Homozygous deletions of UGT2B17 modifies effects of smoking on TP53-mutations and relapse of head and neck carcinoma

Abstract

BackgroundSmoking induces oncogenic TP53-mutations in head and neck squamous cell carcinomas (HNSCCs). Disruptive mutations of TP53-gene and expression of p16 protein [p16 (+)] in tumor tissue associate with worse and better prognosis, respectively. UDP-glucuronosyltransferase 2 family, polypeptide B17 (UGT2B17) detoxifies smoking-related metabolites. Differences among ethnic groups in UGT2B17 are extremely high. Homozygous deletions of UGT2B17 gene (UGT2B17-deletion) are a common copy number variant (CNV) among Japanese, but not a common CNV among Africans and Europeans. Thus, we examined Japanese patients with HNSCC to explore if UGT2B17-deletion and/or p16 (+) modify effects of smoking on TP53-mutations and affect relapse.MethodsWe conducted a posthoc analysis of a prospective cohort. Polymerase chain reaction, immunohistochemistry, and direct sequencing were used to determine UGT2B17-deletion, p16 (+), and detailed TP53-mutations, respectively.ResultsUGT2B17-deletion was observed in 80% of this study population. For this 80%, TP53-mutations were significantly more common among smokers than non-smokers (P = 0.0016), but this difference between smokers and nonsmokers was not significant for the 20% with UGT2B17. In patients with UGT2B17-deletion and p16 (+), simultaneously, TP53-mutations were much more common among smokers than among non-smokers (81% versus 17%; P = 0.0050). Patients with both UGT2B17-deletion and disruptive TP53-mutations had higher relapse rates than other patients (hazard ratio, 2.22; 95% confidence interval, 1.30 to 3.80, P = 0.004) in a stepwise method.ConclusionsThese results suggest that UGT2B17-deletion interacting with p16 (+) may modify effects of smoking on TP53-mutations and may further interact with the disruptive TP53-mutations to raise relapse rates among Japanese patients with HNSCC.

Evidence for different molecular parameters in head and neck squamous cell carcinoma of nonsmokers and nondrinkers: Systematic review and meta‐analysis on HPV, p16, and TP53

“…More specific definitions for nonsmoking varied from "<100 cigarettes in their lifetime" to "…smoked less than 10 pack-years prior to the surgical resection of HNSCC." 67,71 For nondrinking, the definitions ranged from never having "consumed at least 1 drink/week continuously for at least 6 months" to "drinking less than five units of sake (=140 g alcohol) per day for 1 year" (Table 1). 37,52 3.3 | Meta-analysis on molecular parameters HPV, p16 overexpression, and TP53 mutations Twelve studies detected HPV presence using at least two identification techniques in HNSCC of nonsmokers, and Figure 3A,B).…”

“…52,81,84,88 In addition, mutations in the abovementioned studies were reported in exons 4 to 8 and 10, repeatedly at a CpG site, and were less common in nasopharyngeal squamous cell carcinoma and HPVpositive OPSCC. 52,71,[79][80][81]84…”

Factors Affecting Interindividual Variability of Hepatic UGT2B17 Protein Expression Examined Using a Novel Specific Monoclonal Antibody

“…Besides additional genetic variants in the UGT2B17 gene locus, those affecting expression of the FOXA1 transcription factor might also be important. This knowledge will help understand the biologic impact of this enzyme in health and diseases, namely, on the endocrine system (Juul et al, 2009;Mouritsen et al, 2018), osteoporosis (Yang et al, 2008), carcinogen exposure (Chen et al, 2010), head and neck cancer (Mafune et al, 2015), prostate cancer (Kpoghomou et al, 2013;Li et al, 2016), chronic lymphocytic leukemia (Gruber et al, 2013;Bhoi et al, 2016), pediatric cancer (Ishimaru et al, 2017), and on inactivation of antineoplastic and other therapeutic agents (Kang et al, 2010;Sun et al, 2010;Wang et al, 2012).…”

Develop and validation a nomogram to predict the recurrent probability in patients with major salivary gland cancer

“…Smoking was associated with increasing risk of developed benign salivary gland tumor 20 , however, the relation of smoking and malignant salivary gland cancer still under debated 21 , and seen probably influenced male only 16 , 21 . Smoking induced oncogenic TP-53 mutation 22 , which significantly associated higher relapse rate 24 and reduced survival 23 , in head and neck squamous cell carcinoma. TP53 gene alternation also associated with a poor outcome in salivary gland cancer 25 .…”