Title

Mutation signature analysis identifies increased mutation caused by tobacco smoke associated DNA adducts in larynx squamous cell carcinoma compared with oral cavity and oropharynx.

Authors

Andrew P. South, Thomas Jefferson UniversityFollow
Nicoline Y den Breems, Lincoln University
Tony Richa, Thomas Jefferson UniversityFollow
Uche Nwagu, Thomas Jefferson UniversityFollow
Tingting Zhan, Thomas Jefferson UniversityFollow
Shiv Poojan, Thomas Jefferson UniversityFollow
Ubaldo E. Martinez-Outshoorn, Thomas Jefferson UniversityFollow
Jennifer M. Johnson, Thomas Jefferson UniversityFollow
Adam J. Luginbuhl, Thomas Jefferson UniversityFollow
Joseph Curry, Thomas Jefferson UniversityFollow

Document Type

Article

Presentation Date

12-17-2019

Comments

This article is the author’s final published version in Scientific Reports, Volume 9, Issue 1, December 2019, Article number 19256

The published version is available at https://doi.org/10.1038/s41598-019-55352-y. Copyright © South et al.

Abstract

Squamous cell carcinomas of the head and neck (HNSCC) arise from mucosal keratinocytes of the upper aero-digestive tract. Despite a common cell of origin and similar driver-gene mutations which divert cell fate from differentiation to proliferation, HNSCC are considered a heterogeneous group of tumors categorized by site of origin within the aero-digestive mucosa, and the presence or absence of HPV infection. Tobacco use is a major driver of carcinogenesis in HNSCC and is a poor prognosticator that has previously been associated with poor immune cell infiltration and higher mutation numbers. Here, we study patterns of mutations in HNSCC that are derived from the specific nucleotide changes and their surrounding nucleotide context (also known as mutation signatures). We identify that mutations linked to DNA adducts associated with tobacco smoke exposure are predominantly found in the larynx. Presence of this class of mutation, termed COSMIC signature 4, is responsible for the increased burden of mutation in this anatomical sub-site. In addition, we show that another mutation pattern, COSMIC signature 5, is positively associated with age in HNSCC from non-smokers and that larynx SCC from non-smokers have a greater number of signature 5 mutations compared with other HNSCC sub-sites. Immunohistochemistry demonstrates a significantly lower Ki-67 proliferation index in size matched larynx SCC compared with oral cavity SCC and oropharynx SCC. Collectively, these observations support a model where larynx SCC are characterized by slower growth and increased susceptibility to mutations from tobacco carcinogen DNA adducts.

Recommended Citation

South, Andrew P.; den Breems, Nicoline Y; Richa, Tony; Nwagu, Uche; Zhan, Tingting; Poojan, Shiv; Martinez-Outshoorn, Ubaldo E.; Johnson, Jennifer M.; Luginbuhl, Adam J.; and Curry, Joseph, "Mutation signature analysis identifies increased mutation caused by tobacco smoke associated DNA adducts in larynx squamous cell carcinoma compared with oral cavity and oropharynx." (2019). Kimmel Cancer Center Papers, Presentations, and Grand Rounds. Paper 65.
https://jdc.jefferson.edu/kimmelgrandrounds/65

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Language

English