Familial Melanoma and Pancreatic Cancer: studies on genotype, phenotype and surveillance

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 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. Dutch Cancer Society (KWF) ZOLEON foundationLUMC / Geneeskund

Limited resection of pancreatic cancer in high-risk patients can result in a second primary

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Surveillance for familial melanoma: recommendations from a national centre of expertise

Dermatology-oncolog

Psychosocial issues of individuals undergoing surveillance for increased risk of melanoma and pancreatic cancer due to a germline CDKN2A variant: a focus group study

Individuals with a germline CDKN2A pathogenic variant (PV) are at high risk of developing melanoma and pancreatic cancer and are therefore offered surveillance. The potential advantages and disadvantages associated with genetic testing and surveillance are discussed during medical counseling, although little is known about the associated psychosocial factors that are relevant to this population. This study sought to provide a qualitative exploration of psychosocial factors related to genetic testing and participation in skin and pancreatic surveillance in (potential) carriers of a CDKN2A PV. Fifteen individuals—both at-risk individuals and confirmed variant carriers—participated in one of the three online focus groups. Pre-defined discussion topics, including genetic testing, cancer surveillance, influence on lifestyle and family planning, were discussed. Patients reported that important reasons to engage in genetic testing included the possibility to participate in surveillance to gain control over their cancer risk and to get clarification on the potential carrier status of their children. We observed considerable differences in risk perception and experienced burden of surveillance. Knowledge of the PV has had a positive influence on lifestyle factors and altered attitudes toward life in some. Most participants were not aware of preimplantation genetic testing. This focus group study provided insight into a variety of psychosocial themes related to (potential) carriership of a CDKN2A PV. Future efforts should focus on identifying those who may benefit from additional psychosocial support, development of a centralized source of information, and assessing the knowledge, needs, and timing of counseling for family planning. Dermatology-oncolog

Prospective risk of cancer and the influence of tobacco use in carriers of the p16-Leiden germline variant

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Application of a Serum Protein Signature for Pancreatic Cancer to Separate Cases from Controls in a Pancreatic Surveillance Cohort

BACKGROUND: Pancreatic cancer (PC) surveillance is currently offered to individuals with a genetic predisposition to PC, but routinely used radiological screening modalities are not entirely reliable in detecting early-stage PC or its precursor lesions. We recently identified a discriminating PC biomarker signature in a sporadic patient cohort. In this study, we investigated if protein profiling can accurately distinguish PC from non-PC in a pancreatic surveillance cohort of genetically predisposed individuals. METHODS: Serum samples of 66 individuals with a CDKN2A germline mutation who participated in the pancreatic surveillance program (5 cases, 61 controls) were obtained following a standardized protocol. After sample clean-up, peptide and protein profiles were obtained on an ultrahigh-resolution matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron resonance mass spectrometry platform. A discriminant score for each sample was calculated with a previously designed prediction rule, and the median discriminant scores of cases and controls were compared. Individuals with precursor lesions of PC (n = 4) and individuals with a recent diagnosis of melanoma (n = 4) were also separately considered. RESULTS: Cases had a higher median discriminant score than controls (0.26 vs 0.016; P = .001). The only individual with pathologically confirmed precursor lesions of PC could also be clearly distinguished from controls, and having a (recent) medical history of melanoma did not influence the protein signatures. CONCLUSIONS: Peptide and protein signatures are able to accurately distinguish PC cases from controls in a pancreatic surveillance setting. Mass spectrometry-based protein profiling therefore seems to be a promising candidate for implementation in the pancreatic surveillance program as an additional screening modality.Surgical oncolog

Pancreatic Cancer Surveillance in Carriers of a Germline CDKN2A Pathogenic Variant: Yield and Outcomes of a 20-Year Prospective Follow-Up

