Promising melanoma predictor studied

For this deadly variety of skin cancer, effective treatment continues to be bedeviled by challenges in detection.

By Victoria Stagg Elliott, amednews staff. Sept. 10, 2001.

Mapping Disease
As the results of the Human Genome Project began to shake out into clinical applications, this 2001-02 series detailed progress in the prevention and treatment of a variety of diseases and conditions -- both on the near horizon and possibilities far into the future.

Researchers are proposing that a protein found in many early-stage melanomas may become the basis for an early diagnostic test for the cancer that kills 7,800 people annually .

The protein in question appears to deactivate a tumor suppressor gene. Its identification could improve patients' chances for early detection -- crucial because melanoma has a high cure rate if caught early. Few patients whose cancer has spread survive beyond five years.

Cancer, skin deep
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"Melanoma is a disease that progresses very quickly, and it kills you very quickly," said Rhoda Alani, MD, assistant professor of oncology, dermatology, molecular biology and genetics at Johns Hopkins University in Baltimore.

But early diagnosis is not easy. It depends on patient alertness and the pathologist's ability to distinguish between an atypical mole and early-stage melanoma.

"If it was just considered to be an atypical mole, you wouldn't be as aggressive, so it's an important distinction to make, but not an easy one," said Dr. Alani.

According to papers published in last month's Cancer Research and the July issue of Proceedings of the National Academy of Sciences, researchers noted that a protein produced by a cell regulatory gene, Id1, deactivates the tumor suppressor gene, p16/Ink4a, and allows cancer cells to grow unchecked. The research was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, but the work was conducted at several institutions.

Id1 is not expressed at the later stages or in precancerous or noncancerous moles. P16/Ink4a is sometimes deactivated because of genetic heritage rather than the work of Id1. Because rates of melanoma have increased rapidly in the past 10 years, with many cases not linked to family history, researchers are suggesting that a test for Id1 might become a useful marker to distinguish early-stage malignant melanoma from abnormal but otherwise benign moles. Ultimately, this could help determine who needs more aggressive treatment.

"Telling the difference between precancerous moles and early-stage melanoma can be very difficult, and the treatments for these two lesions differ significantly," said Dr. Alani, who is the director of the study. "If it's melanoma, you want to catch it very early and treat it aggressively by removing as much tissue as possible to cure the disease."

Researchers say this line of research could lead to new treatments.

"It might be possible to turn off Id1," said Dr. Alani. "Then you'd get the normal p16 back because it's normal. It's not mutated. It's just being turned on and off the wrong way."

Much still left to learn

Those who treat melanoma said the finding was very interesting, but that it was far too early to determine its utility.

"It's an extremely well-done study, but it's a bit premature to say it could be used as a diagnostic," said Anna C. Pavlick, MD, assistant professor of medicine at New York University Medical School, who specializes in melanoma. "If this pans out -- and it looks like it may -- having an early indicator would clearly impact on how they get managed, how they get screened, how they get followed, and we may be able to target therapy directly against it."

The study was small, but researchers say a large study is their next step.

"We don't know at this point what the real significance of the finding is," said Dr. Alani. "But it's tantalizing enough to suggest that if this holds up ... in a large scale study, the implication is that Id1 can be used as an important marker for early melanoma."

Skin cancer experts also say that in addition to early diagnosis, a tool to determine who is most likely to experience a recurrence is also needed.

"With melanomas, no matter how big or how small they are, there's always a chance it may come back. ... [T]here's no prognostic indicators that we know of right now that can tell us who will relapse and who won't," said Dr. Pavlick.

Melanoma, although it is the least common skin cancer, is also the most deadly.

"Public awareness of this disease is just horrific," said Dr. Pavlick.

ADDITIONAL INFORMATION:

Cancer, skin deep

Objective: To determine whether proteins produced by the cell regulatory gene Id1 affect the tumor suppressor gene p16/Ink4a and, hence, the growth of early melanomas.
Method: Examined 21 lesions at various stages ranging from irregular but benign moles to advanced melanoma.
Results: Advanced invasive melanomas did not express Id1, but were found to have deactivating mutations in the p16/Ink4a gene. Benign melanocytic nevi did not express Id1. Id1 was expressed only in early stage melanomas.
Conclusion: Tests for Id1 may play a critical role in classification of melanoma lesions and may help determine the appropriate treatment and prognosis.

Source: Cancer Research, August 15

Weblink

Abstract, "The Transcriptional Repressor of p16/Ink4a, Id1, Is Upregulated In Early Melanomas," Cancer Research, August 15 (http://cancerres.aacrjournals.org/cgi/content/abstract/61/16/6008)

Article, "Id1 regulation of cellular senescence through transcriptional repression of p16/Ink4a," Proceedings of the National Academy of Sciences, July 3 (http://www.pnas.org/cgi/content/full/98/14/7812)