Genetic Study of Familial Uveal Melanoma: Association of Uveal and Cutaneous Melanoma with Cutaneous and Ocular Nevi

doi:10.1016/j.ophtha.2006.08.041

Ophthalmology

Volume 114, Issue 4, April 2007, Pages 774-779

https://doi.org/10.1016/j.ophtha.2006.08.041 Get rights and content

Purpose

To evaluate a kindred with familial uveal and cutaneous melanoma and to identify potential genetic and environmental factors that may predispose individuals to develop uveal melanoma.

Design

Family-based case report with detailed clinical and genetic evaluation.

Participants

Ten siblings in a single nuclear family.

Methods

Evaluation of a large sibship via family history, complete eye and skin examinations, environmental risk factor questionnaire, and genetic testing, as well as a MEDLINE search of familial uveal melanoma kindreds.

Main Outcome Measures

Cutaneous and ocular nevi, benign and malignant neoplasms of skin and other sites, brief skin cancer risk assessment tool risk classification for cutaneous melanoma, DNA sequencing of p16INK4a and p14ARF genes, and citations on familial uveal melanoma.

Results

The proband and his mother had uveal melanoma, 3 cutaneous melanomas occurred among 2 siblings, and 2 other siblings had basal cell carcinomas. No germline mutations were detected in the melanoma-associated tumor suppressor genes p16INK4a and p14ARF. Seven out of 10 siblings had a history of cutaneous and/or ocular nevi. Of the 3 subjects without nevi, 2 had histories of eye or skin malignancies (1 uveal melanoma, 1 basal cell carcinoma). Three of the 10 siblings had relevant ocular findings (2 choroidal nevi, 1 uveal melanoma). Six were also found to be in the “high-risk” classification for cutaneous malignancies based on scores from a previously validated risk assessment tool. This family, combined with the 91 previously reported familial uveal melanoma kindreds, brings to 92 the total number thus far recorded.

Conclusions

Our results strengthen the association between uveal melanoma, atypical nevi, and cutaneous melanoma. This relationship supports the recommendation that individuals with a personal or family history of uveal melanoma, particularly in combination with atypical nevi, should be regularly screened for uveal and cutaneous melanoma.

Section snippets

Materials and Methods

Approval by the Evanston Northwestern Healthcare Research Institute Institutional Review Board was obtained before beginning the study (protocol EH02-172), and informed consent was obtained from all subjects. This work is compliant with the Healthcare Insurance Portability and Accountability Act, and regulations regarding human subjects research were followed. The proband (FUM-10) and all 9 of his siblings participated in this study. The parents and most of their siblings were already deceased.

Family History Evaluation

A 57-year-old man (FUM-10) of Czech and English descent presented with advanced uveal melanoma in 1 eye. The eye was enucleated and melanoma was confirmed by pathologic examination of the tumor. He was employed as a software engineer for 20 years and subsequently worked in computer retail for 10 years. His medical history was otherwise unremarkable except for a congenital dislocated hip treated with multiple surgeries. Figure 1 illustrates the family pedigree. The patient’s family history was

Discussion

Among patients with uveal melanoma, only 0.6% have a family history of uveal melanoma.⁴¹ Our report brings to 92 the total number of familial uveal melanoma kindreds that have been reported thus far in the literature. Although rare, statistical analysis shows that the occurrence of uveal melanoma among first-degree relatives exceeds that expected by chance alone by a factor of over 200.⁴ Thus, the likelihood of a hereditary predisposition to uveal melanoma in this family is high. Furthermore,

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Cited by (31)

