DNA-based analysis identifies risk factor for metastasis of uveal melanoma

August 13, 2017

Carol. L. Shields, MD, highlighted the results of collaborative efforts among four Philadelphia institutions: Wills Eye Hospital, Thomas Jefferson Hospital, the Genetics Department of the University of Pennsylvania, and the Wistar Instituate. The findings were published in Ophthalmology (Shields et al. 2017; published online May 7, 2017).

DNA-based analysis of cytogenetic abnormalities identified correlations of clinical features in patients with uveal melanoma-namely, that larger ocular melanomas and older patient age are associated with increased risk for metastasis. Small-to-medium uveal melanomas are associated with lower metastatic risk.

Carol. L. Shields, MD, highlighted the results of collaborative efforts among four Philadelphia institutions: Wills Eye Hospital, Thomas Jefferson Hospital, the Genetics Department of the University of Pennsylvania, and the Wistar Instituate. The findings were published in Ophthalmology (Shields et al. 2017; published online May 7, 2017).

“This study found that the strongest predictor of patient prognosis depends on chromosomal status, particularly chromosomes 3, 6, and 8,” said Dr. Shields, associate professor of ophthalmology, The Ocular Oncology Service, Wills Eye Hospital, Philadelphia.

The study of 1,059 patients with uveal melanoma found that if there is an abnormality in chromosome 3, there is a four times greater risk for metastatic disease, she explained.

If there are abnormalities in chromosomes 3 and 8q, there is a 19 times greater risk for metastatic disease, and if there are abnormalities in 3, 6p and 6q, and 8q there is a 77 times greater risk for metastatic disease. If chromosomes 3, 6, and 8 are all mutated, the risk for metastatic disease is 123 times greater.

“This is profound and personalized diagnosis,” she said.

Dr. Shields and colleagues examined the study patients over a 10-year period. All had findings obtained by fine-needle aspiration biopsy and DNA analysis.

Mutations in chromosomes 3 and 8 are deleterious and worsen the prognosis, while mutations in chromosome 6 might be, but are not always, protective, she pointed out.

Fine-needle aspiration biopsy successful obtained adequate DNA in 96% of cases, even in melanomas that are as thin as 2.5 mm. This allowed sampling of every tumor.

Mutations were found in chromosome 3 in 48% of cases, in chromosome 6 in 32%, chromosome 8 in 41%, and any mutations in chromosomes 3, 6, or 8 in 60% of cases, according to Dr. Shields.

Correlation of clinical features

 

Correlation of clinical features

The significant clinical features that were correlated with any mutations in chromosomes 3, 6, or 8 were ciliary body location, greater distance from the optic nerve and the foveola, greater tumoral diameter, and greater thickness. Dr. Shields pointed out that these findings are very similar to those identified by investigators doing RNA analysis.

A noteworthy finding was that in patients diagnosed with a choroidal nevus who were later found to have a melanoma, there was a significantly lower risk for mutations in chromosomes 3, 6, or 8-which probably represents a lower grade tumor, she explained.

Patients with melanoma in the ciliary body, a large base, and great thickness were more likely at risk for mutations in chromosomes 3, 6, or 8, she noted.

When considering tumoral size in relation to chromosomes 3, the study found small melanomas had a mutation in chromosome 3 in 35% of cases, medium tumors in 52%, and large tumors in 65%. Similarly, chromosome 8 was mutated, respectively, in 19%, 49%, and 69%.

“The greater tumor size shows greater rates of mutations in chromosomes 3 and 8,” Dr. Shields said.

When medium and small tumors were compared, there was a 2.6 times greater risk for chromosome 3 monosomy. When large tumors were compared with medium and small tumors, the risk was 2.7 times greater, and when medium and large tumors were compared with small tumors, the risk was 3 times greater. The findings were similar with chromosome 8.

“Greater tumoral size correlates with an increasing mutational profile by at least 3 to 6 times,” she said.

Older patient age risk

 

Older patient age was associated with a 1.8 times higher risk of chromosome 3 monosomy. Melanocytosis promotes a 1.7 times greater risk for chromosome 3 monosomy. Ciliary body location carried an increased risk of 8.2 times, tumoral diameter exceeding 10 mm a 2.6 times higher risk, and thickness over 8 mm a 2.7 times greater risk, Dr. Shields said.

In association with chromosome 8, melanocytosis was an important predictor of chromosome 8p and 8q loss, a 2.8 to 4 times greater risk for a mutation. When tumors were in the ciliary body, there was a 53 to 102 times greater risk of chromosome 8 mutation.

“Our results showed that large melanoma and older age are great risks for mutational abnormalities, which puts the patient at greater risk for metastasis,” she said. “This underscores the importance of early detection of uveal melanoma. Small melanoma has a substantially reduced mutational profile that is correlated with better systemic prognosis.

“Catch the tumor early when it is thinner and there are fewer complications of treatment and a more favorable genetic profile,” Dr. Shields said.

Dr. Shields has no financial interest in any aspect of this report. She presented her study results at the 2017 meeting of the American Society of Retina Specialists in Boston.