Abstract
Patients with HPV-positive head neck squamous cell carcinomas (HNSCC) usually have a better prognosis than the HPV-negative cases while the underlying mechanism remains far from being well understood. We investigated this issue by an integrative analysis of clinically-annotated multi-omics HNSCC data released by the Cancer Genome Atlas. As confirmatory results, we found: (1) Co-occurrence of mutant TP53 and HPV infection was rare; (2) Regardless of HPV status, HNSCCs of wild-type TP53 implied a good survival chance for patients and had fewer genome-wide somatic mutations than those with a mutation burden on the gene. Our analysis further led to some novel observations. They included: (1) The genes involved in “DNA mismatch repair” pathway were up-regulated in HPV-positive tumors compared to normal tissue samples and HPV-negative cases, and thus constituted a strong predictive signature for the identification of HPV infection; (2) HPV infection could disrupt some regulatory miRNA-mRNA correlations operational in the HPV-negative tumors. In light of these results, we proposed a hypothesis for the favorable clinical outcomes of HPV-positive HNSCC patients. That is, the replication of HPV genome and/or its invasion into the genomes of cancer cells may enhance DNA repair mechanisms, which in turn limit the accumulation of lethal somatic mutations.
Highlights
D induction chemotherapy plus concurrent chemoradiation)[4,18]
Shi et al.[28] found that the glucocorticoid mediated regulation of a HPV-E6-p53-miRNA-145 pathway could modulate invasion and therapy resistance of cervical cancer cells[28]. These results suggest that the interference of HPVs to the miRNA-mRNA interactions may play a role in the mechanisms underlying various clinical outcomes of head neck squamous cell carcinomas (HNSCC) patients
It is worth noting that silent mutations were excluded from our analysis, implying that the tumor stratifications based on the genotypes of TP53 and CDKN2A genes could be potentially related to the status, i.e. normal or disrupted, of p53 and p16 proteins
Summary
D induction chemotherapy plus concurrent chemoradiation)[4,18]. While the underlying mechanisms for this association remain unclear, some relevant hints can be extracted by scrutinizing the mutation spectra of HNSCCs. This is because the cancer driver mutations in the subtype is not limited to those present in PIK3CA, and the observed mutation spectrum is often the consequence of DNA mutations and mismatch/aberration repairs In this regard, further scrutinizing the subtype specific gene expression profile in HNSCCs may help elucidate the favorable survival rate of patients with HPV infected tumors. Shi et al.[28] found that the glucocorticoid mediated regulation of a HPV-E6-p53-miRNA-145 pathway could modulate invasion and therapy resistance of cervical cancer cells[28] These results suggest that the interference of HPVs to the miRNA-mRNA interactions may play a role in the mechanisms underlying various clinical outcomes of HNSCC patients. We modeled and characterized the subtype-specific survival profiles, somatic mutation spectra, gene expression alterations and miRNA-mRNA interactions Based on these results, we proposed a heuristic explanation for the favorable clinical outcomes of HNSCC patients with HPV infection. We further extended the analysis to predict the HPV status of HNSCC patients using expression signatures and to identify the alterations of miRNA-mRNA correlation network modules across various HNSCC subtypes
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