Uveal Melanoma UK National Guidelines
2015, European Journal of Cancer
Citation Excerpt :
The role of sunlight is uncertain [20]. Familial cases are very rare but some patients may have familial atypical mole and melanoma syndrome; these cases require monitoring by a dermatologist as they are also at risk of cutaneous melanoma [22]. Rare families carry germline mutations of the BAP1 gene on chromosome 3, which predisposes them to develop uveal melanoma, mesothelioma and other cancers [2].
The United Kingdom (UK) uveal melanoma guideline development group used an evidence based systematic approach (Scottish Intercollegiate Guidelines Network (SIGN)) to make recommendations in key areas of uncertainty in the field including: the use and effectiveness of new technologies for prognostication, the appropriate pathway for the surveillance of patients following treatment for primary uveal melanoma, the use and effectiveness of new technologies in the treatment of hepatic recurrence and the use of systemic treatments. The guidelines were sent for international peer review and have been accredited by NICE. A summary of key recommendations is presented. The full documents are available on the Melanoma Focus website.
Epidemiology and Management of Uveal Melanoma
2012, Hematology/Oncology Clinics of North America
Citation Excerpt :
Development of uveal melanoma is usually considered a sporadic event. However, approximately 90 cases of familial uveal melanoma have been reported in the literature,33,34 and recently, germline BAP1 (BRCA1 [breast cancer 1, early onset]-associated protein 1) mutations have been shown to predispose to uveal melanoma, cutaneous melanocytic tumors, and other malignancies.35–37 Pregnancy,38,39 ovarian cancer,40 and history of malignancy in women41 have been implicated as well but without substantial evidence.
Uveal melanoma prognostication: From lesion size and cell type to molecular class
2012, Canadian Journal of Ophthalmology
Citation Excerpt :
A multitude of gene mutations have been implicated in pathways such as tumour suppression, G protein–coupled signaling, cell adhesion marker expression, and retinoic acid response.47,48 Although some predisposing mutations have been detected in uveal melanoma, the association is much weaker than that seen in cutaneous melanoma.49,50 Population-based studies of uveal melanoma first suggested a genetic basis for the disease,51 and we are now finding evidence of autosomal dominant inheritance in families carrying germ line mutations of BAP1.7,52
To review the evidence for molecular genetic testing of uveal melanoma in the context of prognostic indicators of metastasis and tumour-related mortality.
Review of the literature and personal experiences of the authors.
We conducted a MEDLINE, Embase, and PubMed literature search (1980–2011) for English-language abstracts and full-text references regarding molecular genetic testing of uveal melanoma. Search terms included uveal, melanoma, cytogenetic, gene, and molecular. All studies in which patients with primary uveal melanoma underwent molecular genetic testing with survival data for disease-related metastasis and mortality were reviewed.
From 176 identified articles, 40 were scientific studies of uveal melanomas that included histologic and molecular genetic analysis. Of those, 24 included survival data, correlation of molecular genetic features with other prognostic indicators, or both. Cytogenetic and microarray gene expression analysis allows uveal melanoma lesions to be classified as high risk or low risk for metastasis and disease-related mortality. Gene expression profiling supersedes clinical, histologic, and cytogenetic prognosticators.
Uveal melanoma comprises a heterogeneous group of malignancies based on its molecular biology. Molecular class by gene expression profiling has the most strongly predictive value for uveal melanoma metastasis and mortality.
Examen des données probantes du test de génétique moléculaire du mélanome uvéal dans le contexte des indicateurs pronostiques de la métastase et de la mortalité due à la tumeur.
Examen de la littérature et de l'expérience personnelle des auteurs.
Nous avons fait une recherche de la littérature anglaise dans MEDLINE, Embase et PubMed (1980–2011) pour y trouver des résumés et des textes entiers de références concernant le test de génétique moléculaire du mélanome uvéal, incluant des termes comme uvéal, mélanome, cytogénétique, gêne et moléculaire. L'examen a porté sur toutes les études concernant les patients qui avaient subi des tests génétiques moléculaires du mélanome uvéal primaire avec des données de survivance au métastase et à la mortalité liés à la maladie.
Parmi les 176 articles relevés, 40 étaient des études scientifiques des mélanomes uvéaux, comportant des analyses histologiques et de génétique moléculaires. Vingt-quatre études présentaient des données de survivance et/ou des éléments de corrélation de la génétique moléculaire avec d'autres indicateurs de pronostic. L'analyse de l'expression cytogénétique et des gènes sur micropuces permet de classifier les lésions du mélanome uvéal en tant que risques élevés ou faibles de métastases et de mortalité liée à la maladie. Le profil d'expression génétique remplace les pronostiques cliniques, histologiques, et cytogéniques.
Le mélanome uvéal comprend un groupe hétérogène de malignités fondées sur sa biologie moléculaire. La classe moléculaire selon le profil d'expression génétique a la plus grande valeur de prédiction de la métastase et de la mortalité dues au mélanome uvéal.
Inability to perform posterior segment monitoring by scanning laser ophthalmoscopy or optical coherence tomography with some occlusive intraocular lenses in clinical use
2012, Journal of Cataract and Refractive Surgery
Citation Excerpt :
B-scan ultrasound is the only posterior segment imaging modality for IOLs that do not transit near-IR light. Patients with indications for an occlusive IOL who are at higher risk for choroidal melanoma13 or malignant transformation in an existing choroidal naevus14 may benefit from an IOL that transmits near-IR light. Occlusive IOL implantation is a technically reversible procedure, and therapeutic exchange to clear media may be considered in patients with visual loss in the contralateral eye.
