Loading

JSM Ophthalmology

Uveal Melanoma: Beyond a Baptism

Editorial | Open Access | Volume 1 | Issue 1

  • 1. Department of Ophthalmology and Visual Science, Havener Eye Institute, USA
  • 2. Division Human Genetics, The Ohio State University, Columbus, USA
+ Show More - Show Less
Corresponding Authors
Colleen M. Cebulla, Ocular Oncology and Vitreoretinal Diseases, 915 Olentangy River Rd, Suite 5000, Columbus, OH 43212, Tel: 614-652-2600; Fax: 614-652-2610;
Citation

Cebulla CM, Davidorf FH, Abdel-Rahman MH (2013) Uveal Melanoma: Beyond a Baptism. JSM Ophthalmol 1: 1009

INTRODUCTION

Ophthalmologists focus on a very specialized region of the body; however, our years of general medical training are useful for patients, especially those with uveal melanoma. While hereditary uveal melanoma (UM) is very rare (<1% of uveal melanomas) [1], patients with a high frequency of personal and/or family history of cancer are found inabout 12% of unselected patients with UM [2]. The increased cancer predisposition is not limited to UM and isa diverse cancer phenotype. It is interesting that concurrent second primary cancers have been reported in 8-13% of patients with UM [3-6]. Furthermore, some studies have detected a small increased risk of additional primary malignancies in UM patients [3,7]. In the Collaborative Ocular Melanoma Study, the 10 year cumulative rate of second primary cancer was 14.9% (95% CI 12.9-17.1%), while the estimated 10-year rate for similar patients was only 9% [6]. Interestingly, the COMS excluded patients who had prior malignancy; thus,the increased rate of second primary cancer is striking since the exclusion criteria likely created a bias against patients with elevated cancer predisposition. These studies suggest that a subset of patients with UM is at an increased risk of cancer. Why do some UM patients have the propensity to develop multiple cancers? Is this the effect of inheritance of one dominant gene or a combination of multiple genes? Is there any genetic/environmental interaction? The answers to these questions are unknown at this time.

Recently, we and others have identified a novel cancer syndrome due to germline mutation in the BAP1 gene, which increases the patient’s risk for several cancers including uveal melanoma, cutaneous melanoma, renal cell carcinoma, mesothelioma, lung adenocarcinoma, breast carcinoma and several other internal malignancies [8-11].

However, BAP1 mutation is not the whole story when it comes to hereditary cancer risk and UM. For example, we found that only 1/53 such families in our study had a disease-associated germline mutation [8]. Similarly, Aoude et al. [12] and Njauw et al. [13] showed that the frequency of germline BAP1mutation is rare. Overall, the literature suggeststhat approximately 3% of uveal melanoma-associated hereditary cancer predisposition syndromes are caused by germline BAP1mutation. Germline mutations in BRCA2 have been reported in several UM patients with personal or family history of breast cancer [14,15]. Also, germline mutation in CDKN2A has been identified in a single family with UM and cutaneous melanomas [16]. However, larger studies have indicated that the frequency of germline mutation in these genes is less than 1% in UM patients with evidence of hereditary cancer predisposition [17,18]. We are currently working to identify other genes and mechanisms which are responsible for this hereditary cancer risk. Importantly, identification of cancer predisposition syndromes would not have been possible without asking a thorough personal and family cancer history, which includes grandparents, aunts/uncles, and cousins.

Although UM and cutaneous melanoma are biologically different, they appear to be associated in hereditary cancer predisposition. Importantly, the most common cancer associated with UM in our study of unselected UM patients was cutaneous melanoma (relative risk: 2.97, 95% CI: 1.00-6.94) [2]. Others have demonstrated the association of UM with cutaneous melanoma and other pigmented lesions. For example, Bataille et al. reported a series of patients with ocular melanoma (3 choroidal, 1 conjunctival, 1 primary acquired melanosis), in 5 patients out of a cohort of 207 patients [19]. Bergman et al. found an increased odds ratio, 1.75 (95% CI 0.78-3.89), for UM patients developing cutaneous melanoma. Similarly, the case-control study by Lischko et al. identified that prior skin malignancy (melanoma and basal or squamous cell types) tended to increase the estimated risk for developing UM in both non-related and sibling case comparisons (relative risk, 1.5 (95% Cl, 0.67-3.5) and 1.7 (95% Cl, 0.93-2.9), respectively).Furthermore, in a metaanalysis, Weis and colleagues found an association between UM and iris nevi, cutaneous common and atypical nevi [20]. Thus, there appears to be a significant association between UM and cutaneous melanoma and possibly other skin cancers. To address this risk we now include dermatology referral in our practice pattern for most patients with UM, particularly for any who have pigmented skin lesions.

