44 results on '"Wadt, Karin A. W."'
Search Results
2. Clinical implications of genetic testing in familial intermediate and late-onset colorectal cancer
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Djursby, Malene, Hansen, Thomas van Overeem, Wadt, Karin A. W., Madsen, Majbritt Busk, Berchtold, Lukas Adrian, Lautrup, Charlotte Kvist, Markholt, Sara, Jensen, Uffe Birk, Krogh, Lotte Nylandsted, Lundsgaard, Malene, Gerdes, Anne Marie, Nilbert, Mef, and Therkildsen, Christina
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- 2022
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3. Characterization of somatic mutations in sporadic uveal melanoma and uveal melanoma in patients with germline BAP1 pathogenic variants.
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Wadt, Karin A. W., Harbst, Katja, Sjøl, Mette M. B., Rosengren, Frida, Yde, Christina Westmose, Rohrberg, Kristoffer Staal, Jensen, Marlene Richter, Heegaard, Steffen, Kiilgaard, Jens Folke, Gerdes, Anne-Marie, Hayward, Nicholas, and Jönsson, Göran B.
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SOMATIC mutation , *OVERALL survival , *GERM cells , *METASTASIS , *MELANOMA - Abstract
Genetic analyses were conducted on tumor samples from 88 patients with uveal melanoma (UM), 6 of whom carry pathogenic germline variants in BAP1. We assessed the frequency, pattern, and prognostic significance of somatic aberrations, and investigated differences between germline BAP1 variant carriers compared to sporadic cases. The frequency of the main oncogenic driver mutations was not significantly different between these groups. Patients with germline BAP1 variants did not have significantly different overall survival compared to the wildtype or somatic BAP1 mutation groups. Patients with a somatic BAP1 mutation (n = 24) had a significantly worse prognosis compared to wildtype (n = 58). All patients with stage III tumors and a somatic BAP1 mutation (n = 7) developed metastasis, however four of 28 stage I-II tumors without metastasis had somatic BAP1 mutations, with observation time >5 years. The tumor from one germline BAP1 carrier (stage IIIC) with a somatic EIF1AX splice variant, has not developed metastasis within a 22-year observation time. [ABSTRACT FROM AUTHOR]
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- 2024
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4. National Experiences from 30 Years of Provider-Mediated Cascade Testing in Lynch Syndrome Families—The Danish Model.
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Lindberg, Lars Joachim, Wadt, Karin A. W., Therkildsen, Christina, and Petersen, Helle Vendel
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DIAGNOSIS of hereditary nonpolyposis colorectal cancer , *GENETIC testing laws , *PATIENTS' families , *MEDICAL care use , *MEDICAL personnel , *HEALTH , *INFORMATION resources , *DESCRIPTIVE statistics , *GENETIC counseling , *FAMILY relations , *PATIENT-professional relations , *COMMUNICATION , *HEALTH promotion , *GENETIC testing - Abstract
Simple Summary: Cascade genetic testing is crucial for families with hereditary cancer syndromes like Lynch syndrome, where clinically established surveillance programs reduce illness and death. However, communicating genetic information within families faces barriers, with only a small uptake of genetic testing in family members informed through family-mediated contact. Provider-mediated interventions via letter or phone call increase testing uptake but raise legal and ethical concerns. We describe 30 years of national experience with cascade testing using unsolicited letters, covering administration, legislation, public attitudes, and testing rates. Our approach resulted in an average of 7.3 additional tests per family. Overall uptake of genetic testing was 54.4% after family-mediated and 64.9% after provider-mediated contact by letter. The uptake of genetic testing was highest in the first year after diagnosis of Lynch syndrome in the family, with 72.5% tested after provider-mediated contact. We propose a model for cascade genetic testing combining family- and provider-mediated contact. Cascade genetic testing and surveillance reduce morbidity and mortality in Lynch syndrome. However, barriers to conveying information about genetic disorders within families result in low uptake of genetic