Human papillomavirus (HPV) is one of the major risk factors for oropharyngeal squamous cell carcinoma (SCC). However, its role in oral cavity SCC is not well established. HPV DNA positivity is seen in about 30% of oral cavity SCC however, it doesn’t correlate with p16 expression or survival. [1,2] Large scale genomic studies show distinct genomic characteristics of HPV-positive and HPV-negative head and neck cancer squamous cell carcinomas (HNSCC). [3,4] While HPV-positive HNSCC has high a frequency of PIK3CA mutation; TP53 mutation, CDKN2A or CCND1 alterations are common in HPV-negative HNSCC. More recently, the immune microenvironment of HPV-positive HNSCC is shown to be enriched with B lymphocyte population. [5–7] Here, in this study, we evaluated the molecular signature of the HPV-positive HNSCC in The Cancer Genome Atlas (TCGA) database depending on the tumor site.
TCGA database for the HNSCC included 72 samples with HPV-positive subtype in the cBioPortal. [8,9] We determined the tumor sites depending on the International Classification of Diseases (ICD) codes; base of tongue (BOT) (n=11), oropharynx (OP) (n=9), tonsil (n=32), oral cavity (n=13), overlapping sites of lip, oral cavity, pharynx (n=5), hypopharynx (n=3), and larynx (n=2). (Figure 1A). For the analysis, we compared group of oral cavity with group of BOT/OP/tonsil and excluded the ICD codes with hypopharynx, larynx and overlapping sites of lip, oral cavity, pharynx.
Figure 1.
HPV positive HNSCC samples in the TCGA database depending on the tumor site (A). Progression-free survival (B) and disease-free survival (C) of HPV-positive oral cavity and BOT/OP/tonsil SCC.
HPV-positive oral cavity cancer progression-free survival and disease-free survival did not more closely resemble HPV-positive oropharyngeal cancers. (Figure 1B–C). However, the molecular signature was similar in both groups. PIK3CA mutation frequency was high in HPV-positive oral cavity, while the molecular alterations (i.e. TP53, CDKN2A, CCND1) commonly seen in HPV-negative cancers were not observed frequently. We compared the B cell gene expression profile between the two groups. Interestingly, oral cavity cancers did not show overexpression of B cell related genes in contrast to HPV-positive oropharyngeal SCC. (Figure 2)
Figure 2:
PIK3CA, TP53, CCND1 and CDKN2A alterations of HPV-positive HNSCC depending on the tumor site and gene expression profile of B cell related genes depending on the tumor site.
Our results show that HPV-positive oral cavity cancers do not have improved survival. Although the molecular alterations were similar to HPV-related BOT/OP/tonsil SCC and distinct from HPV-negative HNSCC; immune microenvironment is similar to HPV-negative HNSCC. Therefore the studies analyzing the TCGA or other large-scale genomic datasets for HPV-positive HNSCC should consider the tumor site.
HIGHLIGHTS:
HPV-positive head and neck squamous cell carcinoma (HNSCC) has better overall survival when compared to HPV-negative HNSCC
Large-scale genomic studies including The Cancer Genome Atlas Project include HPV-positive and HPV-negative subtypes.
HPV-positive oral cavity cancers have similar molecular profile with HPV-positive oropharyngeal cancers.
B cell related genes are overexpressed in HPV-positive oropharyngeal cancers, but not in HPV-positive oral cavity cancers
The studies analyzing the HPV-positive HNSCC should indicate the tumor site
Funding
EY and MAO were supported in part by the University of New Mexico Comprehensive Cancer Center NCI Cancer Center Support Grant P30CA118100.
GG was supported in part by the NIH/NIGMS COBRE P20GM130423 and CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute (# UL1TR002366) The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or NCATS.
Footnotes
Conflicts of Interest:
Emrullah Yilmaz
None Declared
Michelle A Ozbun
None Declared
Gregory N Gan
None Declared
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