To evaluate whether occlusive intraocular lenses (IOLs) produced by several manufacturers for clinical use equivalently transmit near-infrared (IR) light for scanning laser ophthalmoscopy (SLO) or optical coherence tomography (OCT) imaging.
Nuffield Laboratory of Ophthalmology, Oxford University, United Kingdom.
Evaluation of diagnostic test or technology.
The study evaluated 6 black IOLs of 2 designs: 3 poly(methyl methacrylate) (PMMA) and 3 iris-claw anterior chamber IOLs. Each IOL was placed between a broad-spectrum white light source and a spectroradiometer to generate transmission spectra. Transmission in the near-IR range was examined using an 850 nm light-emitting diode. Scanning laser ophthalmoscopy or OCT imaging using Spectralis spectral-domain SLO or OCT was attempted through occlusive IOLs in a model eye.
Artisan iris-claw and MS 612 PMMA occlusive IOLs totally occluded all wavelengths of light, including in the near IR range in which SLO and OCT imaging systems operate. It was not possible to capture SLO or OCT images through the iris-claw and PMMA occlusive IOLs in a model eye.
Results suggest the property of near-IR transmission that permits SLO or OCT imaging through occlusive IOLs is restricted to the Morcher range of occlusive IOLs. Patients with non-near IR transmitting IOLs will not be able to receive detailed posterior segment monitoring with SLO or OCT. This finding may have a significant impact on preoperative occlusive IOL selection and the management of current patients with occlusive IOLs.
No author has a financial or proprietary interest in any material or method mentioned.
Prevalence and characteristics of choroidal nevi: The multi-ethnic study of atherosclerosis
2011, Ophthalmology
Citation Excerpt :
Malignant melanomas of the skin are thought to arise from nevi, usually from dysplastic nevi. Although there are no studies describing the familial aggregation of benign choroidal nevi, there is evidence to suggest familial aggregation of uveal melanoma53–55 and an association between that condition and atypical nevi of the skin and cutaneous melanoma.56 Thus, it seems likely that genetic determinants of choroidal nevi may exist, and, as with skin nevi, the effects of genes are likely to be modified by environmental and other personal and ethnic characteristics.
To describe the prevalence of choroidal nevi in 4 racial or ethnic groups (white, black, Hispanic, and Chinese) in the United States.
Cross-sectional study.
Participants of the second examination of the Multi-Ethnic Study of Atherosclerosis (MESA), involving 6176 persons 44 to 84 years of age without clinical cardiovascular disease at baseline selected from 6 United States communities.
Fundus images were taken using a 45° digital camera through dark-adapted pupils and were graded for choroidal nevi using the modified Wisconsin Age-Related Maculopathy Grading System and the Blue Mountains Eye Study protocol.
Choroidal nevi.
The overall prevalence of choroidal nevi in the whole cohort was 2.1%, with prevalences higher in whites (4.1%) than blacks (0.7%), Hispanics (1.2%), and Chinese (0.4%; P<0.001 for any differences among groups). The lowest prevalence of choroidal nevi occurred in those 75 to 84 years of age. The nevi were subfoveal in 4% of eyes with nevi and were not associated with a decrease in visual acuity. Characteristics of the nevi (size, shape, location, color, drusen on surface) did not differ among racial or ethnic groups. With the exception of associations with higher C-reactive protein levels (odds ratio [OR] per mg/dl on the logarithmic scale, 1.23; 95% confidence interval [CI], 1.06–1.43; P = 0.01) and lower systolic blood pressure (OR per 10 mmHg, 0.90; 95% CI, 0.82–0.99; P = 0.04), choroidal nevi were not associated with other potential risk factors (e.g., gender, smoking status, alcohol consumption, lipid levels, coagulation factors, or kidney disease).
Low prevalences of choroidal nevi were found in the 4 groups participating in the MESA cohort, with whites having higher prevalence than the other racial or ethnic groups. The higher prevalence in whites than in other groups was not explained by any of the factors studied. When choroidal nevi were present, their characteristics did not differ among racial or ethnic groups.
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
The Association of Cutaneous and Iris Nevi with Uveal Melanoma: A Meta-analysis
2009, Ophthalmology
Citation Excerpt :
As such, it is important to elucidate potentially modifiable causal factors for uveal melanoma. Epidemiologic studies have documented an association with the light phenotype and uveal melanoma, and several reports on familial and bilateral uveal melanomas55,56 have provided evidence of a possible genetic predisposition for uveal melanoma. If simple mendelian genetics were the sole etiologic factor, we would expect to find a stronger genetic association.
To study the relationship between cutaneous and iris nevi with uveal melanoma.
Meta-analysis.
Three researchers independently searched the literature using Medline from 1966 to August 2007 (with both Ovid and PubMed), EMBASE, MD Consult, and the Web of Science. All bibliographies were searched, and an attempt to contact all primary authors was made to find further unpublished studies.
Risk factor data were extracted into 4 a priori groups: (1) atypical cutaneous nevi, (2) common cutaneous nevi, (3) cutaneous freckles, and (4) iris nevi.
Meta-analysis of 4 studies (850 cases) examining atypical cutaneous nevi yielded a summary odds ratio (OR) of 2.82 (95% confidence interval [CI], 1.10–7.26; P = 0.032). Common cutaneous nevi were reported in 4 studies (825 cases), yielding a summary OR of 1.74 (CI, 1.27–2.39; P = 0.001). Cutaneous freckles using 7 studies (2122 cases) found an OR of 1.22 (CI, 1.03–1.45; P = 0.022). Iris nevi using 4 studies (825 cases) found an OR of 1.53 (CI, 1.03–2.27; P = 0.036). There was no evidence of publication bias for the aforementioned risk factors, with the exception of atypical cutaneous nevi (P = 0.03).
This meta-analysis supports an association between uveal melanoma and atypical cutaneous nevi, common cutaneous nevi, cutaneous freckles, and iris nevi.
The author(s) have no proprietary or commercial interest in any materials discussed in this article.

