Sequana and National Cancer Institute Discover Hereditary Skin Cancer Gene.

Therapeutics (NASDAQ: SQNA) and the National Cancer Institute (NCI) today announced that they have discovered a gene associated with a particular form of skin cancer.

Using samples of DNA provided by NCI, Sequana researchers have identified an alteration in a specific gene that increases the risk of getting hereditary melanoma, an aggressive form of skin cancer that may rapidly spread to internal organs unless diagnosed at an early stage. Today's discovery is published in the January issue of Nature Genetics.

Alisa M. Goldstein, Ph.D., a scientist at NCI's Genetic Epidemiology Branch and one of the paper's authors, said, "This discovery is an important part of the melanoma puzzle, but there are many additional pieces that have yet to be uncovered."

Skin cancer, associated with excessive sun exposure, is the most common type of cancer in the United States. In 1995, over 800,00 new cases were diagnosed, and it is estimated that 40 to 50 percent of Americans who live to age 65 will get skin cancer at least once. Although most skin cancers are highly curable, melanoma can be particularly deadly if not detected early. In 1995, melanoma struck about 34,000 Americans and claimed the lives of nearly 7,000.

Approximately ten percent of people diagnosed with melanoma are members of families that have a high incidence of the disease. These people are likely to have inherited certain genes that increase their chance of getting melanoma. The DNA analyzed for this study is from several such families.

Sequana and NCI found the cancer-causing alteration in a gene known as CDK4. In a healthy cell, CDK4 binds to a regulatory protein, p16, that controls the normal rate of cell division. A 1993 study showed that family members who inherit an alteration in the p16 gene have an 80 percent lifetime risk of getting melanoma, compared with a one percent risk in the general population. But p16 alterations account for only one-third to one-half of hereditary melanoma cases. Therefore, researchers in the current study searched for alterations in the CDK4 gene, reasoning that normal cell division could be affected just as easily by an alteration in CDK4 as in p16. The DNA they used was from high-risk melanoma families known to have a normal p16 gene.

The results demonstrate that a mutation in CDK4 effectively eliminates the negative regulation of CDK4 by p16, thus allowing the tumor cells to replicate unchecked. In two unrelated families studied at NCI, all of the 11 patients with melanoma had the same alteration in the CDK4 gene. According to these results, having this CDK4 mutation increases a person's risk of getting melanoma to about 80 percent. It is not known whether a CDK4 alteration is associated with an increased risk of getting melanoma in the general population.

In addition to the two families discussed in the paper, the researchers analyzed DNA from 29 other families with hereditary melanoma (with a normal p16 gene) and found no alterations in CDK4. This indicates that CDK4 alterations account for somewhere between one and twenty percent of hereditary melanoma cases and that other genes will likely play a role in the development of the disease.

"This discovery is an important step in the process of identifying all of the genes that give rise to melanoma," said Nic Dracopoli, Ph.D., Sequana's vice president of molecular genetics. Dracopoli added, "this is only the second known example of a dominant cancer gene transmitted in the human germline."

Sequana is collaborating with NCI under a proposed Cooperative Research and Development Agreement (CRADA). Sequana will seek patent protection for this discovery, with Drs. Dracopoli, Goldstein, and Margaret Tucker (of NCI) as co-inventors, and will conduct additional research on CDK4 to determine its potential role in other types of cancer.

"Not only do we have the identification of CDK4 as a melanoma predisposition gene, but we have insight into cancer that is beginning to make sense," remarked Richard D. Klausner, M.D., director of NCI. "We are beginning to understand these cancer predisposition genes as more than isolated pieces of a puzzle and can start to see how the pieces fit together."

Sequana was founded to discover and characterize genes that cause or predispose individuals to common diseases. Sequana has developed a proprietary gene discovery technology which is based on positional cloning, a method that uses statistical analysis of disease inheritance patterns to isolate disease genes. The Company expects that identification of disease genes will provide insights into the causes of common diseases and facilitate the development of highly specific diagnostic and therapeutic products.

CONTACT: Bob Giargiari

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Sequana Therapeutics, Inc.

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National Cancer Institute

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