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

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.

Chlorine and Chromium Elements, Proteins of Oxidative Stress and Dna Repair Pathways Are Related to Tumor Aggressiveness and Prognosis of Patients With Oral Cancer

“…The classical relation between alcohol consumption and worse prognosis [26][27][28][29] was also documented here. Unexpectedly, in contrast with previous reports [30][31][32] the smoking habit was not determinant of worse prognosis. It is possible that, in our study, the fact that among non-smokers few had never smoked, and many were ex-smokers, has concealed this rather classical relationship.…”

Rural–urban scaling of age, mortality, crime and property reveals a loss of expected self-similar behaviour

“…These two were also most closely related to each other in the clustering analysis. Cancer of the larynx has long been associated with alcohol 37 and smoking 38 and preventative measures beyond cessation are limited. The association with suicide as well as the positive correlations of cancer of the larynx and suicide with ASB, CD&A, violence, accidents, diabetes, liver and lung cancers suggests health care delivery focusing on mental health 39,40 , alcohol 41 , and community safety may be beneficial for this group.…”

“…Older people (55 and above) clustered with mortality except for bone cancer. The very young (0-14) and middle-aged people(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54) clustered with property. Most correlations in the first two clusters were positive, while most property indicators were anti-correlated with children aged 0-14.…”

Human Papilloma Virus: Current Knowledge and Focus on Oral Health

“…Cutaneous HPV genotypes 5, 8, 9, 12, 14, 15, 17, 19, 20, 47, and 49 are associated with epidermodysplasia Lewandowsky-Lutz verruciform. This is a rare familiar dermatosis, with chronic evolution, characterized by a dissemination of numerous papular and macular elements, which usually appears in childhood and which within 20-30 years of onset can encounter a neoplastic transformation (first bowenoid carcinoma in situ and subsequently squamous cell epithelioma) which manifests itself in the form of flat warts and reddish macules and which can also degenerate into squamous cell carcinomas [ 27 , 28 ].…”