View all citing articles on Scopus

: Manuscript no. 2005-910.

: Supported by the Illinois Society for the Prevention of Blindness, Chicago, Illinois, and Myriad Genetic Laboratories, Inc., Salt Lake City, Utah.

¹: Dr Rubinstein is on the Speaker’s Bureau of Myriad Genetic Laboratories.

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Original ArticleGenetic Study of Familial Uveal Melanoma: Association of Uveal and Cutaneous Melanoma with Cutaneous and Ocular Nevi

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Section snippets

Materials and Methods

Family History Evaluation

Discussion

Ophthalmology

Am J Ophthalmol

J Biol Chem

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Surv Ophthalmol

Cancer Detect Prev

Surv Ophthalmol

Am J Ophthalmol

Can J Ophthalmol

Uveal melanoma in Finland: an epidemiological, clinical, histological and prognostic study

Acta Ophthalmol Suppl

Malignant melanomas of the human uvea: 25-year follow-up of cases in Denmark, 1943–1952

Acta Ophthalmol (Copenh)

Familial uveal melanomaIII. Is the occurrence of familial uveal melanoma coincidental?

Arch Ophthalmol

Heredity and intraocular malignant melanomaStudy of two families and review of forty-five cases

Cancer

Tumour spectrum in the FAMMM syndrome

Br J Cancer

Nonrandom chromosomal abnormalities in primary uveal melanoma

J Natl Cancer Inst

Abnormalities of chromosomes 3 and 8 in posterior uveal melanoma correlate with prognosis

Genes Chromosomes Cancer

Fine mapping of chromosome 3 in uveal melanoma: identification of a minimal region of deletion on chromosomal arm 3p25.1-p25.2

Cancer Res

Familial uveal melanoma: absence of constitutional cytogenic abnormalities in 14 cases [letter]

Arch Ophthalmol

Tumor classification based on gene expression profiling shows that uveal melanomas with and without monosomy 3 represent two distinct entities

Cancer Res

Prognostic implications of monosomy 3 in uveal melanoma

Lancet

Increased expression and mutation of p53 in choroidal melanoma

Br J Cancer

Deregulation of the Rb and p53 pathways in uveal melanoma

Am J Pathol

Inactivation of retinoblastoma protein in uveal melanoma by phosphorylation of sites in the COOH-terminal region

Cancer Res

Abnormalities of the transforming growth factor-beta pathway in ocular melanoma

J Pathol

Promoter hypermethylation: a common cause of reduced p16(INK4a) expression in uveal melanoma

Cancer Res

Partial deletions of the long and short arm of chromosome 3 point to two tumor suppressor genes in uveal melanoma

Cancer Res

Original Article
Genetic Study of Familial Uveal Melanoma: Association of Uveal and Cutaneous Melanoma with Cutaneous and Ocular Nevi