testing. Provider-mediated interventions may increase uptake but raise legal and ethical concerns. We describe 30 years of national experience with cascade genetic testing combining family- and provider-mediated contact in Lynch syndrome families in the Danish Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Register. We aimed to estimate the added value of information letters to family members in Lynch syndrome families (provider-mediated contact) compared to family members not receiving such letters and thus relying on family-mediated contact. National clinical practice for cascade genetic testing, encompassing infrastructure, legislation, acceptance, and management of the information letters, is also discussed. Cascade genetic testing resulted in 7.3 additional tests per family. Uptake of genetic testing was 54.4% after family-mediated and 64.9% after provider-mediated contact, corresponding to an odds ratio of 1.8 (p < 0.001). The uptake of genetic testing was highest in the first year after diagnosis of Lynch syndrome in the family, with 72.5% tested after provider-mediated contact. In conclusion, the Danish model combining family- and provider-mediated contact can increase the effect of cascade genetic testing. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Germline (epi)genetics reveals high predisposition in females: a 5-year, nationwide, prospective Wilms tumour cohort
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Stoltze, Ulrik Kristoffer, primary, Hildonen, Mathis, additional, Hansen, Thomas Van Overeem, additional, Foss-Skiftesvik, Jon, additional, Byrjalsen, Anna, additional, Lundsgaard, Malene, additional, Pignata, Laura, additional, Grønskov, Karen, additional, Tumer, Zeynep, additional, Schmiegelow, Kjeld, additional, Brok, Jesper Sune, additional, and Wadt, Karin A W, additional
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- 2023
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6. Germline (epi)genetics reveals high predisposition in females:a 5-year, nationwide, prospective Wilms tumour cohort
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Stoltze, Ulrik Kristoffer, Hildonen, Mathis, Hansen, Thomas Van Overeem, Foss-Skiftesvik, Jon, Byrjalsen, Anna, Lundsgaard, Malene, Pignata, Laura, Grønskov, Karen, Tumer, Zeynep, Schmiegelow, Kjeld, Brok, Jesper Sune, Wadt, Karin A. W., Stoltze, Ulrik Kristoffer, Hildonen, Mathis, Hansen, Thomas Van Overeem, Foss-Skiftesvik, Jon, Byrjalsen, Anna, Lundsgaard, Malene, Pignata, Laura, Grønskov, Karen, Tumer, Zeynep, Schmiegelow, Kjeld, Brok, Jesper Sune, and Wadt, Karin A. W.
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Background: Studies suggest that Wilms tumours (WT) are caused by underlying genetic (5%-10%) and epigenetic (2%-29%) mechanisms, yet studies covering both aspects are sparse. Methods: We performed prospective whole-genome sequencing of germline DNA in Danish children diagnosed with WT from 2016 to 2021, and linked genotypes to deep phenotypes. Results: Of 24 patients (58% female), 3 (13%, all female) harboured pathogenic germline variants in WT risk genes (FBXW7, WT1 and REST). Only one patient had a family history of WT (3 cases), segregating with the REST variant. Epigenetic testing revealed one (4%) additional patient (female) with uniparental disomy of chromosome 11 and Beckwith-Wiedemann syndrome (BWS). We observed a tendency of higher methylation of the BWS-related imprinting centre 1 in patients with WT than in healthy controls. Three patients (13%, all female) with bilateral tumours and/or features of BWS had higher birth weights (4780 g vs 3575 g; p=0.002). We observed more patients with macrosomia (>4250 g, n=5, all female) than expected (OR 9.98 (95% CI 2.56 to 34.66)). Genes involved in early kidney development were enriched in our constrained gene analysis, including both known (WT1, FBXW7) and candidate (CTNND1, FRMD4A) WT predisposition genes. WT predisposing variants, BWS and/or macrosomia (n=8, all female) were more common in female patients than male patients (p=0.01). Conclusion: We find that most females (57%) and 33% of all patients with WT had either a genetic or another indicator of WT predisposition. This emphasises the need for scrutiny when diagnosing patients with WT, as early detection of underlying predisposition may impact treatment, follow-up and genetic counselling.
