Targeted next-generation sequencing of TP53 in oral tongue carcinoma from non-smokers

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Abstract

Background

Little is known regarding the etiology and genomic underpinnings of Oral Tongue Squamous Cell Carcinoma (OTSCC) in patients who lack traditional risk factors, yet the incidence is increasing. In particular, the rate, and role, of TP53 mutations in this cohort has been heavily debated in the literature.

Methods

Tumor DNA from forty-three non-smokers with OTSCC underwent next generation sequencing of TP53.

Results

Sixty percent of samples contained a TP53 mutation. The G > T transversion rate was 5.7 %. TP53 status did not differ by age.

Conclusions

OTSCC in non-smokers have TP53 mutation rates similar to other Head and Neck cancers yet these mutations do not appear related to carcinogen exposure based on the mutational spectrum and clinical history. The mechanisms driving tumorigenesis in this cohort, including mutations in TP53, remain elusive and further studies are needed.

Electronic supplementary material

The online version of this article (doi:10.1186/s40463-016-0160-4) contains supplementary material, which is available to authorized users.

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Most cited references 7

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Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.

N. Agrawal, M Frederick, C. R. Pickering … (2011)

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA, and HRAS, we identified mutations in FBXW7 and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.

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Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain.

W Gu, R G Roeder (1997)

The tumor suppressor p53 exerts antiproliferation effects through its ability to function as a sequence-specific DNA-binding transcription factor. Here, we demonstrate that p53 can be modified by acetylation both in vivo and in vitro. Remarkably, the site of p53 that is acetylated by its coactivator, p300, resides in a C-terminal domain known to be critical for the regulation of p53 DNA binding. Furthermore, the acetylation of p53 can dramatically stimulate its sequence-specific DNA-binding activity, possibly as a result of an acetylation-induced conformational change. These observations clearly indicate a novel pathway for p53 activation and, importantly, provide an example of an acetylation-mediated change in the function of a nonhistone regulatory protein. These results have significant implications regarding the molecular mechanisms of various acetyltransferase-containing transcriptional coactivators whose primary targets have been presumed to be histones.

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Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers.

Gerd Pfeifer, Mikhail F Denissenko, Magali Olivier … (2002)

It is estimated that cigarette smoking kills over 1 000 000 people each year by causing lung cancer as well as many other neoplasmas. p53 mutations are frequent in tobacco-related cancers and the mutation load is often higher in cancers from smokers than from nonsmokers. In lung cancers, the p53 mutational patterns are different between smokers and nonsmokers with an excess of G to T transversions in smoking-associated cancers. The prevalence of G to T transversions is 30% in smokers' lung cancer but only 12% in lung cancers of nonsmokers. A similar trend exists, albeit less marked, in laryngeal cancers and in head and neck cancers. This type of mutation is infrequent in most other tumors aside from hepatocellular carcinoma. At several p53 mutational hotspots common to all cancers, such as codons 248 and 273, a large fraction of the mutations are G to T events in lung cancers but are almost exclusively G to A transitions in non-tobacco-related cancers. Two important classes of tobacco smoke carcinogens are the polycyclic aromatic hydrocarbons (PAH) and the nicotine-derived nitrosamines. Recent studies have indicated that there is a strong coincidence of G to T transversion hotspots in lung cancers and sites of preferential formation of PAH adducts along the p53 gene. Endogenously methylated CpG dinucleotides are the preferred sites for G to T transversions, accounting for more than 50% of such mutations in lung tumors. The same dinucleotide, when present within CpG-methylated mutational reporter genes, is the target of G to T transversion hotspots in cells exposed to the model PAH compound benzo[a]pyrene-7,8-diol-9,10-epoxide. As summarized here, a number of other tobacco smoke carcinogens also can cause G to T transversion mutations. The available data suggest that p53 mutations in lung cancers can be attributed to direct DNA damage from cigarette smoke carcinogens rather than to selection of pre-existing endogenous mutations.

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Author and article information

Contributors

Daniel L. Faden: 734-717-2814 , Daniel.Faden@ucsf.edu

Sarah T. Arron: Sarah.Arron@ucsf.edu

Chase M. Heaton: chase.heaton@ucsf.edu

Joseph DeRisi: joe@derisilab.ucsf.edu

Andrew P. South: Andrew.South@jefferson.edu

Steven J. Wang: Steven.Wang@ucsf.edu

Journal

Journal ID (nlm-ta): J Otolaryngol Head Neck Surg

Journal ID (iso-abbrev): J Otolaryngol Head Neck Surg

Title: Journal of Otolaryngology - Head & Neck Surgery

Publisher: BioMed Central (London )

ISSN (Print): 1916-0208

ISSN (Electronic): 1916-0216

Publication date (Electronic): 17 September 2016

Publication date PMC-release: 17 September 2016

Publication date Collection: 2016

Volume: 45

Electronic Location Identifier: 47

Affiliations

[1 ]Department of Otolaryngology-Head and Neck Surgery, University of California, 2380 Sutter St First Floor, San Francisco, CA 94115 USA

[2 ]Department of Dermatology, University of California, San Francisco, CA USA

[3 ]Department of Biochemistry and Biophysics, University of California, San Francisco, CA USA

[4 ]Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA USA

Article

Publisher ID: 160

DOI: 10.1186/s40463-016-0160-4

PMC ID: 5027093

PubMed ID: 27640185

SO-VID: 9678d340-7489-411d-9bd2-ea680b2f0bef

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 9 August 2016

Date accepted : 5 September 2016

Custom metadata

Keywords: oral tongue carcinoma,tp53

Data availability:

Keywords: oral tongue carcinoma, tp53

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Targeted next-generation sequencing of TP53 in oral tongue carcinoma from non-smokers

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

Related collections

Global Health Next Generation Network

Most cited references 7

Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.

Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain.

Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers.

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