In summary, UM is a disease with a genetic basis and an association with other cancers in a subset of patients. Germline mutation in BAP1 is responsible for only a minority of UM with hereditary cancer predisposition; the remaining genes/ mechanisms are being explored. Since cutaneous melanoma is the cancer most associated with UM, dermatology referral may be considered in the management of these patients.

ACKNOWLEDGMENTS

We thank the Patti Blow fund and the Ohio Lions Eye Research Foundation. Research reported in this publication was supported by the National Eye Institute of the National Institutes of Health under Award Number K08EY022672. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 

REFERENCES

1. Singh AD, Shields CL, De Potter P, Shields JA, Trock B, Cater J, et al. Familial uveal melanoma. Clinical observations on 56 patients. Arch Ophthalmol. 1996; 114: 392-399.

2. Abdel-Rahman MH, Pilarski R, Ezzat S, Sexton J, Davidorf FH. Cancer family history characterization in an unselected cohort of 121 patients with uveal melanoma. Fam Cancer. 2010; 9: 431-438.

3. Lischko AM, Seddon JM, Gragoudas ES, Egan KM, Glynn RJ. Evaluation of prior primary malignancy as a determinant of uveal melanoma. A case-control study. Ophthalmology. 1989; 96: 1716-1721.

4. Holly EA, Aston DA, Ahn DK, Kristiansen JJ, Char DH. No excess prior cancer in patients with uveal melanoma. Ophthalmology. 1991; 98: 608-611.

5. Kindy-Degnan N, Char DH, Kroll SM. Coincident systemic malignant disease in uveal melanoma patients. Can J Ophthalmol. 1989; 24: 204- 206.

6. Diener-West M, Reynolds SM, Agugliaro DJ, Caldwell R, Cumming K, Earle JD, et al. Second primary cancers after enrollment in the COMS trials for treatment of choroidal melanoma: COMS Report No. 25. Arch Ophthalmol. 2005; 123: 601-4.

7. Bergman L, Nilsson B, Ragnarsson-Olding B, Seregard S. Uveal melanoma: a study on incidence of additional cancers in the Swedish population. Invest Ophthalmol Vis Sci. 2006; 47: 72-77.

8. Abdel-Rahman MH, Pilarski R, Cebulla CM, Massengill JB, Christopher BN, Boru G, et al. Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet. 2011; 48: 856-859.

9. Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, Cox NJ, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011;43:1022-5.

10. Wiesner T, Obenauf AC, Murali R, Fried I, Griewank KG, Ulz P, et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet. 2011; 43: 1018-1021.

11. Popova T, Hebert L, Jacquemin V, Gad S, Caux-Moncoutier V, Duboisd’Enghien C, et al. Germline BAP1 Mutations Predispose to Renal Cell Carcinomas. Am J Hum Genet. 2013; 92: 974-80.

12. Aoude LG, Vajdic CM, Kricker A, Armstrong B, Hayward NK. Prevalence of germline BAP1 mutation in a population-based sample of uveal melanoma cases. Pigment Cell Melanoma Res. 2013; 26: 278-279.

13. Njauw CN, Kim I, Piris A, Gabree M, Taylor M, Lane AM, et al. Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. PLoS One. 2012; 7: e35295.

14. Scott RJ, Vajdic CM, Armstrong BK, Ainsworth CJ, Meldrum CJ, Aitken JF, et al. BRCA2 mutations in a population-based series of patients with ocular melanoma. Int J Cancer. 2002; 102: 188-191.

