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M. H. Abdel-Rahman, R. Pilarski, J. B. Massengill, M.-A. Craven, J. L. Sexton, F. H. Davidorf; Cancer Family History Characterization and Candidate Gene Testing in an Unselected Cohort of 121 Patients With Uveal Melanoma. Invest. Ophthalmol. Vis. Sci. 2010;51(13):852.
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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 prospectively accrued 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, cervix, and lung cancers due to their strong environmental etiological link), 4) Family history meeting the high risk criteria for a known hereditary cancer predisposition syndrome as defined by Hampel et al. (2004) (1). Germline mutations in CDKN2A, p14/ARF, MC1R, and exon 2 of CDKN4 were assessed by direct gene sequencing in patients with a high risk for hereditary disease.
One patient had a family history of UM (0.8%), ten (8.3%) had a personal and/or family history consistent with predisposition to a known hereditary cancer syndrome,three (2.5%) had very early onsetand 23 (19%) had a personal history of a second cancer. The frequency of cutaneous melanoma 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 significantly higher risks for having a second cancer than the rest of UM patients (p=0.02). A novel non-synonymous germline mutation in p14/ARF was identified in the patient with a family history of UM in his mother. No pathogenic mutations were identified in any of the other patients in the tested genes.
Our results indicate that the frequency of UM patients with increased risk for hereditary cancer predisposition (UM-IRHCP) is much higher than in 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. It also suggests that patients with a hereditary predisposition to UM have a higher risk for development of other cancers. Finally, characterization of the germline genetic alterations in UM-IRHCP patients is highly warranted.
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