Genetic Testing

The genetic makeup of the OM tumor - and the patient's own genetics - is fast becoming a powerful prognostic indicator and valuable guide to inform treatment and surveillance, especially since most patients do not have evidence of metastatic disease at the time of primary diagnosis. Some tumors are genetically predisposed to mutate differently and may be more likely to metastasize, so patients in this subset will be monitored more aggressively. You can only make these informed decisions, though, if you are armed with the best data on your disease, though, and OMF encourages all patients to discuss genetic testing with their doctor early on, ideally before treatment of their primary tumor.

Before the introduction of the now widely used Gene Expression Profile (GEP) test, a widely used predictor of metastatic disease was the detection of monosomy 3. A monosomy is any form of aneuploidy (chromosomal abnormality) with the presence of only one chromosome (instead of the typical two in humans) from a pair. Abnormalities in chromosomes 1, 3, 6 and 8 may indicate an increased risk of OM metastasis. About half of OM tumors will show an alteration of chromosome 3 and metastatic OM occurs almost exclusively in patients with a loss of chromosome 3 (monosomy 3).  Put another way, the majority of tumors with the monosomy 3 abnormality have a poor prognosis (i.e. result in metastatic disease) versus less than 5% of tumors that have not had chromosome 3 deleted.

Here is the link to a paper that states 66% of metastasizing OM tumors with the monosomy 3 abnormality have a poor prognosis: "Monosomy 3 Predicts Death but Not Time until Death in Choroidal Melanoma"

It is believed that gains on chromosomes 6 and 8 can increase the predictive value of monosomy 3 (source: Melanoma Research Foundation). A gain of 6p indicates a better prognosis and a gain of 8q indicates a worse prognosis. This information can help predict risk of developing metastatic disease and can be obtained from a fine needle biopsy at the time of treatment of the primary eye tumor, but not after brachytherapy.

This test measures the gene expression profile (GEP), or molecular signature, of the tumor. It is based on a 15-GEP test and groups the tumor into low-, medium- or high-risk for metastasis over the next five years. The test results are individualized to the patient’s tumor, which is classified as one of the following phenotypes based on its risk profile:

Around half of ocular melanomas are shown to be “class 1” tumors and these tumors exhibit a distinct gene expression pattern, most often have chromosome 3, and thus have a low risk of metastasis. The other half of ocular melanomas, though, fall into the “class 2” category. These exhibit a different gene expression pattern, usually have lost one copy of chromosome 3, and have a relatively high risk of metastasis.

DecisionDx-UM is the name of the mainstream GEP test. Castle Biosciences is the company that makes the test. Since its availability in 2009, over 10,000 patients have been clinically tested with DecisionDx-UM, making it the most widely used uveal melanoma prognostic test in the US.

BAP1 mutations in OM cells seem to independently predict metastatic death and are associated with larger tumor size and ciliary body involvement. Germline mutations in BAP1 also seem to be particularly common in familial uveal melanoma and in familial cancer syndromes which commonly include cutaneous melanoma, mesothelioma, and other tumors.

PRAME expression in uveal melanoma cells also seems to be positively associated with larger tumor diameter, shorter time to metastasis, and increased risk of melanoma-associated mortality and is independently predictive when added to GEP Class 1 or Class 2 distinction. PRAME is under investigation as a potential target for immunotherapy in cutaneous melanoma and may possibly constitute a treatment pathway for uveal melanoma in the future.

GNAQ or GNA11 gene mutations are found in approximately 83% of OM tumors, but may also be found in nevi and do not seem to predict the development of metastases.

To dive deeper into the science here, Dr. Michael Seiber's recent article in RETINA is a great primer on the state of the art in genetic testing.

According to the MRF, studies have shown that, if given the opportunity, most patients prefer to know their risk. Patients often feel that they can make more informed decisions and have reported that knowing the results of the genetic test were valuable regardless of the results. Ultimately, the hope with genetic testing is that individual clinical follow-up can be tailored to a patient’s risk of metastasis and, perhaps, lead to earlier detection and therapy.

Castle Biosciences offers an informative Patient Guide to help patients think through their testing options.

Your doctor may refer you to a genetic counselor to discuss the results of your genetic test. A genetic counselor is a health care professional with a master’s degree in human genetics or genetic counseling. The role of a genetic counselor is to help you better understand your results and how they may impact your treatment outlook. The training they receive enables them to discuss technical genetic information in practical, useful terms.

The DecisionDx-UM test, developed by Bill Harbour, MD of Bascom Palmer Eye Institute, is an advanced GEP test to better understand genetic makeup. It can determine Class 1A (very low risk), Class 1B (low risk; 21% chance of metastasis over 5 years) and Class 2 (high risk of metastasis; 72% chance of metastasis over 5 years). Learn more > 

Available since 2014, this test uses a mix of MLPA and MSA to evaluate for complete or
partial loss, duplications, or isodisomy of Chromosomes 1p, 3, 6, and 8. In addition, genetic sequencing of the GNAQ and GNA11 genes is offered for select specimens.
 Learn more >