15. Sinilnikova OM, Egan KM, Quinn JL, Boutrand L, Lenoir GM, StoppaLyonnet D, et al. Germline brca2 sequence variants in patients with ocular melanoma. Int J Cancer. 1999; 82: 325-328.

16. Kannengiesser C, Avril MF, Spatz A, Laud K, Lenoir GM, Bressacde-Paillerets B. CDKN2A as a uveal and cutaneous melanoma susceptibility gene. Genes Chromosomes Cancer. 2003; 38: 265-268.

17. Hearle N, Damato BE, Humphreys J, Wixey J, Green H, Stone J, et al. Contribution of germline mutations in BRCA2, P16(INK4A), P14(ARF) and P15 to uveal melanoma. Invest Ophthalmol Vis Sci. 2003; 44: 458- 462.

18. Abdel-Rahman MH, Pilarski R, Massengill JB, Christopher BN, Noss R, Davidorf FH. Melanoma candidate genes CDKN2A/p16/INK4A, p14ARF, and CDK4 sequencing in patients with uveal melanoma with relative high-risk for hereditary cancer predisposition. Melanoma Res. 2011; 21: 175-179.

19. Bataille V, Pinney E, Hungerford JL, Cuzick J, Bishop DT, Newton JA. Five cases of coexistent primary ocular and cutaneous melanoma. Arch Dermatol. 1993; 129: 198-201.

20. Weis E, Shah CP, Lajous M, Shields JA, Shields CL. The association of cutaneous and iris nevi with uveal melanoma: a meta-analysis. Ophthalmology. 2009;

