Genetic Analysis Identifies 4 Subsets of Squamous Cell Carcinoma of the Head and Neck

Comprehensive genetic analysis by The Cancer Genome Atlas (TCGA) identified 4 different subtypes of squamous cell carcinoma of the head and neck (SCCHN). The analysis included 279 patients with previously untreated SCCHN. This is the eighth tumor type analysis of TCGA to be presented.

“Our study will likely become a landmark research tool for HNSCC for many years as we gradually unlock the secrets of this massive data set,” said David N. Hayes, MD, MPH, a medical oncologist who is associate professor at the University of North Carolina at Chapel Hill, at the American Association for Cancer Research (AACR) Annual Meeting.

SCCHN is the fifth most common cancer worldwide and the sixth most common type in the United States. Forty-five thousand new cases are diagnosed each year. Smoking is a risk factor, as is the epidemic of human papillomavirus (HPV). Among the 279 patients included in the study, 80% were tobacco related and 13% were HPV positive.

“There is incredible pressure for these tumors to acquire a specific set of losses and gains. If you look across different tumor types, they have assumed a similar set of gains and losses across chromosomes; this may provide patterns that can be leveraged across a set of tumors,” he said. “We need to understand the mutations or individual alterations in the 15 most significant mutated genes in SCCHN.”

In the study, significant mutations were found in the following genes: CDKN2A, TP53, PIK3CA, NOTCH1, HRAS, and NFE2L2.

Looking at all gene expression subtypes of SCCHN, tumors organize themselves into 4 groups that are reproducible.

These subtypes tend to go along with differences in mutation patterns and chromosomal alterations, Hayes explained. The 4 subtypes are:

1. Atypical subtype with no amplification of epidermal growth factor receptor (EGFR), HPV positive, and a high rate of phosphatidylinositide 3-kinase (PIK3CA) mutations
2. Classical subtype, also seen in squamous cell lung cancer, associated with 2 key mutations: KEAP 1 and NFE2L2
3. Mesenchymal subtype, mostly mutations of FGR 1 and FGR, and
4. Basal subtype, highly associated with SOX2 amplifications and overexpression.

Some of these alterations overlap with squamous cell carcinoma of the lung, which is also a tobacco-related cancer. “We frequently see altered genomes in other tobacco-related cancers. One of the striking findings we observed was a high degree of similarity to other squamous tumors, including lung squamous cell carcinoma. Lessons learned from studying the similarities and differences between tumors, such as copy number alterations, will be an angle to pursue to better understand altered pathways in cancer. The idea that they share properties that go beyond the type of cancer means that this could be studied at a model systems level.”

Additional key observations of this study include:

• Other patients as well as those who are HPV positive have infrequent EGFR gene amplification
• HPV-positive tumors have a high rate of PIK3CA gene mutations
• Patients infected with HPV almost never have p53 alterations
• In patients who are HPV negative, druggable mutations include EGFR, FGR, and CNCCC21.

“We have made a lot of observations, but this also makes things more complicated. We are able to recognize patterns, and some of these patterns may turn out to be druggable, or actionable in the future,” Hayes stated.

“This is robust information that gives us data on mutational analysis and copy numbers, expression, promoter methylation, and other aspects of SCCHN. This data set confirms other publications indicating that there is a clear difference between HPV-positive patients who usually have a better prognosis and are easier to treat than HPV-negative patients. HPV-negative patients have many more mutations than HPV-positive patients,” stated Giuseppe Giaccone, MD, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC. Giaccone moderated an AACR press conference at which these data were presented.

Reference
Hayes DN, Grandis J, El-Naggar AK. Comprehensive genomic characterization of squamous cell carcinoma of the head and neck in The Cancer Genome Atlas. Presented at: American Association for Cancer Research 2013 Annual Meeting; April 7, 2013; Washington, DC. Abstract 1117.