Melanomas are notoriously difficult to classify because of a lack of discrete clinical and pathological stages. Here, we show that primary uveal melanomas surprisingly cluster into two distinct molecular classes based on gene expression profile. Genes that discriminate class 1 (low-grade) from class 2 (high-grade) include highly significant clusters of down-regulated genes on chromosome 3 and up-regulated genes on chromosome 8q, which is consistent with previous cytogenetic studies. A three-gene signature allows biopsy-size tumor samples to be assigned accurately to tumor classes using either array or PCR platforms. Most importantly, this molecular classification strongly predicts metastatic death and outperforms other clinical and pathological prognostic indicators. These studies offer new insights into melanoma pathogenesis, and they provide a practical foundation for effective clinical predictive testing.

https://cancerres.aacrjournals.org/content/canres/64/20/7205.full.pdf

Gene Expression Profiling in Uveal Melanoma Reveals Two Molecular Classes and Predicts Metastatic Death

Michael Zeschnigk and colleagues identify recurrent somatic mutations of EIF1AX and SF3B1 in uveal melanomas with disomy 3. The EIF1AX mutations specifically alter the N-terminal tail of the protein and were found exclusively in tumors lacking SF3B1 mutations.

Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3.

Melanomas comprise multiple biologically distinct categories, which differ in cell of origin, age of onset, clinical and histologic presentation, pattern of metastasis, ethnic distribution, causative role of UV radiation, predisposing germ-line alterations, mutational processes, and patterns of somatic mutations. Neoplasms are initiated by gain-of-function mutations in one of several primary oncogenes, which typically lead to benign melanocytic nevi with characteristic histologic features. The progression of nevi is restrained by multiple tumor-suppressive mechanisms. Secondary genetic alterations override these barriers and promote intermediate or overtly malignant tumors along distinct progression trajectories. The current knowledge about the pathogenesis and clinical, histologic, and genetic features of primary melanocytic neoplasms is reviewed and integrated into a taxonomic framework.

/pdf/the-molecular-pathology-of-melanoma-an-integrated-taxonomy-tbokjudu7l.pdf

The Molecular Pathology of Melanoma: An Integrated Taxonomy of Melanocytic Neoplasia

Although it is a relatively rare disease, primarily found in the Caucasian population, uveal melanoma is the most common primary intraocular tumor in adults with a mean age-adjusted incidence of 5.1 cases per million per year. Tumors are located either in iris (4%), ciliary body (6%), or choroid (90%). The host susceptibility factors for uveal melanoma include fair skin, light eye color, inability to tan, ocular or oculodermal melanocytosis, cutaneous or iris or choroidal nevus, and BRCA1-associated protein 1 mutation. Currently, the most widely used first-line treatment options for this malignancy are resection, radiation therapy, and enucleation. There are two main types of radiation therapy: plaque brachytherapy (iodine-125, ruthenium-106, or palladium-103, or cobalt-60) and teletherapy (proton beam, helium ion, or stereotactic radiosurgery using cyber knife, gamma knife, or linear accelerator). The alternative to radiation is enucleation. Although these therapies achieve satisfactory local disease control, long-term survival rate for patients with uveal melanoma remains guarded, with risk for liver metastasis. There have been advances in early diagnosis over the past few years, and with the hope survival rates could improve as smaller tumors are treated. As in many other cancer indications, both early detection and early treatment could be critical for a positive long-term survival outcome in uveal melanoma. These observations call attention to an unmet medical need for the early treatment of small melanocytic lesions or small melanomas in the eye to achieve local disease control and vision preservation with the possibility to prevent metastases and improve overall patient survival.

/pdf/uveal-melanoma-relatively-rare-but-deadly-cancer-33jnnz9xzb.pdf

Uveal melanoma: relatively rare but deadly cancer.

Posterior uveal melanomas have nonrandom alterations affecting chromosomes 3, 6, and 8. Loss of chromosome 3 in uveal melanoma has been shown to act as a predictor of disease-free and overall survival. To confirm the significance of chromosome 3 loss and to extend the observations to include those of the associated alterations of chromosome 8, we have conducted a cytogenetic analysis on a series of 42 tumours from patients with primary uveal melanoma who were followed up for a median of 31 months (range = 8-96 months). Abnormalities of chromosomes 3 and 8 were the commonest changes and were confirmed in 10 tumours using flourescence in situ hybridization. Monosomy of chromosome 3 was found in 21 (50%) of the tumours, and 23 (54%) tumours had additional copies of 8q. Alterations of chromosomes 3 and 8 were found occurring together in 19 (45%) of the tumours and were significantly associated with a ciliary body component (P < 0.0001). Prognostic indicators and changes of chromosomes 3 and 8 were analysed for correlation with patient survival. Of the chosen parameters, only ciliary body involvement (P = 0.003), monosomy of chromosome 3 (P = 0.0007), and additional copies of 8q (P = 0.003) correlated with reducted survival. Evaluation of the dosage effect of additional copies of chromosome arm 8q showed a significant association with reduced survival (P = 0.0001), which was also predictive of a decreased disease-free interval (P = 0.01). Thus, the cytogenetic analysis of uveal melanoma may provide a valuable predictor of prognosis. Genes Chromosom. Cancer 19:22–28, 1997. © 1997 Wiley-Liss, Inc.

H Hirche

Papers

Prognostic implications of monosomy 3 in uveal melanoma