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- 2023
7. Germline TERT promoter mutations are rare in familial melanoma
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Harland, Mark, Petljak, Mia, Robles-Espinoza, Carla Daniela, Ding, Zhihao, Gruis, Nelleke A., van Doorn, Remco, Pooley, Karen A., Dunning, Alison M., Aoude, Lauren G., Wadt, Karin A. W., Gerdes, Anne-Marie, Brown, Kevin M., Hayward, Nicholas K., Newton-Bishop, Julia A., Adams, David J., and Bishop, D. Timothy
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- 2016
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8. High accuracy of family history of melanoma in Danish melanoma cases
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Wadt, Karin A. W., Drzewiecki, Krzysztof T., and Gerdes, Anne-Marie
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- 2015
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9. Maternal versus paternal inheritance of a 132 bp 11p15.5 microdeletion affectingKCNQ1OT1and associated phenotypes
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Stoltze, Ulrik Kristoffer, primary, Hansen, Thomas Van Overeem, additional, Brok, Jesper Sune, additional, Grønskov, Karen, additional, Tumer, Asuman Z, additional, Ahlborn, Lise Barlebo, additional, Schmiegelow, Kjeld, additional, and Wadt, Karin A W, additional
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- 2022
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10. Risk of somatic hospitalization in parents after cancer in a child, a nationwide cohort study
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von Heymann, Annika, Alef-Defoe, Sierra, Salem, Hanin, Andersen, Elisabeth Anne Wreford, Dalton, Susanne Oksbjerg, Schmiegelow, Kjeld, Wadt, Karin A. W., Winther, Jeanette Falck, Johansen, Christoffer, Bidstrup, Pernille Envold, von Heymann, Annika, Alef-Defoe, Sierra, Salem, Hanin, Andersen, Elisabeth Anne Wreford, Dalton, Susanne Oksbjerg, Schmiegelow, Kjeld, Wadt, Karin A. W., Winther, Jeanette Falck, Johansen, Christoffer, and Bidstrup, Pernille Envold
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Objective The diagnosis of cancer in a child is a profoundly stressful experience. The impact on parents' somatic health, including lifestyle-related diseases, however, is unresolved. This paper assesses parents' risk of hospitalization with somatic disease after a child's cancer diagnosis. Methods We conducted a nationwide population- and register-based study with parents of all children under age 20 diagnosed with cancer in Denmark between 1998 and 2013 and parents of cancer-free children, matched (1:10) on child's age and family type. We estimated HR with 95% CI in Cox proportional hazard models for 13 major International Classification of Diseases-10 disease groups, selected stress- and lifestyle-related disease-groups, and investigated moderation by time since diagnosis, parental sex, and cancer type. Results Among n = 7797 parents of children with cancer compared with n = 74,388 parents of cancer-free children (51% mothers, mean age 42), we found no overall pattern of increased risk for 13 broad disease groups. We found increases in digestive system diseases (HR 1.06, 95% CI 1.01-1.12), genitourinary system diseases (HR 1.08, 95% CI 1.02-1.14), and neoplasms (HR 1.20, 95% CI 1.13-1.27), the latter attributable mostly to increased rates of tobacco-related cancers and mothers' diet-related cancers. Conclusions This is the first attempt to document the impact of childhood cancer on parents' somatic health. With the exception of increased risk for neoplasms, likely due to shared genetic or lifestyle factors, our findings offer the reassuring message, that the burden of caring for a child with cancer does not in general increase parents' risk for somatic diseases.
