Researchers ID genetic alterations, shedding light on hereditary melanoma

Banff, Alberta - Identifications of mutations such as those that lie in the telomerase reverse transcriptase (TERT) promoter area are shedding light on hereditary melanoma, according to the Director of the Massachusetts General Hospital Melanoma and Pigmented Lesion Center and Professor of Dermatology at Harvard Medical School in Boston.

“Telomerase is a crucial part of cancer biology,” says Hensin Tsao, M.D., Ph.D., who discussed the genetics of melanoma risk at the 8th annual Canadian melanoma conference. He is clinical director of Massachusetts General Hospital’s Melanoma and Pigmented Lesion Center and director of the hospital’s Melanoma Genetics Program, Boston. “Many cancer cells upregulate telomerase to maintain telomeres.”

Theoretically, the inherited mutation in the promoter region of TERT recruits more transcription factors to this area with subsequent upregulation of telomerase although the precise mechanism by which this predisposes individuals to melanoma is still under investigation, Dr. Tsao says.

“In theory, any genetic alteration that upregulates oncogenes and downregulates tumor suppressor cells could predispose individuals to melanoma,” he says.

The discovery of the TERT promoter mutation started with a single large melanoma kindred. Linkage analysis of this family revealed that members of families affected by melanoma carried the same small piece of chromosome 5 that contains the TERT gene. Subsequent sequencing led to the identification of the promoter mutation. The rate of TERT promoter mutations among families with melanoma is not precisely known, though it is not thought to be high.

Studying BAP1

Another significant avenue of research in hereditary melanoma is BAP1, the loss of which has been linked to ocular melanoma metastasis. The BAP1 pathway has been noted as a pathway that could be a therapeutic target ( Science. 2010;330(6009):1410-1413).

“In one of our collaborative studies, we found that individuals who had metastatic ocular melanoma had a greater likelihood of carrying a BAP1 mutation than those patients whose ocular melanoma did not metastasize,” Dr. Tsao says. “The study was small in number and therefore needs to be replicated. If it holds up, it’s an interesting new test since it does suggest that we can inherit a metastatic cancer risk beyond just melanoma risk.

“As we discover new genes and their different impacts on risk, we will know not just about cancer risk, but about survival risk,” he says. “It will change how we look at how we use molecular information to take care of patients.”

BAP1 has been linked to cutaneous melanoma and also very characteristic small, dome-shaped papules that do not clinically resemble melanomas but may be quite aggressive looking under the microscope. In addition, patients who carry BAP1 are at an elevated risk of developing mesotheliomas or renal cell carcinoma among other cancers, Dr. Tsao says.  

“Melanoma exists in cancer complexes,” he says. “It is not just melanoma, but things like renal cell carcinoma or a family history of ocular melanoma. Patients and their family members may have had nothing on the skin, but they were not asked about eye cancer or kidney cancer in the family.

“If dermatologists don’t ask, they may miss an opportunity to recognize certain patterns of cancer complexes,” he notes. “Taking a family history of malignancies expands beyond the skin, beyond cutaneous melanoma. The notion of a family history of cancers includes ocular melanoma and other cancers.”

Next: Managing cancer complexes

Opportunities for management

As these melanoma cancer complexes are better understood, more relevant and specific guidelines may be developed to help in management, according to Dr. Tsao.

Although skin surveillance and sun protection are recommended regardless of an individual’s genetic status, individuals who are known carriers of CDKN2A mutations do undergo pancreatic cancer screening. Carriers of BAP1 mutation s or melanoma patients who have a family history of ocular melanoma should also receive routine eye examinations by ophthalmologists.

The discovery of more genetic pieces of the puzzle with regards to melanoma could also lead to the discovery of new therapies that implicate biology, Dr. Tsao says.

It is important to distinguish between the genetic determinants that put individuals at risk for melanoma and the genetic determinants of cancer progression, he says. Although they may be related, the biologic pathways  and clinical utility of this information may be very different.

“Even if you inherit certain risk factors, it is not a guarantee you will get melanoma,” Dr. Tsao says. “We want to know what are the additional triggers that direct the cell to proliferate and metastasize.”

Disclosures: Dr. Tsao reports no relevant financial interests.