Tests zero in on uveal melanoma

Key Points

Orlando, FL-Recent findings about uveal melanoma indicate that patients can be divided into high- and low-risk classes, and that a mutation in one gene on chromosome 3, BAP1, is closely associated with the high metastatic risk class 2 form of uveal melanoma.

A small percentage of patients were found to carry the mutant BAP1 in their germline, indicating that a detailed family history is very important. J. William Harbour, MD, described the recent developments in this area during Retina Subspecialty Day at the annual meeting of the American Academy of Ophthalmology.

Survival data indicate that nearly 50% of patients with uveal melanoma develop metastatic disease within 15 years of treating the primary eye tumor. Further, the survival curve of those patients is biphasic. There is an initial rapid onset of metastatic disease in some patients, and there is a second phase of later metastases that continues for years. Interestingly, the survival curve has not changed in the past century, said Dr. Harbour, the Paul A. Cibis Distinguished Professor of Ophthalmology and director of the Ocular Oncology Service at Washington University School of Medicine, St. Louis, MO.

He noted some courses of action that might result in improvements in the survival rates. The first would involve identification of effective therapies for established metastatic disease or for adjuvant therapy, and the second would be initiation of early treatment rather than waiting for advanced metastatic disease to develop.

"There is now a great deal of genetic information about a number of different genes (i.e., pl6, Rb, Pten, Cyclin D, Mdm2, and Bcl2) that are involved in uveal melanoma; these genes are activated, or inactivated," he said. "However, none of these genes is mutated, and they don't explain the metastatic disease."

Dr. Harbour provided one insight that chromosomal changes such as monosomy 3 are closely related to metastatic disease. The question that arises is: Is it possible that the genemutation that is responsible for metastasis is actually on chromosome 3?

That question has been a consideration for years, but the development of genome sequencing techniques has facilitated sequencing of the entire chromosome 3 in detail.

"When that sequencing was done, we found only one gene on chromosome 3, BAP1, that was mutated in virtually all metastasizing tumors," he said. "This mutation is almost 100% associated with metastasis. The mutations can occur anywhere throughout the gene. These are inactivating mutations, so any mutation that blocks the gene from producing its protein can lead to a metastatic phenotype when the other copy of chromo-One finding regarding uveal melanoma was discovered in a group of 31 patients with class 2 metastasizing uveal melanoma. One of the patients had a germline mutation in BAP1, which suggested that uveal melanoma might occur in families.

Based on that information, Dr. Harbour and his colleagues revisited some families of patients with uveal melanoma and identified a family with both uveal and cutaneous melanomas. The family carried a BAP1 germline mutation, and other types of cancers were present in the family (stomach, bladder, breast, and bone). Dr. Harbour and colleagues reported their findings in Science [2010;330(6009):1410-1413].

Subsequent investigations by other research groups published in 2011 found families with uveal melanoma with BAP1 mutations in me-sothelioma, cutaneous melanoma, meningi-oma, and lung adenocarcinoma, according to Dr. Harbour.

He theorized that the association was overlooked in the past because of low penetrance.

"Unless the family is large, this might not be recognized," Dr. Harbour said. "However, it is important to obtain careful family histories. When there is a suspicion of an accumulation of an excess cancer risk in a family, family members can be tested for BAP1 germline mutations."