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- 2022
11. Germline RAD51B truncating mutation in a family with cutaneous melanoma
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Wadt, Karin A. W., Aoude, Lauren G., Golmard, Lisa, Hansen, Thomas V. O., Sastre-Garau, Xavier, Hayward, Nicholas K., and Gerdes, Anne-Marie
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- 2015
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12. Risk of somatic hospitalization in parents after cancer in a child, a nationwide cohort study
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von Heymann, Annika, primary, Alef‐Defoe, Sierra, additional, Salem, Hanin, additional, Andersen, Elisabeth Anne Wreford, additional, Dalton, Susanne Oksbjerg, additional, Schmiegelow, Kjeld, additional, Wadt, Karin A. W., additional, Winther, Jeanette Falck, additional, Johansen, Christoffer, additional, and Bidstrup, Pernille Envold, additional
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- 2022
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13. New hereditary polyposis syndromes in the patient with intestinal polyps
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Anne Marie Jelsig, Niels Jespersen, John Gásdal Karstensen, Zohreh Ketabi, Karina Rønlund, Lone Ena Munk Sunde, Ole Thorlacius-Ussing, Wadt, Karin A. W., Niels Qvist, and Charlotte Kvist Lautrup
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Humans ,Intestinal Polyps ,Nasopharyngeal Neoplasms ,Genetic Testing ,Colorectal Neoplasms ,Intestinal Polyposis/diagnosis ,Neoplastic Syndromes, Hereditary/diagnosis - Abstract
Fund af tarmpolypper ved endoskopiske undersøgelser er hyppige, idet man antager, at 30-50% af befolkningen har en eller flere polypper i tyktarmen efter 50-årsalderen [1]. Som oftest foretages der polypektomi, og patienten kontrolleres efterfølgende i overensstemmelse med gældende retningslinjer for de forskellige underliggende årsager/sygdomme. Polypperne kan dog være en manifestation af et arveligt polyposesyndrom, som er vigtigt at kende, da patienterne og deres familiemedlemmer har en høj risiko for udvikling af kræft i både gastrointestinalkanalen og andre organer. Nogle af syndromerne er også karakteriseret ved ekstraintestinale manifestationer. Behandling og opfølgning afhænger af det tilgrundliggende syndrom.
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- 2022
14. Novel germline TP53variant (p.(Phe109Ile)) confers high risk of cancer
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Byrjalsen, Anna, Stoltze, Ulrik Kristoffer, Lautrup, Charlotte, Christensen, Lise Lotte, Mikkelsen, Torben, Hjalgrim, Lisa, Brok, Jesper Sune, Dahl, Christine, Schmiegelow, Kjeld, Borgwardt, Lotte, Diness, Birgitte Rode, Hansen, Thomas Van Overeem, and Wadt, Karin A W
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- 2024
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15. Melanoma genetics
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Read, Jazlyn, Wadt, Karin A W, and Hayward, Nicholas K
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- 2016
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16. Variation in the Risk of Colorectal Cancer for Lynch Syndrome: A retrospective family cohort study
