What is Uveal Melanoma? (UM)

Uveal melanoma (UM) is a melanoma (type of cancer) of the eye, involving the iris, ciliary body or choroid (collectively referred to as the uvea). These malignant (cancerous) tumors arise from the pigmented cells (melanocytes) within the uvea.

Genetics

Approximately 50% of patients diagnosed with UM will develop metastases within 10 years of treatment of the primary intraocular tumor. Multiple factors contribute to the survival prognosis of a patient with uveal melanoma including genetics of the tumor, histologic grade, size and clinical stage of the tumor [Damato, B. et al. Progress in Retinal and Eye Research, 2011].

One of the most important indicators of poor prognosis in UM is loss of chromosome 3 (monosomy 3). Metastatic disease develops almost exclusively in patients with this genetic abnormality. Other genetic factors contributing to the survival prognosis include copy number variation of chromosomes 1, 6 and 8 [Damato, B. and Coupland, S.E. Arch Ophthalmol. 2009]. The prevalence of monosomy 3 in small tumors (basal diameter <10 mm) is as high as 35% [Damato, B. and Coupland, S.E. Arch Ophthalmol. 2009]. For this reason, it is important to analyze the genetics of the tumor in addition to other factors such as size.

What causes UM?

The majority of UM is thought to occur by chance (often referred to as sporadic), and everyone is at risk of developing UM. The genes that control growth in uveal cells obtain a mistake or become missing altogether. It is believed that certain risk factors including eye (iris) color, skin color, ancestry, tanning ability and a family history of uveal melanoma can predispose an individual to UM.

Mistakes in tumor suppressor genes can be inherited from a parent. These mistakes are called germline mutations and can be passed from one generation to another. An example of this is the BRCA1, gene, associated with breast and ovarian cancer. Germline mutations are present in every cell of a person’s body, including their egg or sperm cells. For this reason, each child has a 50% risk of inheriting a mutation from the parent.

Mistakes can also happen in a healthy cell by chance. These are called somatic mutations and they are not passed on within a family. Somatic mutations happen in a single cell and are not inherited. Similar to other types of cancer, UM is most often caused by somatic mutations.

The cause of somatic mutations is generally unknown; however, certain factors, such as sun exposure, radiation, cigarette smoking and certain chemicals, are known to increase risk of mutations in genes that control cancer. They are typically referred to as carcinogens.

What genetic mistakes cause UM?

It is well documented that the cells that become mutated and become eye cancer cells are missing either sections of chromosomes or entire chromosomes. Each chromosome contains thousands of genes, many of which are tumor suppressor genes. If a chromosome goes missing or is altered, then the genes that are contained in that chromosome no longer function and do not provide protection from uncontrolled growth.

Monosomy:
The most common genetic mistake that can be linked to risk of metastasis (and subsequent survival) is referred to as monosomy 3. “Mono” means “one” and “3” refers to chromosome 3. Every cell should have two copies of chromosome 3, called disomy 3; however, some cancer cells only have one. Cancer cells that have only one copy of chromosome 3 are thought to be much more aggressive than those that have two copies. The chance that these cancer cells can spread (metastasize) is much higher than for other cancer cells with two copies of chromosome 3. Approximately 50% of UM tumors will show an alteration of chromosome 3 copy number [Thomas, S. et al. British Journal of Cancer. 2012]. Monosomy in chromosomes 1, 3 and 8 are also shown to be indicative of prognosis [Damato, B. et al. Clin Cancer Res. 2010].

Trisomy:
Sections of chromosomes 6 and 8 can have a third (extra) copy, called trisomy, which can predict if the cancer will spread [Damato, B. et al. Clin Cancer Res. 2010].

Isodisomy:
When a cell loses one copy of a chromosome (typically chromosome 3 in UM), it may create a copy of its one remaining chromosome, leaving it with two identical copies. It is known that in order for a cell to function properly, two NON-identical copies of a chromosome are needed (one from your mother, one from your father). Two copies of an identical chromosome function as one, and it is well documented that this situation causes the same effect as having just one chromosome 3 (monosomy 3). Isodisomy is thought to occur in up to 16% of UM tumors, and these tumors would be considered to be at high risk to metastasize [Werdich. et al. SemOphthal. 2013].

Single gene mutations:
BAP1 gene mutations can occur by chance in tumor cells or they can be inherited (germline mutation). Families that have a germline BAP1 mutation commonly show a pattern of various types of cancer including UM plus lung adenocarcinoma, UM plus neuroendocrine carcinoma, as well as meningioma, abdominal adenocarcinoma and cutaneous melanoma [Abdel-Rahman, M. et al. J Med Genet. 2011].

Why would I want to know if my tumor has changes in its chromosomes?

When a cancer cell metastasizes (spreads) from the eye, the most common place it goes is to the liver. Survival prognosis is thought to be much better if the cancer does not spread beyond the eye. Genetics of the tumor has been linked to the likelihood that the cancer may spread or may have already spread.

Even small tumors can have genetic changes that would put them at high risk to metastasize. As many as 35% of tumors smaller than 10mm can show genetic changes that put them at high risk to spread [Damato, B. et al. Arch Ophthal. 2009].

Cancer is often unpredictable and many patients find it difficult to come to terms with a diagnosis of cancer. Sharing this information with family members and friends can be very challenging. Some patients feel, however, that knowing their chance of survival is valuable. This knowledge empowers life planning and may initiate the development of support strategies. Many individuals diagnosed with this condition state that they have hope they will be considered to be at low risk for the cancer to spread; however, knowing either way can allow them to understand more clearly their risk for the future. If cancer spreads to the liver, there is limited treatment available to cure it at this time.

Some specialists will change treatment and/or surveillance for metastases depending upon the genetic make-up of cancer cells (determined through genetic prognostic testing).

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