HemOnc Today New York
HemOnc Today New York
April 04, 2013
3 min read

Review offers new insights into mechanisms of melanoma heritability

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NEW YORK — New concepts in melanoma heritability include mechanisms of cancer predisposition, according to a presenter at the HemOnc Today Melanoma and Cutaneous Malignancies meeting.

“About 10% of melanoma are familial and about 90% are sporadic,” said Hensin Tsao, MD, PhD, director of the Melanoma and Pigmented Lesion Center and the Melanoma Genetics Program at Massachusetts General Hospital, Boston. “Our understanding of melanoma genetics has really evolved over the past few years. Some familial clustering of melanoma are clearly due to a single high risk gene being transmitted in an autosomal dominant way. However, there are also inklings that some families develop melanoma because they harbor several moderate risk genes and that different members may in fact harbor different melanoma-predisposing variants.”

Tsao focused on “new genes that fall into the first category.”


He presented a report from Germany by Horn and colleagues published in Science that looked at a large kindred with 18 melanomas. The family had other cancers besides melanoma.

Hensin Tsao, MD 

Hensin Tsao

The study found that there was a promoter variant in the telomerase reverse transcriptase (TERT) gene, which encodes the catalytic subunit of telomerase.

“The [patients] that inherited this TERT promoter alteration almost invariably developed melanoma, among other cancers; those that were spared this change were largely melanoma-free,” Tsao said.

The mutation variance was detected before the transcription start site, in the promoter area or “outside of the coding region…this is a good example of how changes in the DNA can alter the expression of genes rather than changing the amino acid and structure of protein encoded by the gene.”

“When they then looked at … the tumors themselves, they found that within this large promoter area of telomerase, there were multiple changes. Seventy-four percent of the cell lines and about 30% of primary melanomas had evidence of genetic change in the TERT promoter region.”

A second study from Levi Garraway’s group also had similar findings.

“Right now, there’s some excitement about telomerase,” Tsao said. “The promoter mutation … [is] both an inherited and acquired variant.”


Tsao also discussed a family he treated in Massachusetts, where a patient and her brother had cutaneous melanoma but her father had ocular melanoma. “She developed crops of small orange-colored papules that looked quite banal. To our surprise, many of these were diagnosed as ‘severely atypical’ or outright melanoma lesions. What was common to these lesions was a pathologic pattern called ‘nevoid’. But what was the underlying genetic defect?” Tsao had a clue given the link to ocular melanoma in the family.

BRCA1-associated protein 1 (BAP1) gene carriers had been studied by Harbour and colleagues in a study published in Science in 2010. Somatic BAP1 mutations were found in ocular tumors which were largely metastatic. Given the high frequency of BAP1 mutation in ocular melanomas, Tsao and colleagues wondered if a germline BAP1 mutation was being transmitted in this family. They indeed found a germline change in this original Massachusetts family and two additional mutations out of 200 families analyzed.  This included another large ocular-cutaneous family and one cutaneous-cutaneous family. There appeared to be an increased risk for germline BAP1 mutations in families with cutaneous-ocular melanoma, Tsao said.

In a collaboration with Ivana K. Kim, MD, at the Massachusetts Eye and Ear Infirmary, the team also discovered that ocular melanoma patients who developed metastases were more likely to carry BAP1 alterations than ocular melanoma patients who did not develop metastasis. They also studied an entire cohort of 300 families and separated them into cutaneous and ocular families and sequenced them, and found three different kindreds with BAP1 mutations, including one.

“The mutations are associated with a cancer complex that has cutaneous and ocular melanomas, atypical melanocytic proliferations and other internal neoplasms” Tsao said. He coined the complex, “COMMON syndrome,” to clinically capture the key components of the phenotype.

“The truth of the matter is there’s still a huge amount of unknown out there accounting for familial melanoma and better technologies will help us sort those out in the coming years,” Tsao concluded.

For more information:

Tsao H. Recent insights into familial melanoma syndromes. Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; March 22-23, 2013; New York.

Disclosure: Tsao has been a consultant with Quest Diagnostics, Genentech, WorldCare Clinical and Rhythm. He has served on the editorial boards of Journal Watch, British Journal of Dermatology, Journal of the American Academy of Dermatology, The Journal of Infectious Diseases and International Journal of Oncology. He has received funding from the National Institutes of Health, American Skin Association, American Cancer Society, Melanoma Research Alliance and the Department of Defense.