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Win, Aung Ko, Dowty, James G., Reece, Jeanette C., Lee, Grant, Templeton, Allyson S., Plazzer, John-Paul, Buchanan, Daniel D., Akagi, Kiwamu, Aksoy, Seçil, Alonso, Angel, Alvarez, Karin, Amor, David J., Ankathil, Ravindran, Aretz, Stefan, Arnold, Julie L., Aronson, Melyssa, Austin, Rachel, Backman, Ann-Sofie, Bajwa–ten Broeke, Sanne W., Barca-Tierno, Verónica, Barwell, Julian, Bernstein, Inge, Berthet, Pascaline, Betz, Beate, Bignon, Yves-Jean, Boisjoli, Talya, Bonadona, Valérie, Briollais, Laurent, Brunet, Joan, Bucksch, Karolin, Buecher, Bruno, Buettner, Reinhard, Burn, John, Caldés, Trinidad, Capella, Gabriel, Caron, Olivier, Casey, Graham, Chew, Min H., Choi, Yun-hee, Church, James, Clendenning, Mark, Colas, Chrystelle, Cops, Elisa J., Coupier, Isabelle, Cruz-Correa, Marcia, de la Chapelle, Albert, de Wind, Niels, Dębniak, Tadeusz, Della Valle, Adriana, Delnatte, Capuccine, Dhooge, Marion, Dominguez-Valentin, Mev, Drouet, Youenn, Duijkers, Floor A., Engel, Christoph, Esperon, Patricia, Evans, D. Gareth, de Vargas, Aída Falcón, Figueiredo, Jane C, Foulkes, William, Fourme, Emmanuelle, Frebourg, Thierry, Gallinger, Steven, Garre, Pilar, Genuardi, Maurizio, Gerdes, Anne-Marie, Gima, Lauren M., Giraud, Sophie, Goodwin, Annabel, Görgens, Heike, Green, Kate, Guillem, Jose, Guillén-Ponce, Carmen, Guimbaud, Roselyne, Guindalini, Rodrigo S. C., Half, Elizabeth E., Hall, Michael J, Hampel, Heather, Hansen, Thomas V. O., Heinimann, Karl, Hes, Frederik J., Hill, James, Ho, Judy W.C., Holinski-Feder, Elke, Hoogerbrugge, Nicoline, Hüneburg, Robert, Huntley, Vanessa, James, Paul A., Jensen, Uffe B, John, Thomas, Juhari, Wan K.W., Kalady, Matthew, Kastrinos, Fay, Kloor, Matthias, Kohonen-Corish, Maija RJ, Krogh, Lotte N., Kupfer, Sonia S., Ladabaum, Uri, Lagerstedt-Robinson, Kristina, Lalloo, Fiona, Lasset, Christine, Latchford, Andrew, Laurent-Puig, Pierre, Lautrup, Charlotte K., Leggett, Barbara A., Lejeune, Sophie, LeMarchand, Loic, Ligtenberg, Marjolijn, Lindor, Noralane, Loeffler, Markus, Longy, Michel, Lopez, Francisco, Lowery, Jan, Lubiński, Jan, Lucassen, Anneke M, Lynch, Patrick M., Malińska, Karolina, Matsubara, Nagahide, Mecklin, Jukka-Pekka, Møller, Pål, Monahan, Kevin, Morrison, Patrick J., Nattermann, Jacob, Navarro, Matilde, Neffa, Florencia, Neklason, Deborah, Newcomb, Polly A., Ngeow, Joanne, Nichols, Cassandra, Nielsen, Maartje, Nixon, Dawn M., Nogues, Catherine, Okkels, Henrik, Olschwang, Sylviane, Pachter, Nicholas, Pai, Rish K., Palmero, Edenir I., Pande, Mala, Parry, Susan, Patel, Swati G., Pearlman, Rachel, Perne, Claudia, Pineda, Marta, Poplawski, Nicola K, Pylvänäinen, Kirsi, Qiu, Jay, Rahner, Nils, Ramesar, Raj, Rasmussen, Lene J., Redler, Silke, Reis, Rui M., Ricciardiello, Luigi, Rogoża-Janiszewska, Emilia, Rosty, Christophe, Samadder, N. Jewel, Sampson, Julian R., Schackert, Hans K., Schmiegel, Wolff, Schulmann, Karsten, Schuster, Helène, Scott, Rodney, Senter, Leigha, Seppälä, Toni T, Shtoyerman, Rakefet, Sijmons, Rolf H., Snyder, Carrie, Solomon, Ilana B., Soto, Jose Luis, Southey, Melissa C., Spigelman, Allan, Spirandelli, Florencia, Spurdle, Amanda B., Steinke-Lange, Verena, Stoffel, Elena M., Strassburg, Christian P., Sunde, Lone, Susman, Rachel, Syngal, Sapna, Tanakaya, Kohji, Tezcan, Gülçin, Therkildsen, Christina, Thibodeau, Steve, Tomita, Naohiro, Tucker, Katherine M., Tunca, Berrin, Turchetti, Daniela, Uhrhammer, Nancy, Utsunomiya, Joji, Vaccaro, Carlos, van Duijnhoven, Fränzel J.B., van Wanzeele, Meghan J., Vangala, Deepak B., Vasen, Hans F.A., von Knebel Doeberitz, Magnus, von Salomé, Jenny, Wadt, Karin A. W., Ward, Robyn L., Weitz, Jürgen, Weitzel, Jeffrey N., Williams, Heinric, Winship, Ingrid, Wise, Paul E., Wods, Julie, Woods, Michael O., Yamaguchi, Tatsuro, Zachariae, Silke, Zahary, Mohd N., Hopper, John L., Haile, Robert W., Macrae, Finlay A., Möslein, Gabriela, and Jenkins, Mark A.
