Gene Expression May Simplify Search for Effective Therapy in Head and Neck Cancer

Charles Bankhead

May 2013, Vol 4, No 4 - Personalized Medicine

Washington, DC—Therapeutic development in head and neck cancer could eventually hone in on a handful of gene-expression patterns and signaling pathways that can identify a few discrete subtypes of the disease, data from The Cancer Genome Atlas suggest.

Sequencing of the entire tumor genome of 279 patients revealed 18 frequently mutated genes, of which expression patterns in squamous-cell carcinoma of the head and neck have simplified the search for new, more effective therapies.

“The data allow us to recognize patterns and simplify things somewhat,” said D. Neil Hayes, MD, MPH, Associate Professor of Clinical Re­search, Division of Hematology/Oncology, Department of Otolary­n­gology/Head and Neck Cancer Sur­gery, North Carolina Cancer Hos­pital, Chapel Hill, NC, at a press briefing during the 2013 American As­sociation for Cancer Research annual meeting. “Gene-expression data defined 4 subtypes of head and neck cancer, not hundreds, but 4, that might be leveraged in terms of pathways that might be altered and therapies that might be offered for patient benefit.”

The discovery of the 18 frequently mutated genes has redefined the mutation rates that are traditionally associated with head and neck cancer. For example, mutations in p53 occur in 72% of head and neck cancers, whereas historical estimates placed the rate at 46%.

The research also has provided insight into differences in tumors that originate from human papillomavirus (HPV) and those that are HPV-negative. In general, HPV-positive tumors have almost no actionable or druggable mutations. The one notable exception is PIK3CA, which harbors mutations in approximately 40% of head and neck cancers, including HPV-positive tumors.

Mutations in p53 are almost universal in HPV-negative tumors, most of which also have mutational combinations. The most frequent combinations involve HRAS paired with either CASP8 or FAT1. Combinations of these 3 genes were found almost universally in HPV-negative tumors, whereas all
3 genes were absent in HPV-positive tumors. HPV-positive tumors also have few receptor tyrosine kinase mutations.

“These [18] genes must be the most important genes in head and neck cancer, because they are the most frequent,” said Dr Hayes. “These are the driving genes behind the cancer, and we really need to understand them.”

A better understanding of the genes of head and neck cancer may prove applicable to other cancers. Squamous-cell lung cancer and cervical cancer have somatic copy number alterations similar to those found in head and neck cancer.

“This suggests there is the possibil­ity to begin looking at cancer across tumor types as molecular patterns that can be leveraged and understood for both biologic and therapeutic sampling,” said Dr Hayes.

Profiling of messenger RNA expression has revealed 4 distinct gene-expression patterns, each associated with its own somatic copy number alterations and mutations: classical, basal, mesenchymal, and atypical.

Not every tumor has actionable mutations, leading researchers to go beyond individual genes and mutations and into signaling pathways.
“We can put these head and neck cancer mutations into pathways and determine which pathways might be most productive for targeting downstream events,” said Dr Hayes.