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

Aki Mafune,Kota Wada,Yutaka Suzuki,Chikako Sakanashi,Masahiro Ikegami,Mitsuyoshi Urashima,Takashi Yokoo,Satoko Imai,Hiromi Kojima,Akio Nakashima,Toshihito Suda,Takanori Hama

doi:10.1186/s12885-015-1220-2

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.

Highlights

Smoking induces oncogenic TP53-mutations in head and neck squamous cell carcinomas (HNSCCs)
Because UGT2B17 deletion is common among Japanese, the power to detect interacting effects between smoking and UGT2B17deletion on TP53-mutations can be enhanced by focusing on Japanese patients with HNSCC
Using this cohort of Japanese patients with HNSCC as post hoc analysis, we newly explored if UGT2B17-deletion modify effects of smoking on TP53-mutations, in combination with p16 (+)

Summary

Introduction

Smoking induces oncogenic TP53-mutations in head and neck squamous cell carcinomas (HNSCCs). Copy number variants (CNVs) of UGT2B17 gene, known to vary greatly among ethnic populations; for example, homozygous deletion of UGT2B17 (0 copy) is not a Mafune et al BMC Cancer (2015) 15:205 common CNV among Africans or Europeans e.g., 14% of Nigerians, but it is common among East Asian populations, e.g., 92% of Japanese [6]. We reported that heavy alcohol consumption triggered previously known and unknown somatic copy number alterations (SCNAs) including CDKN2A, but that smoking induced TP53-mutations [14]. Using this cohort of Japanese patients with HNSCC as post hoc analysis, we newly explored if UGT2B17-deletion modify effects of smoking on TP53-mutations, in combination with p16 (+). We studied if combinations among UGT2B17-deletion, p16 (+), and disruptive TP53-mutations affect cancer relapse

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