Gene in Eye Melanomas Linked to Good Prognosis

Get Permission

A complete understanding of the molecular basis of this tumor will be invaluable in predicting prognosis and in the identification and development of novel treatments for this cancer.

—Anne Bowcock, PhD

Melanomas that develop in the eye often are fatal. Now, researchers at Washington University School of Medicine and the Siteman Cancer Center, St. Louis, Missouri, report they have identified a mutated gene in melanoma tumors of the eye that appears to predict a good outcome. The research was published in the advance online edition of Nature Genetics.1

“We found mutations in a gene called SF3B1,” said senior author Anne Bowcock, PhD, Professor of Genetics. “The good news is that these mutations develop in a distinct subtype of melanomas in the eye that are unlikely to spread and become deadly.”

Uveal melanomas occur in about 2,000 patients a year, making up about 5% of all melanomas. In many patients, there are no symptoms, and the tumors become fatal when they spread to the liver.

Study Background

Several years ago, Dr. Bowcock and the study’s lead author, J. William Harbour, MD, a former Washington University eye surgeon who is now at the University of Miami, identified a commonly mutated gene, BAP1, in patients with uveal melanomas. They found BAP1 alterations in about 80% of uveal melanomas with a poor prognosis, called class II tumors. About 75% of patients with these tumors die within 5 years, a sharp contrast to the generally favorable outcomes of patients whose tumors don’t have BAP1 mutations, called class I.

For the new study, Dr. Bowcock and her colleagues initially sequenced the DNA of uveal melanomas from 18 patients whose BAP1 status was already known. Seven had no BAP1 mutations, and 11 had BAP1 mutations. The researchers’ analysis uncovered alterations in the SF3B1 gene in three of the patients.

“This is the first time mutations in this gene have been found in uveal melanoma,” said Dr. Bowcock, who also is a Professor of Pediatrics and of Medicine.

As part of the current study, the researchers also looked for SF3B1 mutations in uveal melanoma tumors from 102 patients, finding it in nearly 20% of them. Mutations in the gene were linked to favorable features, including a younger age at diagnosis and a far lower metastasis rate.

Mutually Exclusive Mutations

Interestingly, SF3B1 mutations always occurred at the same site of the gene. And the SF3B1 and BAP1 mutations were found to be almost mutually exclusive.

“This suggests mutations in these genes may represent alternative pathways in tumor progression,” Dr. Bowcock said.

The SF3B1 gene also has been reported recently by other researchers to be mutated in myelodysplastic syndrome. For these patients, SF3B1 mutations mean the condition is less likely to develop into a full-blown leukemia. Changes in the SF3B1 gene also have been found in chronic lymphocytic leukemia and less frequently in breast cancer and other solid tumors. The gene’s link to prognosis is unclear for these cancers.

Next Step

Normally, the SF3B1 gene is involved in converting RNA into messenger RNA. The researchers don’t yet understand how mutations in this gene are involved in cancer but it’s the next step of their research.

“We want to understand the functional consequences of mutations in SF3B1,” Dr. Bowcock said. “How are changes in this gene linked to cancer development? This is the fourth gene known to be mutated in uveal melanoma along with BAP1 and the genes GNAQ and GNA11. A complete understanding of the molecular basis of this tumor will be invaluable in predicting prognosis and in the identification and development of novel treatments for this cancer.”

This research was supported by grants from the National Institutes of Health (NIH), the Melanoma Research Alliance, the Melanoma Research Foundation, the Tumori Foundation, Research to Prevent Blindness, Inc, and awards to the Department of Ophthalmology and Visual Sciences at Washington University from a Research to Prevent Blindness, Inc, unrestricted grant and also the NIH Vision Core grant and an NIH training grant. ■

Disclosure: Drs. Harbour and Bowcock reported that they and Washington University may receive income from the licensing of related technology by Washington University to Castle Biosciences, Inc. This work was not supported by Castle Biosciences.


1. Harbour JW, Roberson EDO, Anbunathan H, et al. Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. Nature Genetics. January 13, 2013.