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Concurrent Genomic Glitches Implicated in Poor Head and Neck Cancer Outcomes

NEW YORK (GenomeWeb) – A new analysis of cancer genome data has uncovered a pair of related mutations linked to poor survival patterns in head and neck cancer.

In a study published in Nature Genetics this weekend, researchers from the University of California at San Diego, the University of Pittsburgh, and the University of North Carolina at Chapel Hill scrutinized data from the Cancer Genome Atlas project to look for molecular and clinical features associated with different survival outcomes in those with a form of head and neck cancer called head and neck squamous cell carcinoma (HNSCC).

Using sequence data for almost 400 head and neck squamous cell carcinoma cases, the team found that average survival time was far lower for individuals whose HNSCC tumors contained co-occurring TP53 mutations and chromosome 3 losses — an effect that was further exacerbated by enhanced expression of a microRNA called mir-548 in and/or the presence of additional gene mutations.

"Our findings raise fundamental questions about the role of TP53 in cancer and suggest that some of the deleterious health effects of TP53 mutations might actually be due to something else going on in the third chromosome," first author Andrew Gross said in a statement. Gross is a graduate student in the lab of senior author Trey Ideker, a bioinformatics and systems biology researcher at UCSD.

Overall, the TP53 mutation and chromosome 3 interaction defined a set of HNSCC tumors that were more common in smokers and had especially dismal outcomes. Whereas survival times for those with TP53 mutations alone was on average more than five years, tumors with the interacting alterations coincided with survival times shorter than two years, the researchers reported.

The researchers brought together tens of thousands of molecular and clinical features described for hundreds of HNSCC cases considered by TCGA members prior to mid-January of this year, including somatic mutation, chromosomal alteration, transcript and miRNA expression, and clinical data.

Patients older than 85 or those with human papillomavirus infection-positive tumors were not included in the initial analysis owing to the specific molecular features and survival outcomes already described in those forms of disease, the study authors noted, leaving 250 HNSCC cases for their initial analysis.

In its search for features associated with survival in the remaining HNSCC cases, the team tracked down so-called pathway-level, survival-related events from mutation profiles and transcriptome patterns in the tumors. That set of events was further refined to reflect those occurring most frequently in tumor tissue.

From the resulting set of almost 900 molecular and clinical events, researchers saw 82 with apparent ties to survival outcomes in the HNSCC patients. The most pronounced survival effects involved mutations in TP53, a well-known cancer risk gene, and deletions affecting the 3p arm of chromosome 3.

As it turned out, those survival effects were not independent of one another. Instead, the investigators' pairwise analysis of the potential prognosis events in HNSCC revealed higher-than-usual rates of chromosome 3p loss in TP53-mutated tumors — an interaction verified using genomic profiling data for another 126 HPV-negative HNSCC tumors.

The poor prognostic outcome associated with TP53 mutation and chromosome 3 loss was further verified in four dozen HPV-negative HNSCC cases treated at the University of Pittsburgh.

Across almost 200 HNSCC tumors marked by both TP53 mutations and chromosome 3 loss, the researchers found that they could get even more refined survival clues by incorporating information on mir-548k miRNA expression and/or MUC5B mutation status.

Generally speaking, less aggressive HNSCC cases lacking TP53 mutations and chromosome 3 losses appeared more prone to caspase-8 enzyme coding gene mutations and alterations affecting the RAS signaling pathway.

In 59 HPV-positive HNSCC tumors, meanwhile, the team saw only infrequent TP53 mutations, though the presence of HPV infection itself is believed to flip off activity by the TP53 protein it encodes.

Again, survival tended to decline in HPV-positive tumors harboring chromosome 3 losses, consistent with the prognostic information associated with the TP53-chromosome 3 alterations in earlier stages of the study.

The effect may extend to other types of cancer, according to a preliminary analysis of TCGA data on more than 4,400 cases representing 17 types of cancer. In addition, the study's authors emphasized that further scrutiny of other interacting molecular and clinical events could uncover still more survival predictors in HNSCC and other cancer types.

"As cancer cohorts become larger, analyses such as this will become more powered, creating the opportunity to reevaluate the cancer landscape from the perspective of pairwise and, ultimately, higher-order interactions among events," they concluded.

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