 publications

(14 citation statements)

References 20 publications

(34 reference statements)

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“…Studies showing a positive association between TP53 mutation and tobacco smoke in patients with head and neck carcinoma are, however, more numerous e.g. [32-36] than studies with no association e.g. [38,58,59].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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“…However, the majority of studies attempting to address these questions used epidemiologic approaches with inconsistent results [27, 28, 54, 55]. In MCF-7 (p53 wild-type) cells with/without p53 knockdown, we characterized alcohol-regulated p53-targeted gene expression, cell cycle progression, and DNA damage.…”

Section: Discussionmentioning

confidence: 99%

p53 pathway determines the cellular response to alcohol-induced DNA damage in MCF-7 breast cancer cells

et al. 2017

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Alcohol consumption is associated with increased breast cancer risk; however, the underlying mechanisms that contribute to mammary tumor initiation and progression are unclear. Alcohol is known to induce oxidative stress and DNA damage; likewise, p53 is a critical modulator of the DNA repair pathway and ensures genomic integrity. p53 mutations are frequently detected in breast and other tumors. The impact of alcohol on p53 is recognized, yet the role of p53 in alcohol-induced mammary carcinogenesis remains poorly defined. In our study, we measured alcohol-mediated oxidative DNA damage in MCF-7 cells using 8-OHdG and p-H2AX foci formation assays. p53 activity and target gene expression after alcohol exposure were determined using p53 luciferase reporter assay, qPCR, and Western blotting. A mechanistic study delineating the role of p53 in DNA damage response and cell cycle arrest was based on isogenic MCF-7 cells stably transfected with control (MCF-7/Con) or p53-targeting siRNA (MCF-7/sip53), and MCF-7 cells that were pretreated with Nutlin-3 (Mdm2 inhibitor) to stabilize p53. Alcohol treatment resulted in significant DNA damage in MCF-7 cells, as indicated by increased levels of 8-OHdG and p-H2AX foci number. A p53-dependent signaling cascade was stimulated by alcohol-induced DNA damage. Moderate to high concentrations of alcohol (0.1–0.8% v/v) induced p53 activation, as indicated by increased p53 phosphorylation, reporter gene activity, and p21/Bax gene expression, which led to G0/G1 cell cycle arrest. Importantly, compared to MCF-7/Con cells, alcohol-induced DNA damage was significantly enhanced, while alcohol-induced p21/Bax expression and cell cycle arrest were attenuated in MCF-7/sip53 cells. In contrast, inhibition of p53 degradation via Nutlin-3 reinforced G0/G1 cell cycle arrest in MCF-7 control cells. Our study suggests that functional p53 plays a critical role in cellular responses to alcohol-induced DNA damage, which protects the cells from DNA damage associated with breast cancer risk.

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“…15 Tobacco exposure is associated with increased rates of TP53 mutations. 4,20 Mutations in TP53 have been associated with decreased overall survival, 21 increased locoregional recurrence rates, 22 and decreased response to therapy. 23,24 …”

Section: Major Pathwaysmentioning

confidence: 99%

Molecular Biology and Immunology of Head and Neck Cancer

Guo

Califano

2015

Surgical Oncology Clinics of North America

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Synopsis In recent years our knowledge and understanding of head and neck squamous cell carcinoma (HNSCC) has expanded dramatically. New high-throughput sequencing technologies have accelerated these discoveries since the first reports of whole exome sequencing of HNSCC tumors in 2011. In addition, the discovery of human papillomavirus (HPV) in relationship with oropharyngeal squamous cell carcinoma has shifted our molecular understanding of the disease. New investigation into the role of immune evasion in HNSCC has also led to potential novel therapies based on immune specific systemic therapies.

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Association Between p53 Gene Mutations and Tobacco and Alcohol Exposure in Laryngeal Squamous Cell Carcinoma

Cited by 16 publications

References 20 publications

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

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

p53 pathway determines the cellular response to alcohol-induced DNA damage in MCF-7 breast cancer cells

Molecular Biology and Immunology of Head and Neck Cancer

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