Pancreatic ductal adenocarcinoma is one of the most lethal forms of cancer. This book describes the outcome of long-term surveillance for p16-Leiden/CDKN2A mutation carriers. Further evaluating the... Show morePancreatic ductal adenocarcinoma is one of the most lethal forms of cancer. This book describes the outcome of long-term surveillance for p16-Leiden/CDKN2A mutation carriers. Further evaluating the role of precursor lesions, including IPMN and PanIN in the development of PDAC. It is also common knowledge that hereditary cancer is associated with the development of multiple tumors due to the fact that all body cells carry the inherited mutation. Therefore the third aid was to evaluate the risk of multiple PDAC in carriers of a p16-Leiden founder mutation. The fourth aim was to evaluate cost-effectiveness of surveillance. During our surveillance study, the program unexpectedly detected also other types of cancer than PDAC including benign lesions (incidentaloma). The fifth aim was to evaluate what type of cancers and benging lesions were detected and whether surveillance and early detection offered any benefit. The final aim was to describe the dilemmas in the management of screen-detected lesions that we experienced during our surveillance program. Show less
Spagnolo, F.; Dalmasso, B.; Tanda, E.; Potrony, M.; Puig, S.; Doorn, R. van; ... ; Ghiorzo, P. 2021
Simple Summary In our study, we retrospectively collected data of patients with germline CDKN2A pathogenic variants who received targeted therapy for advanced melanoma across four European centers.... Show moreSimple Summary In our study, we retrospectively collected data of patients with germline CDKN2A pathogenic variants who received targeted therapy for advanced melanoma across four European centers. Since loss of CDKN2A function may intrinsically limit the activity of MAPK-directed targeted therapy, we decided to assess whether patients with germline CDKN2A pathogenic variants may achieve suboptimal results with BRAF and MEK inhibitors. To the best of our knowledge, this is the first study reporting on patients with BRAF-mutant advanced melanoma and a germline CDKN2A pathogenic variant who received treatment with BRAF with or without MEK inhibitors. Despite the limitations of our study, mostly due to the rare frequency of CDKN2A pathogenic variants, a challenge for the conduction of prospective trials with proper sample size, our results support treatment with targeted therapy in this subset of patients.Inherited pathogenic variants (PVs) in the CDKN2A tumor suppressor gene are among the strongest risk factors for cutaneous melanoma. Dysregulation of the p16/RB1 pathway may intrinsically limit the activity of MAPK-directed therapy due to the interplay between the two pathways. In our study, we assessed, for the first time, whether patients with germline CDKN2A PVs achieve suboptimal results with BRAF inhibitors (BRAFi)+/-MEK inhibitors (MEKi). We compared the response rate of nineteen CDKN2A PVs carriers who received first-line treatment with BRAFi+/-MEKi with an expected rate derived from phase III trials and "real-world" studies. We observed partial response in 16/19 patients (84%), and no complete responses. The overall response rate was higher than that expected from phase III trials (66%), although not statistically significant (p-value = 0.143; 95% CI = 0.60-0.97); the difference was statistically significant (p-value = 0.019; 95% CI = 0.62-0.97) in the comparison with real-world studies (57%). The clinical activity of BRAFi+/-MEKi in patients with germline CDKN2A PV was not inferior to that of clinical trials and real-world studies, which is of primary importance for clinical management and genetic counseling of this subgroup of patients. Show less
The studies in this thesis explored several aspects of genetic dependencies in the development of familial and sporadic melanoma. CDKN2A is the most common high-penetrance susceptibility gene... Show moreThe studies in this thesis explored several aspects of genetic dependencies in the development of familial and sporadic melanoma. CDKN2A is the most common high-penetrance susceptibility gene responsible for up to 40% of melanoma families worldwide. Interestingly, more than half of germline variation in familial predisposition to melanoma remains to be determined. To identify novel high-penetrance melanoma susceptibility genes we applied Whole Exome Sequencing (WES) and co-segregation analysis in a Dutch melanoma family. We identified NEK11 as a candidate high-penetrance melanoma susceptibility gene and performed functional characterization in cancer cell lines to show loss-of-function (chapter 2). Our additional focus of investigation was a specific cohort of familial melanoma patients carrying a CDKN2A founder mutation, a 19-bp deletion known as the p16-Leiden mutation. Due to the variability in occurrence of pancreatic cancer (PC) and melanoma within familial melanoma families, we sought to examine genetic modifiers predicting the risk of PC and melanoma (chapter 3). In this specific cohort of familial melanoma patients, the timing of CDKN2A wild-type allele loss in melanoma development is unknown. We have applied a customized SNP-based digital PCR (dPCR) methodology