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Copy Number Study Reveals Recurrent Deletion in Aggressive, Non-Melanoma Skin Cancer

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – In a paper appearing in the early, online edition of Cancer Prevention Research today, an American research team reported that they have uncovered a recurrent deletion linked to an aggressive form of skin cancer.

The group, led by investigators at the Translational Genomics Research Institute and the Mayo Clinic in Scottsdale, Ariz., used array-based comparative genomic hybridization to assess genome-wide copy number profiles in dozens of healthy, pre-cancerous, and cancerous skin samples. Their findings suggest an aggressive type of skin cancer known as cutaneous squamous cell carcinoma often corresponds to deletions affecting a gene called INPP5A.

Moreover, their follow-up experiments indicate that many SCC tumor and metastasis samples — and a sub-set of samples representing a pre-cursor condition called actinic keratoses — show lower levels of the INPP5A protein.

"Observed deletions in INPP5A represents a highly selected, non-random genetic event in SCC, giving researchers confidence that this is a biomarker with great potential for clinical study and patient benefit," co-author David Alberts, director of the University of Arizona's Arizona Cancer Center, said in a statement.

Squamous cell carcinoma, or SCC, is a form of non-melanoma skin cancer that often metastasizes to other parts of the body. The aggressive nature of SCC, combined with a dearth of effective treatments, have investigators trying to unravel the molecular changes behind SCC, the researchers explained, and searching for biomarkers that could be used to track its progression and treatment.

For the current study, the team used Agilent 44K arrays to do high-resolution array CGH on a series of 40 formalin-fixed, paraffin-embedded skin samples, including normal skin tissue, invasive SCC samples, and everything in between.

Altogether, the team detected 458 copy number changes. More than half of these — 58 percent — were amplifications, while the remaining 42 percent were deletions.

When they looked for recurrent amplifications and deletions in SCC, the researchers found both new and previously reported copy number changes affected chromosomes 1, 3, 8, 9, 14, and 20.

The most common copy number change involved deletions affecting a region of chromosome 10 that is in and around INPP5A — a gene coding for an inositol polyphosphate-5-phosphatase enzyme that regulates molecules involved in cellular proliferation and other processes.

These deletions turned up in nearly a quarter of the SCC samples tested but not in normal or cancer pre-cursor samples, the researchers explained.

During their follow-up immunohistochemistry experiments of 71 more SCC tissues, the team found that more than 70 percent of SCC tumors showed lower INPP5A protein levels compared to matched normal skin samples from the same individuals.

Similarly, they noted, levels of the protein were lower in a sub-set of actinic keratoses cases — a condition that precedes the development of full-fledged SCC. They reported that more than a third of the 26 actinic keratoses samples exhibited decreased INPP5A protein levels.

Even so, the team did not find INPP5A gene deletions when they tested the actinic keratoses samples using fluorescence in situ hybridization. Consequently, they speculated that decreased INPP5A levels and INPP5A deletions might represent steps along the path to SCC and in the progression to metastatic forms of the disease.

Indeed, when they looked specifically at 17 metastatic SCC cases, the researchers found even more dramatic declines in INPP5A protein levels than they had found in primary SCC tumors.

The team reportedly plans to continue investigating the functional role of INPP5A in SCC, if any — studies that they say may eventually offer clues to treating and tracking the disease.

"Continuing studies could lead to new drug targets that could contribute to better treatments for patients with SCC, and some day perhaps even help prevent this type of skin cancer," senior author Michael Bittner, co-director of computational biology at TGen, said in a statement.

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