Edith Cowan University research is one step closer to understanding why uveal melanoma, the deadliest form of eye cancer, has such a high rate of metastasis.
Uveal melanoma is a rare cancer type, affecting 7.6 adults per million in Australia and represents about 5% of all melanomas. Patients with uveal melanoma have a 50% chance of the disease metastasising from the eye, commonly to the liver, even after successful treatment of the tumours within the eye.
Metastases of uveal melanoma can develop up to 20 years after the primary tumour treatment, and the median survival in patients after a diagnosis of metastases is between 5 to 18 months.
The ECU team looked at inactivating mutations and/or loss of expression of the gene encoding BRCA1-associated protein 1 (BAP1) in UM tumours which are associated with an increased risk of metastasis.
To investigate the mechanisms underlying this risk, they studied the functional consequences of BAP1 deficiency.
ECU Vice Chancellor’s Research Fellow, Dr Vivian Chua, said that after diagnosis of the disease in the liver, patient survival was often short due to the lack of effective treatment options.
“The metastatic tumours respond poorly to many treatment options that had been shown to be effective in other cancer types including skin melanoma. It is unclear how and why uveal melanoma spread or metastasise to the liver,” she said.
“Identifying the mechanisms that drive uveal melanoma metastasis will likely uncover strategies to prevent uveal melanoma spreading or the development of metastatic uveal melanoma, which is the cause of death of patients.”
The BAP1 gene is involved in modulating the characteristics of cancer cells, particularly uveal melanoma. Alterations in the BAP1 gene lead to loss of the BAP1 protein function and expression and are associated with an increased risks of metastasis of uveal melanoma and poorer patient survival. BAP1 alterations have also been reported in other cancer types such as mesothelioma and cholangiocarcinoma.
But Dr Chua said the roles of BAP1 loss or deficiency in uveal melanoma had remained unclear.
She engineered human uveal melanoma cell cultures that were BAP1-deficient to re-exhibit BAP1, to allow for a comparison between the BAP1-deficient and BAP1-proficient uveal melanoma cells.
“We found that BAP1-deficient cells are slow-growing, and this was associated with the cells exhibiting low activity of the S6 protein,” she said.
“This is consistent with the known function of the S6 protein to regulate cancer cell growth. These characteristics were also associated with the BAP1-deficient cells surviving better under conditions deprived of amino acids.
“Overall, we have uncovered a role of BAP1 deficiency in uveal melanoma.”
The results suggested BAP1-deficient uveal melanoma cells could survive under conditions that are deprived of nutrients, particularly amino acids, allowing them to spread successfully.
“My research is now aimed at investigating what mechanisms support BAP1-deficient cell survival under amino acid deprivation and identifying co-players of S6,” she said.
“Unlike skin melanoma, sunshine and UV rays are actually not known to be risk factors for uveal melanoma except for maybe a small population of patients with tumours originating from the iris (the outermost area of the uveal tract of the eye). This is reported by a study in Brisbane.
“However, uveal melanoma is most prevalent in adults with fairer skin and eye colours, and hence more common in Caucasians than in other populations such as Africans and Asians.”