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High-Throughput Strategies Identifying Genetic, Epigenetic Changes in Head and Neck Cancers

By Andrea Anderson

CHICAGO (GenomeWeb News) – Researchers are making progress using high-throughput strategies to find previously unappreciated genetic and epigenetic quirks in head and neck cancer — including changes that may prove useful for diagnosing and tracking disease.

Johns Hopkins University head and neck cancer research director David Sidransky described some of the work during an education session on molecular biology, targets, and pathways involved in head and neck cancer at the American Society of Clinical Oncology annual meeting here yesterday.

Speaking during the same session, JHU oncologist Christine Chung and the University of Chicago's Ezra Cohen touched on strategies for targeting the types of mutations previously reported in head and neck cancer and the rationale behind targeted therapeutics already being tested or considered for the disease, respectively.

Past studies have uncovered muted DNA methylation across the genomes of several cancer types, Sidransky explained, though methylation is also bumped up at specific sites in certain tumor types.

Consequently, he said, researchers are using strategies such as real-time quantitative methylation-specific PCR (real-time QMSP) to look at methylation shifts in head and neck squamous cell carcinoma.

In particular, he described work comparing methylation patterns in saliva and serum samples from individuals with HNSCC to those in samples from more than 800 apparently healthy individuals who are considered 'at-risk' of the disease because of smoking status and other exposures.

At least two genes — KIF1A and EDNRB — seem to be more highly methylated in samples from those with HNSCC than at-risk control individuals, Sidransky said, suggesting methylation of these genes might prove useful for diagnosing and monitoring the disease.
Researchers are also finding mutations and rearrangements in several genes that appear to be promising biomarker candidates for distinguishing between HNSCC cases and controls using DNA from blood samples.

Moreover, Sidransky outlined some preliminary findings from exome sequencing studies of 32 head and neck cancer samples, followed by validation in another 88 samples.

Consistent with previous findings for HNSCC, he and his collaborators have found mutations in TP53 in nearly half of the tumors tested, Sidransky said.

But they are also seeing mutations in several other genes not previously linked to the disease, including NOTCH1 — a gene that's known to be mutated in leukemia and other types of cancer. While NOTCH1 mutations are often activating in other cancers, he noted, results so far hint that the gene is frequently inactivated in HNSCC.

In addition, findings from the exome sequencing study point to genetic and epigenetic differences in HNSCC tumors that correspond to the human papilloma virus status. For example, Sidransky said, HPV positive tumors each tend to have fewer mutations overall compared to HPV negative tumors, which often come from smokers.

At the American Association for Cancer Research annual meeting in Orlando earlier this year, researchers from the Broad Institute and the University of Pittsburgh reported on findings from their own genome and exome sequencing studies of head and neck cancer, including whole exome data for 28 tumor-normal pairs and whole genome data for two tumor-normal pairs.

That team identified frequent mutations in TP53, HRAS, PIK3CA, and PTEN, along with somatic rearrangements and recurrent mutations in additional oncogenic pathways.

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