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Potential Prognostic Signature Described in HPV-Positive Squamous Cell Carcinomas

NEW YORK (GenomeWeb) – A retrospective analysis has led to a tumor gene expression signature with apparent ties to patient outcome in individuals with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinomas (OPSCC).

Using RNA sequence data for 80 OPSCC tumors profiled for the Cancer Genome Atlas project, researchers from the University of Texas MD Anderson Cancer Center and elsewhere explored the relationships between HPV transcript variation and tumor expression profiles.

"Since HPV positivity drives radiotherapy sensitivity, we hypothesized that variations in HPV biology may cause differences in treatment response and outcome," senior author Curtis Pickering, a head and neck surgery researcher at MD Anderson Cancer Center, and his colleagues wrote, adding that "our objective was to explore the association between HPV function and molecular and clinical phenotypes."

Their results, reported online today in JCI Insight, produced new clues about HPV-related carcinogenesis and revealed 582 HPV status-associated human genes, which showed expression profiles that clustered the tumors into three groups: one containing HPV-negative tumors and two with HPV-positive tumors.

While the cluster of 28 HPV-negative tumors had the poorest five-year overall survival rates, consistent with prior reports, the team noted that five-year overall survival rates also differed from one HPV-positive OPSCC group to the next. A higher risk group of tumors from 19 of the patients had survival profiles that were slightly better than the HPV-negative group but far worse than those found in a second group of 33 HPV-positive patients.

"The HPV-negative tumors were clearly different, but within HPV-positive there were two different groups," Pickering said in a statement, noting that "one HPV-positive subgroup had survival similar to those of HPV-negative patients."

When he and his team dug into the data further, they narrowed in on 38 HPV-correlated genes that were differentially expressed between the two HPV-positive tumor clusters. Compared to the HPV-negative OPSCC tumors, meanwhile, the HPV-positive tumors with more favorable outcomes showed differential expression at 166 genes, compared to just 94 differentially expressed genes between the HPV-negative and higher risk HPV-positive tumors.

"The high-risk group presented an altered or intermediate gene expression profile between HPV- and HPV+ OPSCC tumors," the authors wrote.

In their subsequent analyses — including efforts to validate the proposed 38-gene prognostic biomarker in independent sets of HPV-positive OPSCCs and in other squamous cell carcinomas such as cervical squamous cell carcinoma — the researchers again saw five-year survival differences. And efforts to whittle down the possible prognostic marker set suggested that HPV-positive OPSCC survival clues might come from the expression of as few as three genes: IKZF3, ARHGAP26, and CACNA1D. 

"[W]e've found some new fundamental aspects of HPV biology related to the carcinogenic process, the progression of the tumor and response to therapy," Pickering said. "If we're able to validate this in future studies, it could be incredibly clinically useful across several HPV-related tumor types."

As HPV-positive OPSCC cases rise, the team explained, there is interest in uncovering prognostic biomarkers to distinguish between low-risk patients who can be spared aggressive radiotherapy and high-risk patients that are more apt to require significant clinical interventions. 

"Patients with HPV-positive oropharyngeal tumors are living a long time after radiation treatment, but often are left with significant long-term morbidity, including problems with speech or swallowing," Pickering said, explaining that "there's a desire among clinicians to reduce, or de-escalate, therapy to lessen severe side effects."