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Article - Abstract
BACKGROUND: Current clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the average age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate how much penetrance varies between carriers of pathogenic variants in the same gene by sex and continent of residence of the carrier. METHODS: We studied 79,809 relatives from 5,255 families, of at least three relatives, in which at least one was a confirmed carrier of a pathogenic or likely pathogenic variant in a mismatch repair gene (1,829 MLH1, 2,179 MSH2, 798 MSH6, 449 PMS2), recruited in 15 countries from North America, Europe and Australasia by the collaborative centres of the International Mismatch Repair Consortium. We used modified segregation analysis conditioned on ascertainment to estimate the average penetrance and modelled unmeasured polygenic factors to estimate the variation in penetrance of colorectal cancer. The existence of familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested using a Wald p-value for the null hypothesis that the polygenic standard deviation is zero. FINDINGS: There was strong evidence of the existence of familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was more prominent for MLH1 and MSH2 variant carriers; depending on gene, sex, and continent, with 7–56% of carriers having a risk of colorectal cancer to age 80 of less than 20%, and 9–44% having a risk of more than 80%, while only 10–19% had a risk of 40–60%. INTERPRETATION: Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessment for precision prevention and early detection of colorectal cancer for Lynch syndrome.
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- 2021
17. Genetics of familial melanoma: 20 years after CDKN2A
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Aoude, Lauren G., Wadt, Karin A. W., Pritchard, Antonia L., and Hayward, Nicholas K.
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- 2015
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18. Additional file 1 of Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families
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Lacson, John Charles A., Zamani, Shawn A., Froes, Luis Alberto Ribeiro, Mitra, Nandita, Qian, Lu, Scarlet H. Doyle, Azizi, Esther, Balestrini, Claudia, D. Timothy Bishop, Bruno, William, Carlos-Ortega, Blanca, Cuellar, Francisco, Cust, Anne E., E., David, Gerdes, Anne-Marie, Ghiorzo, Paola, Thais C. Grazziotin, Gruis, Nelleke A., Hansson, Johan, Hočevar, Marko, Höiom, Veronica, Holland, Elizabeth A., Ingvar, Christian, Landman, Gilles, Larre-Borges, Alejandra, Mann, Graham J., Molgo, Montserrat, Moredo, Luciana Facure, Olsson, Håkan, Out-Luiting, Jacoba J., Perić, Barbara, Pjanova, Dace, Puig, Susana, Salas-Alanis, Julio, Schmid, Helen, Wadt, Karin A. W., Newton-Bishop, Julia A., and Kanetsky, Peter A.
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neoplasms - Abstract
Additional file 1 : Module 1. Residency calendar, demographics, phenotype, and history of melanoma.
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- 2021
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19. Additional file 2 of Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families
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Lacson, John Charles A., Zamani, Shawn A., Froes, Luis Alberto Ribeiro, Mitra, Nandita, Qian, Lu, Scarlet H. Doyle, Azizi, Esther, Balestrini, Claudia, D. Timothy Bishop, Bruno, William, Carlos-Ortega, Blanca, Cuellar, Francisco, Cust, Anne E., E., David, Gerdes, Anne-Marie, Ghiorzo, Paola, Thais C. Grazziotin, Gruis, Nelleke A., Hansson, Johan, Hočevar, Marko, Höiom, Veronica, Holland, Elizabeth A., Ingvar, Christian, Landman, Gilles, Larre-Borges, Alejandra, Mann, Graham J., Molgo, Montserrat, Moredo, Luciana Facure, Olsson, Håkan, Out-Luiting, Jacoba J., Perić, Barbara, Pjanova, Dace, Puig, Susana, Salas-Alanis, Julio, Schmid, Helen, Wadt, Karin A. W., Newton-Bishop, Julia A., and Kanetsky, Peter A.
