CDKN2A Copy Number Loss Is an Independent Prognostic Factor in HPV-Negative Head and Neck Squamous Cell Carcinoma.

William S Chen,Joseph N Contessa,Allen Mo,Jeffrey P Townsend,Stephen G Gaffney,Ranjit S Bindra,Zain Husain,James B Yu,Thomas Hayman

doi:10.3389/fonc.2018.00095

Abstract

HPV infection is associated with high p16 expression and good prognosis in head and neck squamous cell carcinomas (HNSCCs). Analysis of CDKN2A, the gene encoding p16, may further elucidate the association between p16 expression and prognosis. We sought to determine whether CDKN2A copy number loss was associated with poor survival in HPV-negative HNSCCs. The Cancer Genome Atlas HNSCC clinical and genomic data were obtained and integrated. Patients <80 years old with a primary tumor in the oral cavity, oropharynx, hypopharynx, or larynx were included. Stratifying by copy number loss status, CDKN2A mRNA and p16 protein expression levels were examined and overall survival (OS) and disease-free survival (DFS) were evaluated. 401 patients with HPV-negative HNSCC were identified. 146 patients demonstrated CDKN2A copy number loss. The CDKN2A copy number loss group expressed significantly lower levels of CDKN2A mRNA and p16 protein than did the non-copy number loss group. Median OS for patients with and without CDKN2A copy number loss was 16.5 and 46.6 months, respectively (p = 0.007). Median DFS for both groups was 11.6 and 19.2 months, respectively (p = 0.03). In both univariate and multivariable analyses, stage IV designation, receipt of chemotherapy and CDKN2A copy number loss were predictive of OS. CDKN2A copy number loss predicted poor survival independently of other patient and treatment factors and may be a clinically useful prognostic factor.

Highlights

It is well known that head and neck squamous cell carcinomas (HNSCCs) caused by human papillomavirus infection (HPV-positive) have considerably better prognosis than those not associated with HPV infection (HPV-negative) [1,2,3]
Given current understanding that HPV-positive and HPVnegative HNSCCs are clinically and biologically distinct, analysis of HNSCCs should ideally be stratified by HPV status
We aim to investigate the emerging clinical significance of CDKN2A copy number loss in HPV-negative head and neck cancers using The Cancer Genome Atlas (TCGA)

Summary

Introduction

It is well known that head and neck squamous cell carcinomas (HNSCCs) caused by human papillomavirus infection (HPV-positive) have considerably better prognosis than those not associated with HPV infection (HPV-negative) [1,2,3]. Recent studies suggest that p16 expression varies greatly even among only HPV-positive or only HPV-negative HNSCCs [11,12,13] This wide variability in gene expression amongst patients with the same HPV status suggests that differences in p16 expression cannot be explained solely by HPV infection. Given the high prevalence of CDKN2A copy number loss, it is possible that this genomic abnormality may largely explain the wide variability in p16 expression among HPV-negative tumors. We sought to determine whether CDKN2A copy number loss was associated with poor survival in HPV-negative HNSCCs

Objectives

Methods

Results

Conclusion