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TCGA Data Redefines Head and Neck Cancer Subtype with Poorest Outcomes

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NEW YORK (GenomeWeb) — An analysis of data from The Cancer Genome Atlas' comprehensive molecular profiling of squamous cell head and neck cancer has revealed a more complicated molecular landscape for the disease, and has identified a new genomic subset that indicates particularly poor survival.

The results, published this week in Nature Genetics suggests that head and neck cancer patients with a combination of genomic alterations — both a TP53 mutation and chromosome 3 losses — should receive more intense treatment, while those with only a TP53 mutation could receive less intense treatment, thus avoiding potential adverse effects and dangerous complications.

Trey Ideker, the study's senior author and chief of genetics at University of California, San Diego School of Medicine, told PGx Reporter this week that his clinical colleagues on the study are already following up the discovery by looking to see if analyzing patients' genomes for these two alterations and treating them accordingly improves patient outcomes and quality of life. Other authors of the paper included researchers from several clinical departments of the University of California, San Diego, the University of Pittsburgh, and the University of North Carolina, Chapel Hill.

According to Ideker, the study exemplifies the potential of comprehensive genomic analyses to yield not just incremental, but major findings that have eluded scientists in previous efforts.

"This shows the real power and the low-hanging fruits that come out of datasets like this," he said. "One of these genes, P53, is the best studied gene in cancer, yet no one had found the short lifespan of these patients actually depends on a completely different gene. This just fell out of this [study], and it’s a huge effect."

While TP53 alterations have been previously linked to aggressive head and neck cancers, the group's TCGA study has revealed that such mutations are not solely responsible for the aggressiveness of these tumors. Rather, another alteration, loss of portions of the third chromosome, is necessary to unleash and compound the impact of TP53, and thus defines a molecular subtype for whom outcomes are significantly poorer.

The implication of the finding is that it could inform more accurate subtyping in the disease and thus more personalized treatment for patients.

The group analyzed data from 250 squamous cell head and neck cancer cases from patients below age 85 and with HPV-negative tumors, looking at genome sequencing data including somatic mutations and chromosomal alterations, as well as mRNA and microRNA expression.

Among the study's 250 subjects, the researchers found that 179 had both a TP53 mutation and 3p loss. Fifty of the samples had only one of the two markers and 22 had neither. When the group compared these factors with patient outcomes data, they found that half of patients with both mutations were dead within two years while almost two thirds of those with only one or neither of the markers were expected to live five years or more.

The group's discovery was not limited to the strong association of concurrent TP53 mutation and 3p loss with survival. The researchers also looked at factors that could further stratify patients within the TP53-3p subgroup and outside it, and whether these biomarkers could impact therapeutic decision making in the real world.

For example, he said, the group found that for patients with both TP53 mutations and 3p loss, the presence of microRNA mir-548k and also mutations of the MUC5B gene defined a smaller subgroup with even poorer prognosis.

"It looks like those patients are drug resistant out of the box," Ideker said. "That potentially puts them into a whole different category where you could focus on trying new experimental treatments."

For patients without TP53-3p events, the data revealed that the RAS signaling pathway may be an important player in divergent outcomes, Ideker said.

Interestingly, the researchers also found that 3p loss was associated with more aggressive cancer cases when present in HPV-positive tumors. As with TP53, the addition of 3p loss seemed to be a necessary event for increased severity.

According to Ideker, seeing the influence of 3p loss replicated in this way through another pathway provides even more support for the validity of the group's finding and its clinical implications.

Ideker added that authors of the paper are already conducting clinical studies using the subgroup information from the study as a "diagnostic decision tree," with the hope that it will help improve outcomes and avoid overuse of intense therapy in those who either don't need it or are unlikely to benefit.

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