In this thesis, we performed several genotype and phenotype studies in hereditary and familial melanoma patient cohorts. In the first part, our studies focus on patients with the p16-Leiden founder... Show moreIn this thesis, we performed several genotype and phenotype studies in hereditary and familial melanoma patient cohorts. In the first part, our studies focus on patients with the p16-Leiden founder mutation in the CDKN2A gene. This founder mutation is the major cause of the familial melanoma-pancreatic cancer syndrome in the Dutch population. We studied the cancer phenotype and modifiers of cancer risk in these p16-Leiden mutation carriers. We also evaluated the p16-Leiden pancreatic cancer (PC) surveillance program by studying the role of precursor lesions in the development and early detection of PC, by reflecting on the surgical management of early-stage screen-detected PC and by studying potential biomarkers for the early detection of PC. In the second part of this thesis, our focus shifts to Dutch melanoma families in general, of which ~85% do not harbor a germline CDKN2A mutation. We studied which clinical features are associated with the presence of a CDKN2A mutation in a melanoma family and we created a scoring system to predict CDKN2A mutation probability. Lastly, we genetically characterized melanoma families without a CDKN2A mutation for variants in other (candidate) melanoma predisposition genes. Show less
Germline mutations in the major melanoma susceptibility gene CDKN2A explain genetic predisposition in only 10-40% of melanoma-prone families. In our study we comprehensively characterized 488... Show moreGermline mutations in the major melanoma susceptibility gene CDKN2A explain genetic predisposition in only 10-40% of melanoma-prone families. In our study we comprehensively characterized 488 melanoma cases from 451 non-CDKN2A/CDK4 families for mutations in 30 established and candidate melanoma susceptibility genes using a custom-designed targeted gene panel approach. We identified (likely) pathogenic variants in established melanoma susceptibility genes in 18 families (n = 3 BAP1, n = 15 MITF p.E318K; diagnostic yield 4.0%). Among the three identified BAP1-families, there were no reported diagnoses of uveal melanoma or malignant mesothelioma. We additionally identified two potentially deleterious missense variants in the telomere maintenance genes ACD and TERF2IP, but none in the POT1 gene. MC1R risk variants were strongly enriched in our familial melanoma cohort compared to healthy controls (R variants: OR 3.67, 95% CI 2.88-4.68, p <0.001). Several variants of interest were also identified in candidate melanoma susceptibility genes, in particular rare (pathogenic) variants in the albinism gene OCA2 were repeatedly found. We conclude that multigene panel testing for familial melanoma is appropriate considering the additional 4% diagnostic yield in non-CDKN2A/CDK4 families. Our study shows that BAP1 and MITF are important genes to be included in such a diagnostic test. Show less