Received : 21 Aug 2013
Accepted : 26 Aug 2013
Published : 28 Aug 2013
Journals
Annals of Otolaryngology and Rhinology
ISSN : 2379-948X
Launched : 2014
JSM Schizophrenia
Launched : 2016
Journal of Nausea
Launched : 2020
JSM Internal Medicine
Launched : 2016
JSM Hepatitis
Launched : 2016
JSM Oro Facial Surgeries
ISSN : 2578-3211
Launched : 2016
Journal of Human Nutrition and Food Science
ISSN : 2333-6706
Launched : 2013
JSM Regenerative Medicine and Bioengineering
ISSN : 2379-0490
Launched : 2013
JSM Spine
ISSN : 2578-3181
Launched : 2016
Archives of Palliative Care
ISSN : 2573-1165
Launched : 2016
JSM Nutritional Disorders
ISSN : 2578-3203
Launched : 2017
Annals of Neurodegenerative Disorders
ISSN : 2476-2032
Launched : 2016
Journal of Fever
ISSN : 2641-7782
Launched : 2017
JSM Bone Marrow Research
ISSN : 2578-3351
Launched : 2016
JSM Mathematics and Statistics
ISSN : 2578-3173
Launched : 2014
Journal of Autoimmunity and Research
ISSN : 2573-1173
Launched : 2014
JSM Arthritis
ISSN : 2475-9155
Launched : 2016
JSM Head and Neck Cancer-Cases and Reviews
ISSN : 2573-1610
Launched : 2016
JSM General Surgery Cases and Images
ISSN : 2573-1564
Launched : 2016
JSM Anatomy and Physiology
ISSN : 2573-1262
Launched : 2016
JSM Dental Surgery
ISSN : 2573-1548
Launched : 2016
Annals of Emergency Surgery
ISSN : 2573-1017
Launched : 2016
Annals of Mens Health and Wellness
ISSN : 2641-7707
Launched : 2017
Journal of Preventive Medicine and Health Care
ISSN : 2576-0084
Launched : 2018
Journal of Chronic Diseases and Management
ISSN : 2573-1300
Launched : 2016
Annals of Vaccines and Immunization
ISSN : 2378-9379
Launched : 2014
JSM Heart Surgery Cases and Images
ISSN : 2578-3157
Launched : 2016
Annals of Reproductive Medicine and Treatment
ISSN : 2573-1092
Launched : 2016
JSM Brain Science
ISSN : 2573-1289
Launched : 2016
JSM Biomarkers
ISSN : 2578-3815
Launched : 2014
JSM Biology
ISSN : 2475-9392
Launched : 2016
Archives of Stem Cell and Research
ISSN : 2578-3580
Launched : 2014
Annals of Clinical and Medical Microbiology
ISSN : 2578-3629
Launched : 2014
JSM Pediatric Surgery
ISSN : 2578-3149
Launched : 2017
Journal of Memory Disorder and Rehabilitation
ISSN : 2578-319X
Launched : 2016
JSM Tropical Medicine and Research
ISSN : 2578-3165
Launched : 2016
JSM Head and Face Medicine
ISSN : 2578-3793
Launched : 2016
JSM Cardiothoracic Surgery
ISSN : 2573-1297
Launched : 2016
JSM Bone and Joint Diseases
ISSN : 2578-3351
Launched : 2017
JSM Bioavailability and Bioequivalence
ISSN : 2641-7812
Launched : 2017
JSM Atherosclerosis
ISSN : 2573-1270
Launched : 2016
Journal of Genitourinary Disorders
ISSN : 2641-7790
Launched : 2017
Journal of Fractures and Sprains
ISSN : 2578-3831
Launched : 2016
Journal of Autism and Epilepsy
ISSN : 2641-7774
Launched : 2016
Annals of Marine Biology and Research
ISSN : 2573-105X
Launched : 2014
JSM Health Education & Primary Health Care
ISSN : 2578-3777
Launched : 2016
JSM Communication Disorders
ISSN : 2578-3807
Launched : 2016
Annals of Musculoskeletal Disorders
ISSN : 2578-3599
Launched : 2016
Annals of Virology and Research
ISSN : 2573-1122
Launched : 2014
JSM Renal Medicine
ISSN : 2573-1637
Launched : 2016
Journal of Muscle Health
ISSN : 2578-3823
Launched : 2016
JSM Genetics and Genomics
ISSN : 2334-1823
Launched : 2013
JSM Anxiety and Depression
ISSN : 2475-9139
Launched : 2016
Clinical Journal of Heart Diseases
ISSN : 2641-7766
Launched : 2016
Annals of Medicinal Chemistry and Research
ISSN : 2378-9336
Launched : 2014
JSM Pain and Management
ISSN : 2578-3378
Launched : 2016
JSM Women's Health
ISSN : 2578-3696
Launched : 2016
Clinical Research in HIV or AIDS
ISSN : 2374-0094
Launched : 2013
Journal of Endocrinology, Diabetes and Obesity
ISSN : 2333-6692
Launched : 2013
Journal of Substance Abuse and Alcoholism
ISSN : 2373-9363
Launched : 2013
JSM Neurosurgery and Spine
ISSN : 2373-9479
Launched : 2013
Journal of Liver and Clinical Research
ISSN : 2379-0830
Launched : 2014
Journal of Drug Design and Research
ISSN : 2379-089X
Launched : 2014
JSM Clinical Oncology and Research
ISSN : 2373-938X
Launched : 2013
JSM Bioinformatics, Genomics and Proteomics