to precisely quantify CDKN2A allelic imbalance depicting loss-of-heterozygosity (LOH) and attempted to deduce the order of genetic events based on absolute quantification of mutations and losses (CDKN2A LOH, BRAFV600E, TERT promoter, chromosome 9q LOH) (chapter 4). Finally, in addition to high-penetrance genes in familial melanoma, there are genes that are important fitness factors for cancer cell growth and may provide insight into the biology and progression of sporadic melanoma. The application of screening technologies has been successful in identifying genetic dependencies that could possibly be implemented as therapeutic targets in cancer. We have therefore analyzed Clustered Regular Interspaced Short Palindromic Repeats (CRISPR-Cas9) screening data to identify fitness genes in melanoma and used in-vitro systems to validate our findings (chapter 5). Combined, we hope to have uncovered novel genetic dependencies that could be used in the targeted treatment of sporadic as well as familial melanoma. Show less
Christodoulou, E.; Visser, M.; Potjer, T.P.; Stoep, N. van der; Rodriguez-Girondo, M.; Doorn, R. van; Gruis, N. 2019
Carriers of pathogenic variants in CDKN2A have a 70% life-time risk of developing melanoma and 15-20% risk of developing pancreatic cancer (PC). In the Netherlands, a 19-bp deletion in exon 2 of... Show moreCarriers of pathogenic variants in CDKN2A have a 70% life-time risk of developing melanoma and 15-20% risk of developing pancreatic cancer (PC). In the Netherlands, a 19-bp deletion in exon 2 of CDKN2A (p16-Leiden mutation) accounts for most hereditary melanoma cases. Clinical experience suggests variability in occurrence of melanoma and PC in p16-Leiden families. Thereby, the risk of developing cancer could be modified by both environmental and genetic contributors, suggesting that identification of genetic modifiers could improve patients' surveillance. In a recent genome-wide association study (GWAS), rs36115365-C was found to significantly modify risk of PC and melanoma in the European population. This SNP is located on chr5p15.33 and has allele-specific regulatory activities on TERT expression. Herein, we investigated the modifying capacities of rs36115365-C on PC and melanoma in a cohort of 283 p16-Leiden carriers including 29 diagnosed with PC, 171 diagnosed with melanoma, 21 diagnosed with both PC and melanoma and 62 with neither PC nor melanoma. In contrast to previously reported findings, we did not find a significant association of PC risk with risk variant presence as determined by Generalized Estimating Equations (GEE) modelling. Interestingly, carrier-ship of the risk variant had a significant protective effect for melanoma (OR - 0.703 [95% CI - 1.201 to - 0.205], p = 0.006); however, the observed association was no longer significant after exclusion of probands to assess possible influence of ascertainment. Collectively, genetic modifiers for the prediction of PC and melanoma risk in p16-Leiden carriers remain to be determined. Show less
Background: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to... Show moreBackground: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved.Methods: In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics.Results: MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P < .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance.Conclusion: The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling. Show less
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
Being a member of a melanoma family is a major risk factor for cutaneous malignant melanoma. In this thesis clinical characteristics and management of melanoma families are discussed. In the first... Show moreBeing a member of a melanoma family is a major risk factor for cutaneous malignant melanoma. In this thesis clinical characteristics and management of melanoma families are discussed. In the first part of the thesis clinical and histological characteristics of melanoma (patients) from families with a (p16-Leiden) mutation in the high penetrance melanoma susceptibility gene CDKN2A were compared with the general population. Significant differences with respect to several characteristics are reported. In the second part of the thesis the yield, effectiveness, and causes for failure of surveillance of melanoma families are discussed. We report that surveillance is associated with a more favorable tumor stage. Several aspects of surveillance, including interval melanomas, surveillance interval, noncompliance, and overdiagnosis are discussed. Based on analyses of melanoma detection rates in families with different family and genetic characteristics, we propose a risk stratification for members of melanoma families. In the third part of the thesis we investigate the impact of dermoscopy on management decisions. It is demonstrated that dermoscopy by dermoscopy experts in the setting of melanoma family surveillance resulted in a considerable reduction of unnecessary excisions. This effect was considerably less in the setting of dermoscopy non-experts examining patients in general dermatology clinics. Show less
Quint, K.D.; Rhee, J.I. van der; Gruis, N.A.; Huurne, J.A. ter; Wolterbeek, R.; Stoep, N. van der; ... ; Kukutsch, N.A. 2012
