Concurrence of chromosome 3 and 4 aberrations in human uveal melanoma

Abstract

Uveal melanoma (UM) is the most common primary intraocular malignancy with a very poor prognosis. The most frequent chromosome aberration in UM is the monosomy of chromosome 3. Previously, we demonstrated that ~50% of UMs express type-I receptor for luteinizing hormone-releasing hormone (LH-RH-R). The gene encoding LH-RH-R is located in chromosome 4 (location: 4q21.2); however, the occurrence of numerical aberrations of chromosome 4 have never been studied in UM. In the present study, we investigated the abnormalities of chromosome 3 and 4, and the possible correlation between them, as well as with LH-RH-R expression. Forty-six specimens of UM were obtained after enucleation. Numerical aberrations of chromosome 3 and 4 were studied by fluorescence in situ hybridization (FISH). Chromosome 4 was detected in normal biparental disomy only in 14 (30%) samples; however, 32 cases (70%) showed more than 2 signals/nucleus. Monosomy of chromosome 3 could be found in 16 (35%) samples. In 6 specimens (13%), more than 2 copies of chromosome 3 were found, while normal biparental disomy was detected in 24 (52%) samples. Statistical analysis indicated a statistically significant (p<0.05) correlation between the copy number of chromosome 3 and 4. Moreover, moderate difference was revealed in the survival rate of the UM patients with various pathological profiles. No correlation was found between chromosome aberrations and LH-RH-R expression. Our results clearly demonstrate abnormalities in chromosome 3 and 4 and the incidence of the monosomy of chromosome 3 in human UM. In summary, our results provide new incite concerning the genetic background of this tumor. Our findings could contribute to a more precise determination of the prognosis of human UM and to the development of new therapeutic approaches to this malignancy.

Genetic and epigenetic insights into uveal melanoma

“…Notably, the gene encoding LH‐RH‐R is located on chromosome 4q21.2. Based on the chromosome index (CI) values, a correlation between the copy numbers of chromosome 3 and 4 with survival rate of UM patients was found, but the study failed to detect any correlation between LH‐RH‐R expression and chromosome aberrations . In recent years, studies have highlighted the importance of independent mutations at corresponding genetic loci in the etiology of ocular diseases, leading to the identification of several candidate genes also in UM.…”

“…Based on the chromosome index (CI) values, a correlation between the copy numbers of chromosome 3 and 4 with survival rate of UM patients was found, but the study failed to detect any correlation between LH-RH-R expression and chromosome aberrations. 50 In recent years, studies have highlighted the importance of independent mutations at corresponding genetic loci in the etiology of ocular diseases, leading to the identification of several candidate genes also in UM. Particularly, 5 genes (BAP1, EIF1AX, GNA11, GNAQ, SF3B1) have been identified to be more frequently mutated and are often referred to as driver or key genes in UM development and progression.…”

The trends of uveal melanoma research in the past two decades and future perspectives.

“…There are several chromosomes in which abnormalities, losses, or gains are associated with an increased risk of metastasis. Chromosome 3 abnormalities can be useful in prognosis prediction [27]. Structural abnormalities of chromosomes 6, 8, and 11 also play a role in the uveal melanoma oncogenesis [28].…”

Characterization of luteinizing hormone-releasing hormone receptor type I (LH-RH-I) as a potential molecular target in OCM-1 and OCM-3 human uveal melanoma cell lines

“… 9 In our previous study, we demonstrated aneuploidy of chromosome 4 in 70% of human UM specimens. 13 Furthermore, a correlation was found between the copy number of chromosome 3 and 4 and the survival of patients. 13 BRCA1-associated protein 1 (BAP1) is located on chromosome 3p21.1 and is thought to be a tumor suppressor gene.…”

“… 13 Furthermore, a correlation was found between the copy number of chromosome 3 and 4 and the survival of patients. 13 BRCA1-associated protein 1 (BAP1) is located on chromosome 3p21.1 and is thought to be a tumor suppressor gene. 14 Inactivating somatic mutations were found in 84% of the metastasizing UMs, implicating that BAP1 mutations occur late in the UM progression.…”