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Additional file 2 : Module 2. Personal sun exposure
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- 2021
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20. Uptake of hysterectomy and bilateral salpingooophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report
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Seppala, Toni T., Dominguez-Valentin, Mev, Crosbie, Emma J., Engel, Christoph, Aretz, Stefan, Macrae, Finlay, Winship, Ingrid, Capella, Gabriel, Thomas, Huw, Hovig, Eivind, Nielsen, Maartje, Sijmons, Rolf H., Bertario, Lucio, Bonanni, Bernardo, Tibiletti, Maria G., Cavestro, Giulia M., Mints, Miriam, Gluck, Nathan, Katz, Lior, Heinimann, Karl, Vaccaro, Carlos A., Green, Kate, Lalloo, Fiona, Hill, James, Schmiegel, Wolff, Vangala, Deepak, Perne, Claudia, Strauss, Hans-Georg, Tecklenburg, Johanna, Holinski-Feder, Elke, Steinke-Lange, Verena, Mecklin, Jukka-Pekka, Plazzer, John-Paul, Pineda, Marta, Navarro, Matilde, Vida, Joan B., Kariv, Revital, Rosner, Guy, Pinero, Tamara A., Pavicic, Walter, Kalfayan, Pablo, Ten Broeke, Sanne W., Jenkins, Mark A., Sunde, Lone, Bernstein, Inge, Burn, John, Greenblatt, Marc, Cappel, Wouter H. de Vos Tot Nederveen, Della Valle, Adriana, Lopez-Koestner, Francisco, Alvarez, Karin, Buettner, Reinhard, Goergens, Heike, Morak, Monika, Holzapfel, Stefanie, Hueneburg, Robert, Doeberitz, Magnus von Knebel, Loeffler, Markus, Redler, Silke, Weitz, Jurgen, Pylvaenaeinen, Kirsi, Renkonen-Sinisalo, Laura, Lepisto, Anna, Hopper, John L., Win, Aung K., Lindor, Noralane M., Gallinger, Steven, Marchand, Loic Le, Newcomb, Polly A., Figueiredo, Jane C., Thibodeau, Stephen N., Therkildsen, Christina, Wadt, Karin A. W., Mourits, Marian J. E., Ketabi, Zohreh, Denton, Oliver G., Rodland, Einar A., Vasen, Hans, Neffa, Florencia, Esperon, Patricia, Tjandra, Douglas, Moeslein, Gabriela, Rokkones, Erik, Sampson, Julian R., Evans, D. G., Moller, Pal, Seppala, Toni T., Dominguez-Valentin, Mev, Crosbie, Emma J., Engel, Christoph, Aretz, Stefan, Macrae, Finlay, Winship, Ingrid, Capella, Gabriel, Thomas, Huw, Hovig, Eivind, Nielsen, Maartje, Sijmons, Rolf H., Bertario, Lucio, Bonanni, Bernardo, Tibiletti, Maria G., Cavestro, Giulia M., Mints, Miriam, Gluck, Nathan, Katz, Lior, Heinimann, Karl, Vaccaro, Carlos A., Green, Kate, Lalloo, Fiona, Hill, James, Schmiegel, Wolff, Vangala, Deepak, Perne, Claudia, Strauss, Hans-Georg, Tecklenburg, Johanna, Holinski-Feder, Elke, Steinke-Lange, Verena, Mecklin, Jukka-Pekka, Plazzer, John-Paul, Pineda, Marta, Navarro, Matilde, Vida, Joan B., Kariv, Revital, Rosner, Guy, Pinero, Tamara A., Pavicic, Walter, Kalfayan, Pablo, Ten Broeke, Sanne W., Jenkins, Mark A., Sunde, Lone, Bernstein, Inge, Burn, John, Greenblatt, Marc, Cappel, Wouter H. de Vos Tot Nederveen, Della Valle, Adriana, Lopez-Koestner, Francisco, Alvarez, Karin, Buettner, Reinhard, Goergens, Heike, Morak, Monika, Holzapfel, Stefanie, Hueneburg, Robert, Doeberitz, Magnus von Knebel, Loeffler, Markus, Redler, Silke, Weitz, Jurgen, Pylvaenaeinen, Kirsi, Renkonen-Sinisalo, Laura, Lepisto, Anna, Hopper, John L., Win, Aung K., Lindor, Noralane M., Gallinger, Steven, Marchand, Loic Le, Newcomb, Polly A., Figueiredo, Jane C., Thibodeau, Stephen N., Therkildsen, Christina, Wadt, Karin A. W., Mourits, Marian J. E., Ketabi, Zohreh, Denton, Oliver G., Rodland, Einar A., Vasen, Hans, Neffa, Florencia, Esperon, Patricia, Tjandra, Douglas, Moeslein, Gabriela, Rokkones, Erik, Sampson, Julian R., Evans, D. G., and Moller, Pal
- Abstract
Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants. Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years. Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery. Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene-and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syn-drome to improve outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd.
