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Novel epigenetic markers of melanoma may herald new treatments for patients
June 30, 2009Melanoma is the most serious form of skin cancer, diagnosed in more than 50,000 new patients in the United States annually. While the rate of incidences continues to rise, survival rate has not improved and the race is on to find the genetic and cellular changes driving melanoma and to devise new means of detection and treatment. In a study published online in Genome Research (www.genome.org), scientists have mapped chemical modifications of DNA in the melanoma genome, finding new markers that will help develop more effective treatment strategies to fight this disease.
In addition to mutations to the DNA code that can cause malignancies, epigenetic changes - alterations to the chemical modifications of DNA that regulate genes - are frequent in a number of diseases, including cancer. If the normal epigenetic patterns that regulate gene expression are disrupted, cellular functions can go awry and lead to disease.
In this work, researchers led by Drs. Ruth Halaban and Sherman Weissman of Yale University investigated genome-wide epigenetic changes, termed DNA methylation, in melanoma cells. "This is of particular importance in melanomas, because a major etiological factor is sun exposure," Halaban said, explaining that inflammation and reactive oxygen species caused by the sun can produce epigenetic changes and mutations. Halaban added that because DNA methylation can be reversed, it is an attractive target for cancer therapy.
The group surveyed DNA methylation at gene regulatory regions, known as promoters, in both normal melanocytes and melanoma cells. They found 76 promoters with altered methylation patterns in melanomas, most of these showing increased methylation compared to normal. Promoter methylation is correlated with repression of the downstream gene, and this finding is consistent with other research indicating that cancer cells are using DNA methylation to turn off genes that normally inhibit malignancy.
The team then focused on five genes in particular, three of which had not been implicated in melanoma until now. In clinical specimens, methylation of these promoters was predominantly detected in advanced-stage tumors, suggesting that these markers will be useful for monitoring tumor progression. Furthermore, they found that by treating melanoma cells with a drug called decitabine, an inhibitor of DNA methylation, these genes could be reactivated. Decitabine is effective in some patients suffering from cancers such as acute myeloid leukemia and chronic myeloid leukemia, so the identification of these methylation markers is promising for new clinical trials evaluating the efficacy of treatment of melanoma with this drug.
Relapse of melanoma is extremely difficult to predict, and Halaban emphasized that inaccurate estimation of the malignant potential of lesions can have dire consequences for patients. However, the authors are hopeful that these epigenetic markers may provide a better method for determining the aggressiveness of the disease and for setting a course of treatment.
Halaban expects that by combining their method for finding methylation markers with the latest DNA sequencing technologies, researchers will be able to uncover genes where an interaction between genetic mutations and epigenetic changes play a role in the development of melanoma, and perhaps other cancers. With this information in hand, researchers can then devise even more effective strategies to combat the disease.
Cold Spring Harbor Laboratory
The group surveyed DNA methylation at gene regulatory regions, known as promoters, in both normal melanocytes and melanoma cells. They found 76 promoters with altered methylation patterns in melanomas, most of these showing increased methylation compared to normal. Promoter methylation is correlated with repression of the downstream gene, and this finding is consistent with other research indicating that cancer cells are using DNA methylation to turn off genes that normally inhibit malignancy.
The team then focused on five genes in particular, three of which had not been implicated in melanoma until now. In clinical specimens, methylation of these promoters was predominantly detected in advanced-stage tumors, suggesting that these markers will be useful for monitoring tumor progression. Furthermore, they found that by treating melanoma cells with a drug called decitabine, an inhibitor of DNA methylation, these genes could be reactivated. Decitabine is effective in some patients suffering from cancers such as acute myeloid leukemia and chronic myeloid leukemia, so the identification of these methylation markers is promising for new clinical trials evaluating the efficacy of treatment of melanoma with this drug.
Relapse of melanoma is extremely difficult to predict, and Halaban emphasized that inaccurate estimation of the malignant potential of lesions can have dire consequences for patients. However, the authors are hopeful that these epigenetic markers may provide a better method for determining the aggressiveness of the disease and for setting a course of treatment.
Halaban expects that by combining their method for finding methylation markers with the latest DNA sequencing technologies, researchers will be able to uncover genes where an interaction between genetic mutations and epigenetic changes play a role in the development of melanoma, and perhaps other cancers. With this information in hand, researchers can then devise even more effective strategies to combat the disease.
Cold Spring Harbor Laboratory
Melanoma Current Events and Melanoma News RSSNew Notre Dame study provides insights into the molecular basis of tumor cell behavior
A new study by a team of researchers led by Crislyn D'Souza-Schorey, associate professor of biological sciences at the University of Notre Dame, sheds light on the molecular basis by which tumor cells modulate their surroundings to favor cancer progression.
Switching immunosuppressants reduces cancer risk in kidney
Switching to a newer type of immunosuppressant drug may reduce the high rate of skin cancer after kidney transplantation, according to research being presented at the American Society of Nephrology's 42nd Annual Meeting and Scientific Exposition in San Diego, CA.
Cancer survivors may not be getting the help they need to stop smoking
More than a quarter of cancer survivors who still smoke have not been advised to quit smoking by their health care providers in the last year, according to a study published by researchers at Fox Chase Cancer Center in the current issue of the Journal of General Internal Medicine.
Melanoma treatment options 1 step closer
A targeted chemotherapy for the treatment of skin cancer is one step closer, after a team of University of Alberta researchers successfully synthesized a natural substance that shows exceptional potential to specifically treat this often fatal disease.
Resident physicians seldom trained in skin cancer examination
Many resident physicians are not trained in skin cancer examinations, nor have they ever observed or practiced the procedure.
New findings on the formation of body pigment
The skin's pigment cells can be formed from completely different cells than has hitherto been thought, a new study from the Swedish medical university Karolinska Institutet shows. The results, which are published in the journal Cell, also mean the discovery of a new kind of stem cell.
Studying cancer in pet dogs to find new treatments for human patients
A team of scientists at the National Cancer Institute (NCI) in Bethesda, USA, says that studying pet dogs with cancer could yield valuable information on how to diagnose and treat human cancers.
NEDD9 Protein Supports Growth of Aggressive Breast Cancer
Researchers at Fox Chase Cancer Center have demonstrated that a protein called NEDD9 may be required for some of the most aggressive forms of breast cancer to grow. Their findings, based on the study of a mouse model of breast cancer, are presented in a recent issue of Cancer Research, available on-line now.
A potential new imaging agent for early diagnosis of most serious skin cancer
Scientists in Australia are reporting development and testing in laboratory animals of a potential new material for diagnosing malignant melanoma, the most serious form of skin cancer.
Certain cancers more common among HIV patients than non-HIV patients
Researchers at UT Southwestern Medical Center have found that non-AIDS-defining malignancies such as anal and lung cancer have become more prevalent among HIV-infected patients than non-HIV patients since the introduction of anti-retroviral therapies in the mid-1990s.
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