The largest molecular and genomic study of head and neck cancers to date reveals genomic alterations that may help these cancers start and grow. The results also identify a patient subgroup likely to respond to less-aggressive therapy and suggest new treatment targets.

Researchers have published the most comprehensive genomic analysis of head and neck cancers. Their findings may lead to improved treatments for this type of cancer; current therapies are successful only about half of the time.

More than 90% of head and neck cancers are squamous cell carcinomas, and most are triggered by tobacco or alcohol use or by infection with human papillomavirus (HPV). To clarify how these tumors develop and identify potential new treatment targets, researchers with The Cancer Genome Atlas (TCGA) analyzed squamous cell carcinomas from 528 patients, three times as many as in any comparable study. Instead of relying on one technique, as most genome profiling projects for this type of cancer have done, the team used several methods, including whole-exome sequencing, microarray analysis, and copy-number analysis.

“We think of this [project] as an atlas or encyclopedia” of these tumors, says co-author D. Neil Hayes, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill. Hayes and more than 300 colleagues recently reported results for the first 279 patients (Nature 2015;517:576–82).

Researchers have uncovered genomic abnormalities that drive some head and neck cancers. For example, some tumors that tested positive for human papillomavirus (illustrated above) had recurrent deletions and truncating mutations in TRAF3.

Researchers have uncovered genomic abnormalities that drive some head and neck cancers. For example, some tumors that tested positive for human papillomavirus (illustrated above) had recurrent deletions and truncating mutations in TRAF3.

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The researchers uncovered genomic abnormalities that help explain the origin and progression of the cancers. For instance, they discovered that some HPV-positive tumors had recurrent deletions and truncating mutations in TRAF3. This gene is crucial for defense against several viruses, and its absence might impair the immune system's ability to clear HPV.

The study also suggests new treatment avenues and ways to pinpoint patients likely to benefit from therapy. Among HPV-negative patients, Hayes and colleagues found a subset that showed a three-gene signature: normal TP53, mutations that inactivate the cell-death gene CASP8, and mutations that activate HRAS, which promotes cell division. Clinical records indicate that these patients have more favorable outcomes, and the signature could enable doctors to identify those who could be treated successfully with less-aggressive therapy.

In addition, one third of head and neck cancers have amplifications of the cell cycle regulator CCND1, the team discovered. CDK4/6 inhibitors, such as the recently approved drug palbociclib (Ibrance; Pfizer), disrupt this pathway. The paper supports testing these inhibitors in head and neck cancer, Hayes says.

“This study is important because it's laying the foundation for the genomic and molecular characterization of the disease,” says Thomas Ow, MD, of the Montefiore Einstein Center for Cancer Care in New York, NY, who wasn't connected to the research.

Information on all 528 patients, not just the initial group of 279, is now available through www.cancergenome.nih.gov.

For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.