Chromosomal gains and losses in ocular melanoma detected by comparative genomic hybridization in an Australian population-based study

doi:10.1016/S0165-4608(02)00868-3

Cancer Genetics and Cytogenetics

Volume 144, Issue 1, 1 July 2003, Pages 12-17

https://doi.org/10.1016/S0165-4608(02)00868-3 Get rights and content

Abstract

To define the location of potential oncogenes and tumor suppressor genes in ocular melanoma we carried out comparative genomic hybridization (CGH) analysis on a population-based series of 25 formalin-fixed, paraffin-embedded primary tumors comprising 17 choroidal, 2 ciliary body, 4 iris, and 2 conjunctival melanomas. Twelve (48%) of the 25 melanomas showed no chromosomal changes and 13 (52%) had at least one chromosomal gain or loss. The mean number of CGH changes in all tumors was 3.3, with similar mean numbers of chromosomal gains (1.5) and losses (1.8). The highest number of chromosomal changes (i.e., nine) occurred in a conjunctival melanoma and included four changes not observed in tumors at any other ocular site (gains in 22q and 11p and losses in 6p and 17p). The most frequent gains in all primary ocular melanomas were on chromosome arm 8q (69%), 6p (31%) and 8p (23%) and the most frequent losses were on 6q (38%), 10q (23%), and 16q (23%). The most common pairing was gain in 8p and gain in 8q, implying a whole chromosome copy number increase; gains in 8p occurred only in conjunction with gains in 8q. The smallest regions of copy number alteration were mapped to gain of 8q21 and loss of 6q21, 10q21, and 16q22. Sublocalization of these chromosomal changes to single-band resolution should accelerate the identification of genes involved in the genesis of ocular melanoma.

Introduction

Melanoma is the most common ocular malignancy in white adult populations and it is often fatal. Constitutional characteristics such as light eye color, cutaneous nevi, and sun sensitivity are recognized risk factors [1]; however, the genetic events that contribute to its pathogenesis are not yet clear. Unlike cutaneous melanoma, no ocular melanoma inherited susceptibility genes have been identified and familial ocular melanoma is rare [2]. Furthermore, while cutaneous nevi are a risk factor for both cutaneous and ocular melanoma [1], genetic aberrations of CDKN2A, NRAS, and PTEN, which are common in cutaneous melanoma, are rare in ocular melanoma 3, 4, 5. These findings may suggest major differences in the pathways underlying their development.

This study examines chromosomal gains and losses within a subset of a population-based series of all ocular melanoma patients diagnosed in Australia from 1996 to 1998. The entire genome was scanned for chromosomal copy number changes and these changes were mapped to specific chromosomal regions using comparative genomic hybridization (CGH). Regions of gain or loss are likely to harbor oncogenes or tumor suppressor genes, respectively.

Previous CGH analyses of choroid and ciliary body melanomas have identified recurrent chromosomal abnormalities, including loss of chromosome 3 (45%–70%), loss of chromosome arm 6q (20%–62%), 8p (26%–31%), 11q (18%–20%), 1p (9%–22%), and gain in chromosome arm 8q (39%–70%) and 6p (30%–85%) 6, 7, 8, 9. The current study represents the first population-based CGH analysis of ocular melanomas and the only CGH study to include melanomas originating in the iris and conjunctiva. One previous study [7] examined tumors described as uveal tract, a term used to collectively describe the choroid, ciliary body, and iris; however, only choroidal and ciliary body melanomas were examined.

Section snippets

Subjects

The case ascertainment methods have been described in detail elsewhere [1]. Briefly, we identified all incident cases of primary ocular melanoma diagnosed in Australia between January 1996 and July 1998. Incident cases were eligible for the case-control study if they were 18–79 years old, with histopathologically or clinically diagnosed melanoma originating in the choroid, ciliary body, iris, or conjunctiva. Fifty-nine (79%) of the 75 incident cases less than 51 years old were enrolled in the

Results

Due to the very low quality of DNA retrieved from some specimens, CGH was successfully performed on 25 primary tumors from the 39 patients, 17 men and 8 women, with a mean age at diagnosis of 40 years (range 28–50 years). The distribution of tumor primary site, morphology, size, and stage at diagnosis for this series did not differ significantly from the incident case series (data not shown). Conjunctival melanomas, however, were relatively under-represented in the CGH series. Five choroidal

Discussion

CGH was used to analyze DNA copy number changes associated with formalin-fixed, paraffin-embedded primary ocular melanomas in a young Australian population–based sample. Just over half (52%) of the melanomas exhibited one or more chromosomal copy number changes, a smaller proportion than other non–population-based series. The mean overall number of changes (3.3) was similar to that found in another study of fixed tumor material, which analyzed 29 choroidal and ciliary body melanomas (mean 3.1)

Acknowledgements

We acknowledge our collaborators on other aspects of the work, particularly Dr. M. Giblin, Dr. J. McKenzie, and Prof. G. Giles. We thank the patients who participated in the research and the ophthalmologists who notified their patients about the incidence survey and gave permission for us to approach them about the study. This work was supported by The Cancer Council NSW and The National Health and Medical Research Council of Australia.

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Original articlesChromosomal gains and losses in ocular melanoma detected by comparative genomic hybridization in an Australian population-based study

Abstract

Introduction

Section snippets

Subjects

Results

Discussion

Acknowledgements

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Eye color and cutaneous nevi predict risk of ocular melanoma in Australia

Int J Cancer

Familial uveal melanoma, III. Is the occurrence of familial uveal melanoma coincidental?

Arch Ophthalmol

Investigation of the role of the ras protooncogene point mutation in human uveal melanomas

Invest Ophthalmol Vis Sci

Analysis of p16 (CDKN2/MTS-1/INK4A) alterations in primary sporadic uveal melanoma

Invest Ophthalmol Vis Sci

Mutation analysis of the PTEN gene in uveal melanoma cell lines

Int J Cancer

Concomitant loss of chromosome 3 and whole arm losses and gains of chromosome 1, 6 or 8 in metastasising primary uveal melanoma

Invest Ophthalmol Vis Sci

Original articles
Chromosomal gains and losses in ocular melanoma detected by comparative genomic hybridization in an Australian population-based study