LOOC discovers clue to aggressive behaviour of intraocular melanomas
There are two types of intraocular melanoma: low-grade melanomas, which grow slowly, rarely spreading outside the eye; and high-grade melanomas, which grow rapidly and which usually scatter seeds to distant parts of the body, with fatal consequences. About four-in-ten intraocular melanomas develop high grade malignancy.
Intraocular melanomas arise from melanocytes, pigmented cells which give the inside of the eye its dark colour. The behaviour of these cells is controlled by their genes. If these genes develop any critical mutations, the melanocytes multiply chaotically, to form a malignant melanoma.
Normal cells have evolved a mechanism for fixing damaged genes, which pauses cell multiplication until repair is complete. If, however, the mutation is irreparable, then the cell self-destructs (i.e. undergoes ‘apoptosis’). This remarkable protection against cancer is regulated by the P53 gene. Many cancers develop because the P53 gene is itself mutated.
One of the mysteries of intraocular melanomas is that the P53 gene is normal. Why then don’t mutant intraocular melanoma cells self-destruct? Apparently, the P53 gene triggers apoptosis by acting on a second gene, which is known as PERP. We have found that in highly aggressive ocular melanomas PERP function is severely deficient.
This discovery is important because it may one day lead to a cure. Several major therapeutic advances have recently occurred as a result of a better understanding of the genetic mechanisms regulating cell growth and multiplication.
We were able to do this research because in 1996 we said to our hospital that if our patients had a collective voice they would say that what they want most of all is for us to save life as well as treating the eye. The Royal Liverpool University Hospital responded admirably by providing a permanent salary for a full-time scientist in ocular oncology.
The scientific experiments required to unravel the genetic clockwork of ocular melanoma cells are very expensive and would not have been affordable without sponsorship from the Eye Tumour Research Fund. This fund consists entirely of generous donations from patients treated at the Liverpool Ocular Oncology Centre.
Our research in this field has already had a profound impact on our patient care. We were the first to offer cytogenetic testing to ocular melanoma patients as a routine clinical service. Already, over 500 patients have now had such tests (by far the largest series worldwide). The fortunate patients with a low-grade melanoma have been greatly relieved by news of their good prognosis. Those with a life-threatening melanoma are now referred to a general oncologist for regular screening tests and some have benefited from liver surgery.
We are currently evaluating our interim results and considering whether it would be reasonable to offer cytogenetic testing not only to patients treated by surgical removal of the tumour but also those treated with radiotherapy. Such patients would require a biopsy using techniques we have developed (see earlier blog). This is a line of clinical research we are pursuing at the moment. Watch this space.
(Paraoan L, Gray D, Hiscott P, Ebrahimi B, Damato B, Grierson I. Expression of p53-induced apoptosis effector PERP in primary uveal melanomas: Downregulation is associated with aggressive type. Exp Eye Res. 2006 Jun 16; [Epub ahead of print]).