Abstract
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. The extent of the contribution of familial/hereditary predisposition to the development of uveal melanoma is largely unknown. Thus we sought to ascertain the frequency of cancers in patients with UM and their family members to identify the prevalence of hereditary/familial predisposition to cancer in these patients. An unselected series of 121 patients with UM seen in a university-based tertiary referral program were consented to the study. Cancer histories (site and age of diagnosis) were obtained for all first- and second-degree relatives. Patients/families were classified as being potentially at high risk for hereditary predisposition if they met any of the following criteria: (1) Diagnosis of UM at age 30 or under, (2) Two or more cases of UM in the family, (3) UM plus at least one other primary cancer in the same patient (excluding non-melanoma skin and cervix cancers due to their strong environmental etiological link). (4) Family history meeting high risk criteria for a known hereditary cancer predisposition syndrome as defined by Hampel et al. (J Med Genet 41(2): 81–91, 2004). One patient had a family history of UM (0.8%). Ten patients (8.3%) had a personal and/or family history consistent with predisposition to a known hereditary cancer syndrome including six with possible hereditary breast, two with hereditary colon and two with hereditary melanomas. Twenty three patients (19%) had a personal history of a second cancer after exclusion of non-melanoma skin and cervical cancers. The frequency of cutaneous melanomas was significantly higher in UM patients than the general population (RR: 2.97, 95% CI: 1.00–6.94). Patients with a family history suggestive of a high risk predisposition to a known cancer syndrome had a significantly higher risk for having a second cancer than the remaining UM patients (P = 0.02). Our results indicate that the frequency of UM patients with high risk for a hereditary cancer predisposition is much higher than earlier estimates (0.6%) and that it could be as high as 11.6%. Our results suggest that cancer phenotypes in these patients are diverse and include cancers other than UM. Thus, alerting ophthalmologists to the need for expanding their cancer family history intake to include other cancers is warranted. It also suggests that patients with a hereditary predisposition to UM have a higher risk for the development of other cancers and that characterization of the germline genetic alterations in these patients is highly warranted.
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Hampel H, Sweet K, Westman JA, Offit K, Eng C (2004) Referral for cancer genetics consultation: a review, compilation of risk assessment criteria. J Med Genet 41(2):81–91
Singh AD, Damato B, Howard P, Harbour JW (2005) Uveal melanoma: genetic aspects. Ophthalmol Clin North Am 18(1): 85–97, viii
Singh AD, Rennie IG, Seregard S, Giblin M, McKenzie J (2004) Sunlight exposure and pathogenesis of uveal melanoma. Surv Ophthalmol 49(4):419–428
Barker-Griffith AE, Streeten BW (2004) Familial uveal melanoma: a report of four cases in two families and literature review. Can J Ophthalmol 39(4):403–408
Kodjikian L, Nguyen K, Lumbroso L et al (2003) Familial uveal melanoma: a report on two families and a review of the literature. Acta Ophthalmol Scand 81(4):389–395
Hearle N, Damato BE, Humphreys J et al (2003) Contribution of germline mutations in BRCA2, P16(INK4A), P14(ARF) and P15 to uveal melanoma. Invest Ophthalmol Vis Sci 44(2):458–462
Scott RJ, Vajdic CM, Armstrong BK et al (2002) BRCA2 mutations in a population-based series of patients with ocular melanoma. Int J Cancer 102(2):188–191
Iscovich J, Abdulrazik M, Cour C, Fischbein A, Pe’er J, Goldgar DE (2002) Prevalence of the BRCA2 6174 del T mutation in Israeli uveal melanoma patients. Int J Cancer 98(1):42–44
Sinilnikova OM, Egan KM, Quinn JL et al (1999) Germline brca2 sequence variants in patients with ocular melanoma. Int J Cancer 82(3):325–328
Jonsson G, Bendahl PO, Sandberg T et al (2005) Mapping of a novel ocular and cutaneous malignant melanoma susceptibility locus to chromosome 9q21.32. J Natl Cancer Inst 97(18):1377–1382
Singh AD, Shields CL, De Potter P et al (1996) Familial uveal melanoma. Clinical observations on 56 patients. Arch Ophthalmol 114(4):392–399
Wooster R, Bignell G, Lancaster J et al (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378(6559):789–792
Miki Y, Swensen J, Shattuck-Eidens D et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266(5182):66–71
Lynch HT, Smyrk TC, Watson P et al (1993) Genetics, natural history, tumor spectrum, pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 104(5):1535–1549
Canning CR, Hungerford J (1988) Familial uveal melanoma. Br J Ophthalmol 72(4):241–243
Hemminki K, Jiang Y (2001) Association of ocular melanoma with breast cancer but not with cutaneous melanoma: results from the Swedish Family-Cancer Database. Int J Cancer 94(6):907–909
Diener-West M, Reynolds SM, Agugliaro DJ et al (2005) Second primary cancers after enrollment in the COMS trials for treatment of choroidal melanoma: COMS Report No. 25. Arch Ophthalmol 123(5):601–604
Bergman L, Nilsson B, Ragnarsson-Olding B, Seregard S (2006) Uveal melanoma: a study on incidence of additional cancers in the Swedish population. Invest Ophthalmol Vis Sci 47(1):72–77
Berry DA, Parmigiani G, Sanchez J, Schildkraut J, Winer E (1997) Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history. J Natl Cancer Inst 89(3):227–238
Couch FJ, DeShano ML, Blackwood MA et al (1997) BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med 336(20):1409–1415
Shattuck-Eidens D, Oliphant A, McClure M et al (1997) BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. JAMA 278(15):1242–1250
Chen S, Wang W, Lee S et al (2006) Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA 296(12):1479–1487
Wijnen JT, Vasen HF, Khan PM et al (1998) Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med 339(8):511–518
Breslow NE, Day NE (1987) Statistical methods in cancer research. In: Breslow NE, Day NE (eds) The design and analysis of cohort studies. International Agency for Research on Cancer, Lyon
Taeger D, Sun Y, Keil U, Straif K (2000) A stand-alone windows applications for computing exact person-years, standardized mortality ratios, confidence intervals in epidemiological studies. Epidemiology 11(5):607–608
Soufir N, Bressac-de Paillerets B, Desjardins L et al (2000) Individuals with presumably hereditary uveal melanoma do not harbour germline mutations in the coding regions of either the P16INK4A, P14ARF or cdk4 genes. Br J Cancer 82(4):818–822
Lynch HT, Brand RE, Hogg D et al (2002) Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome. Cancer 94(1):84–96
Hemminki K, Chen B (2006) Familial risks for eye melanoma and retinoblastoma: results from the Swedish Family-Cancer Database. Melanoma Res 16(2):191–195
Davidorf FH, Abdel-Rahman MH, Craven M-A, Ohr M, Jarjoura D (2007) Higher colon cancer risk in uveal melanoma patients and their relatives compared to general population. Invest Ophthalmol Vis Sci 48(5):4790
Acknowledgments
This work is funded by the Patti Blow Research fund in Ophthalmology and a Selective Investment grant from the College of Medicine, the Ohio State University. The authors would like to thank Dr. Judith Westman and Ms. Heather Hampel for their critical revision of the manuscript and helpful comments.
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Abdel-Rahman, M.H., Pilarski, R., Ezzat, S. et al. Cancer family history characterization in an unselected cohort of 121 patients with uveal melanoma. Familial Cancer 9, 431–438 (2010). https://doi.org/10.1007/s10689-010-9328-7
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DOI: https://doi.org/10.1007/s10689-010-9328-7