Frequency, molecular pathology and potential clinical significance of partial chromosome 3 aberrations in uveal melanoma

Abstract

The clinical significance of partial chromosome 3 alteration in uveal melanoma is still not clear. Also, the reported frequencies vary considerably in the published literature from 0 to 48%. The aims of the following study were to identify the frequency, molecular pathology and potential clinical significance of partial chromosome 3 alteration in uveal melanoma. We studied 47 uveal melanomas with an average follow-up of 36 months. Of these, 14 had confirmed metastasis. Allelic imbalance/loss of heterozygosity was studied using microsatellite markers on chromosome 3 enriched in markers located in the previously reported smallest regions of deletion overlap. Chromosomal alterations were assessed by conventional cytogenetics or comparative genomic hybridization (CGH) in a subset of patients. Utilizing genotyping, partial chromosome 3 alteration was detected in 14/47 tumors (30%). In the 23 tumors with available cytogenetic/CGH, partial chromosome 3 alteration was detected in 8/23 (38%) and was caused by both gains (4/8) and losses (4/8) of chromosome 3 with high frequency of complex chromosome 3 aberrations detected by cytogenetics. Out of the 14 tumors with confirmed metastasis, only 1 showed partial chromosome 3 alteration and the remaining showed monosomy 3. By limiting the aggressive disease marker to monosomy 3, genotyping showed 93% sensitivity and 67% specificity for detection of aggressive uveal melanoma. In conclusion, partial chromosome 3 alterations are common in uveal melanoma and mostly caused by complex cytogenetic changes leading to partial gains and/or partial losses of chromosome 3. Partial chromosome 3 alteration is not likely to be associated with highly aggressive uveal melanoma that metastasizes within the first 3 years after treatment. Microsatellite-based genotyping of chromosome 3 is highly sensitive for detection of aggressive uveal melanoma.

Chromosome 3 Status in Uveal Melanoma: A Comparison of Fluorescence In Situ Hybridization and Single-Nucleotide Polymorphism Array

“…Some of the variability in the results is influenced by differences in methodology for detection and interpretation of changes in parts of chromosome 3 (gains and losses). 49,52 Data from several studies have indicated that partial loss of chromosome may not be as deleterious as total loss of chromosome 3 in influencing the risk of metastasis because tumors with partial chromosome 3 loss behave similar to tumors classified as disomic. 48,49,52 Our study further underscores the need for standardization of techniques, if results from various centers are to be directly compared.…”

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

“…6). Most recent studies consistently show that these tumors, in contrast to those with monosomy 3, are associated with good prognosis 5,6 .…”

Monosomy 3 status of uveal melanoma metastases is associated with rapidly progressive tumors and short survival

“…In UM there is ample evidence of the association of the primary tumor’s molecular genetics with early development of metastasis, usually within 3 years of diagnosis (Abdel-Rahman et al, 2011; Shields et al, 2011). However, this is the first report linking the molecular genetic alterations of the metastatic lesions with overall tumor progression and patient survival.…”

“…Several genetic studies of the smallest regions of deletion in UM have found multiple regions in chromosome 3 on both the p and q arms; however, these regions don’t generally overlap between different studies(Abdel-Rahman et al, 2011; Hausler et al, 2005; Parrella et al, 2003; Tschentscher et al, 2001). …”

“…Genotyping was carried out utilizing microsatellite markers on chromosomes 1p, 3, 6p and 8q according to our published protocol (Abdel-Rahman et al, 2011). Allelic imbalance factor (AIF) was determined by calculating the ratio of allele heights for both the normal peripheral blood (N) and tumor (T) sample from each patient and then the tumor ratio was divided by the normal ratio: [T1:T2/N1:N2] with N1 as the highest of the two N alleles (Cawkwell et al, 1993; Skotheim et al, 2001).…”