Are Risk Factors for Growth of Choroidal Nevi Associated With Malignant Transformation? Assessment With a Validated Genomic Biomarker

EDITOR:

WE WOULD LIKE TO COMMENT ON HARBOUR AND ASSOCIates’ American Ophthalmological Society thesis “Are risk factors for growth of choroidal nevi associated with malignant transformation? Assessment with a validated genomic biomarker.” ¹ The authors found that of the many clinical features associated with “malignant transformation” of a melanocytic tumor, only 2, tumor thickness greater than 2.25 mm and patient age (over 60), are significant. There are likely a few exceptions to this, such as diffuse melanoma. Herein we wish to offer a few additional insights into these important findings.

Thickness likely is a measure of tumor size, and it is known that a larger tumor will generate more mutant cells, including those with the capacity to metastasize.² The random mutation rate in uveal melanoma cells for any gene appears rather constant, irrespective of tumor size. The larger (thicker) the tumor, the greater the number of mutated cells, including those capable of intravasating into the vasculature, surviving circulation, and seeding successfully in distant organs, hence the higher the likelihood of clinical metastasis. Two mutations are important for the onset of uveal metastasis. Tumors with BAP1 mutations display early clinical metastases, while those with SF3B1 mutations metastasize later.² The finding that these 2 types of mutations are most commonly associated with the progression of a uveal nevus into a metastatic melanoma implies that each confers unique and possibly different advantages in the different steps of metastasis that need to be further elucidated.³

With regard to patient age, Harbour and associates initially hypothesized that older patients may have more BAP1 mutations, but found it was not the case.¹ They then proposed that a weakening in the immune microenvironment of the eye may change with age and favor tumor growth. We wish to expand this view and hypothesize that systemic age-related immune changes impact local and distant growth of uveal melanoma. Age alters the functionality of the immune system, a process called “immune senescence” that affects T cells and macrophages.⁴ Tumor-immune interactions occur both at the primary tumor site and in invaded organs. Metastatic uveal melanoma cells are found in hematopoietic tissue, including bone marrow⁵ and possibly spleen. The expansion of the disseminated cancer cells is constrained by an active immune environment in the liver, the most important end-organ site of uveal melanoma metastasis.³ Thus the dynamic of tumor-immune cell interactions will likely be modified with age, resulting in lessened antitumor response and increased success of metastatic growth.⁴

Additionally, comprehensive genomic studies by TCGA research consortium have revealed hypoxia signaling as a major transcriptional signature in specific subsets of uveal melanoma at high risk for metastasis.⁶ The presence of hypoxia and hypoxia inducible factor 1 (HIF1) signaling in uveal melanoma and the therapeutic value of its targeting have also been recently established.⁷ As aging results in decreased blood flow to the choroid,⁸ this may accelerate the onset of hypoxia in an emerging tumor, and accelerate tumor vascularization/vasculogenic mimicry,⁹ well known risk factors of metastasis. This hypothesis will need to be experimentally assessed in animal models reflecting age-related impediments in blood flow.