ISSN : 2576-1102
Launched : 2014
JSM Chemistry
ISSN : 2334-1831
Launched : 2013
Journal of Trauma and Care
ISSN : 2573-1246
Launched : 2014
JSM Surgical Oncology and Research
ISSN : 2578-3688
Launched : 2016
Annals of Food Processing and Preservation
ISSN : 2573-1033
Launched : 2016
Journal of Radiology and Radiation Therapy
ISSN : 2333-7095
Launched : 2013
JSM Physical Medicine and Rehabilitation
ISSN : 2578-3572
Launched : 2016
Annals of Clinical Pathology
ISSN : 2373-9282
Launched : 2013
Annals of Cardiovascular Diseases
ISSN : 2641-7731
Launched : 2016
Journal of Behavior
ISSN : 2576-0076
Launched : 2016
Annals of Clinical and Experimental Metabolism
ISSN : 2572-2492
Launched : 2016
Clinical Research in Infectious Diseases
ISSN : 2379-0636
Launched : 2013
JSM Microbiology
ISSN : 2333-6455
Launched : 2013
Journal of Urology and Research
ISSN : 2379-951X
Launched : 2014
Journal of Family Medicine and Community Health
ISSN : 2379-0547
Launched : 2013
Annals of Pregnancy and Care
ISSN : 2578-336X
Launched : 2017
JSM Cell and Developmental Biology
ISSN : 2379-061X
Launched : 2013
Annals of Aquaculture and Research
ISSN : 2379-0881
Launched : 2014
Clinical Research in Pulmonology
ISSN : 2333-6625
Launched : 2013
Journal of Immunology and Clinical Research
ISSN : 2333-6714
Launched : 2013
Annals of Forensic Research and Analysis
ISSN : 2378-9476
Launched : 2014
JSM Biochemistry and Molecular Biology
ISSN : 2333-7109
Launched : 2013
Annals of Breast Cancer Research
ISSN : 2641-7685
Launched : 2016
Annals of Gerontology and Geriatric Research
ISSN : 2378-9409
Launched : 2014
Journal of Sleep Medicine and Disorders
ISSN : 2379-0822
Launched : 2014
JSM Burns and Trauma
ISSN : 2475-9406
Launched : 2016
Chemical Engineering and Process Techniques
ISSN : 2333-6633
Launched : 2013
Annals of Clinical Cytology and Pathology
ISSN : 2475-9430
Launched : 2014
JSM Allergy and Asthma
ISSN : 2573-1254
Launched : 2016
Journal of Neurological Disorders and Stroke
ISSN : 2334-2307
Launched : 2013
Annals of Sports Medicine and Research
ISSN : 2379-0571
Launched : 2014
JSM Sexual Medicine
ISSN : 2578-3718
Launched : 2016
Annals of Vascular Medicine and Research
ISSN : 2378-9344
Launched : 2014
JSM Biotechnology and Biomedical Engineering
ISSN : 2333-7117
Launched : 2013
Journal of Hematology and Transfusion
ISSN : 2333-6684
Launched : 2013
JSM Environmental Science and Ecology
ISSN : 2333-7141
Launched : 2013
Journal of Cardiology and Clinical Research
ISSN : 2333-6676
Launched : 2013
JSM Nanotechnology and Nanomedicine
ISSN : 2334-1815
Launched : 2013
Journal of Ear, Nose and Throat Disorders
ISSN : 2475-9473
Launched : 2016
Journal of Pharmacology and Clinical Toxicology
ISSN : 2333-7079
Launched : 2013
Annals of Psychiatry and Mental Health
ISSN : 2374-0124
Launched : 2013
Medical Journal of Obstetrics and Gynecology
ISSN : 2333-6439
Launched : 2013
Annals of Pediatrics and Child Health
ISSN : 2373-9312
Launched : 2013
JSM Clinical Pharmaceutics
ISSN : 2379-9498
Launched : 2014
JSM Foot and Ankle
ISSN : 2475-9112
Launched : 2016
JSM Alzheimer's Disease and Related Dementia
ISSN : 2378-9565
Launched : 2014
Journal of Addiction Medicine and Therapy
ISSN : 2333-665X
Launched : 2013
Journal of Veterinary Medicine and Research
ISSN : 2378-931X
Launched : 2013
Annals of Public Health and Research
ISSN : 2378-9328
Launched : 2014
Annals of Orthopedics and Rheumatology
ISSN : 2373-9290
Launched : 2013
Journal of Clinical Nephrology and Research
ISSN : 2379-0652
Launched : 2014
Annals of Community Medicine and Practice
ISSN : 2475-9465
Launched : 2014
Annals of Biometrics and Biostatistics
ISSN : 2374-0116
Launched : 2013
JSM Clinical Case Reports
ISSN : 2373-9819
Launched : 2013
Journal of Cancer Biology and Research
ISSN : 2373-9436
Launched : 2013
Journal of Surgery and Transplantation Science
ISSN : 2379-0911
Launched : 2013
Journal of Dermatology and Clinical Research
ISSN : 2373-9371
Launched : 2013
JSM Gastroenterology and Hepatology
ISSN : 2373-9487
Launched : 2013
Annals of Nursing and Practice
ISSN : 2379-9501
Launched : 2014
JSM Dentistry
ISSN : 2333-7133
Launched : 2013
Author Information X