PURPOSE Pancreatic cancer surveillance in high-risk individuals may lead to detection of pancreatic ductal adenocarcinoma (PDAC) at an earlier stage and with improved survival. This study evaluated the yield and outcomes of 20 years of prospective surveillance in a large cohort of individuals with germline pathogenic variants (PVs) in CDKN2A. METHODS Prospectively collected data were analyzed from individuals participating in pancreatic cancer surveillance. Surveillance consisted of annual magnetic resonance imaging with magnetic resonance cholangiopancreatography and optional endoscopic ultrasound. RESULTS Three hundred forty-seven germline PV carriers participated in surveillance and were followed for a median of 5.6 (interquartile range 2.3-9.9) years. A total of 36 cases of PDAC were diagnosed in 31 (8.9%) patients at a median age of 60.4 (interquartile range 51.3-64.1) years. The cumulative incidence of primary PDAC was 20.7% by age 70 years. Five carriers (5 of 31; 16.1%) were diagnosed with a second primary PDAC. Thirty (83.3%) of 36 PDACs were considered resectable at the time of imaging. Twelve cases (12 of 36; 33.3%) presented with stage I disease. The median survival after diagnosis of primary PDAC was 26.8 months, and the 5-year survival rate was 32.4% (95% CI, 19.1 to 54.8). Individuals with primary PDAC who underwent resection (22 of 31; 71.0%) had an overall 5-year survival rate of 44.1% (95% CI, 27.2 to 71.3). Nine (2.6%; 9 of 347) individuals underwent surgery for a suspected malignant lesion, which proved to not be PDAC, and this included five lesions with low-grade dysplasia. CONCLUSION This long-term surveillance study demonstrates a high incidence of PDAC in carriers of a PV in CDKN2A. This provides evidence that surveillance in such a high-risk population leads to detection of early-stage PDAC with improved resectability and survival.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Surveillance for pancreatic cancer in high-risk individuals leads to improved outcomes: a propensity score-matched analysis

BACKGROUND & AIMS: Recent pancreatic cancer surveil-lance programs of high-risk individuals have reported improved outcomes. This study assessed to what extent outcomes of pancreatic ductal adenocarcinoma (PDAC) patients with a CDKN2A/p16 pathogenic variant diagnosed under surveillance are better as compared with patients with PDAC diagnosed outside surveillance.METHODS: In a pro-pensity score matched cohort using data from the Netherlands Cancer Registry, we compared resectability, stage, and survival between patients diagnosed under sur-veillance with non-surveillance patients with PDAC. Survival analyses were adjusted for potential effects of lead time.RESULTS: Between January 2000 and December 2020, 43,762 patients with PDAC were identified from the Netherlands Cancer Registry. Thirty-one patients with PDAC under surveillance were matched in a 1:5 ratio with 155 non surveillance patients based on age at diagnosis, sex, year diagnosis, and tumor location. Outside surveillance, 5.8% of the patients had stage I cancer, as compared with 38.7% of surveillance patients with PDAC (odds ratio [OR], 0.09; 95% confidence interval [CI], 0.04-0.19). In total, 18.7% of non surveillance patients vs 71.0% of surveillance patients un- derwent a surgical resection (OR, 10.62; 95% CI, 4.56-26.63). Patients in surveillance had a better prognosis, reflected by 5-year survival of 32.4% and a median overall survival of 26.8 months vs 4.3% 5-year survival and 5.2 months median overall survival in non-surveillance patients (hazard ratio, 0.31; 95% CI 0.19-0.50). For all adjusted lead times, survival remained significantly longer in surveillance patients than non-surveillance patients.CONCLUSION: Surveillance for PDAC in carriers of a CDKN2A/p16 pathogenic variant results in earlier detection, increased resectability, and improved survival as compared with non-surveillance patients with PDAC

Families with BAP1-tumor predisposition syndrome in The Netherlands: Path to identification and a proposal for genetic screening guidelines

Germline pathogenic variants in the BRCA1-associated protein-1 (BAP1) gene cause the BAP1-tumor predisposition syndrome (BAP1-TPDS, OMIM 614327). BAP1-TPDS is associated with an increased risk of developing uveal melanoma (UM), cutaneous melanoma (CM), malignant mesothelioma (MMe), renal cell carcinoma (RCC), meningioma, cholangiocarcinoma, multiple non-melanoma skin cancers, and BAP1-inactivated nevi. Because of this increased risk, it is important to identify patients with BAP1-TPDS. The associated tumors are treated by different medical disciplines, emphasizing the need for generally applicable guidelines for initiating genetic analysis. In this study, we describe the path to identification of BAP1-TPDS in 21 probands found in the Netherlands and the family history at the time of presentation. We report two cases of de novo BAP1 germline mutations (2/21, 9.5%). Findings of this study combined with previously published literature, led to a proposal of guidelines for genetic referral. We recommend genetic analysis in patients with ≥2 BAP1-TPDS-associated tumors in their medical history and/or family history. We also propose to test germline BAP1 in patients diagnosed with UM <40 years, CM <18 years, MMe <50 years, or RCC <46 years. Furthermore, other candidate susceptibility genes for tumor types associated with BAP1-TPDS are discussed, which can be included in gene panels when testing patients

Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation

Genetics of disease, diagnosis and treatmen