- Published
- 2021
21. Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families
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Lacson, John Charles A., Zamani, Shawn A., Froes, Luis Alberto Ribeiro, Mitra, Nandita, Qian, Lu, Doyle, Scarlet H., Azizi, Esther, Balestrini, Claudia, Bishop, D. Timothy, Bruno, William, Carlos-ortega, Blanca, Cuellar, Francisco, Cust, Anne E., Elder, David E., Gerdes, Anne-marie, Ghiorzo, Paola, Grazziotin, Thais C., Gruis, Nelleke A., Hansson, Johan, Hočevar, Marko, Höiom, Veronica, Holland, Elizabeth A., Ingvar, Christian, Landman, Gilles, Larre-borges, Alejandra, Mann, Graham J., Molgo, Montserrat, Moredo, Luciana Facure, Olsson, Håkan, Out-luiting, Jacoba J., Perić, Barbara, Pjanova, Dace, Puig, Susana, Salas-alanis, Julio, Schmid, Helen, Wadt, Karin A. W., Newton-bishop, Julia A., Kanetsky, Peter A., Lacson, John Charles A., Zamani, Shawn A., Froes, Luis Alberto Ribeiro, Mitra, Nandita, Qian, Lu, Doyle, Scarlet H., Azizi, Esther, Balestrini, Claudia, Bishop, D. Timothy, Bruno, William, Carlos-ortega, Blanca, Cuellar, Francisco, Cust, Anne E., Elder, David E., Gerdes, Anne-marie, Ghiorzo, Paola, Grazziotin, Thais C., Gruis, Nelleke A., Hansson, Johan, Hočevar, Marko, Höiom, Veronica, Holland, Elizabeth A., Ingvar, Christian, Landman, Gilles, Larre-borges, Alejandra, Mann, Graham J., Molgo, Montserrat, Moredo, Luciana Facure, Olsson, Håkan, Out-luiting, Jacoba J., Perić, Barbara, Pjanova, Dace, Puig, Susana, Salas-alanis, Julio, Schmid, Helen, Wadt, Karin A. W., Newton-bishop, Julia A., and Kanetsky, Peter A.
- Published
- 2021
22. Maternal versus paternal inheritance of a 132 bp 11p15.5 microdeletion affecting KCNQ1OT1 and associated phenotypes.
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Stoltze, Ulrik Kristoffer, Hansen, Thomas Van Overeem, Brok, Jesper Sune, Grønskov, Karen, Tumer, Asuman Z., Ahlborn, Lise Barlebo, Schmiegelow, Kjeld, and Wadt, Karin A. W.
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- 2023
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23. Novel germline c-MET mutation in a family with hereditary papillary renal carcinoma
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Wadt, Karin A. W., Gerdes, Anne-Marie, Hansen, Thomas V. O., Toft, Birgitte G., Friis-Hansen, Lennart, and Andersen, Mette K.
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- 2012
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24. Maternal versus paternal inheritance of a 132 bp 11p15.5 microdeletion affecting KCNQ1OT1and associated phenotypes
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Stoltze, Ulrik Kristoffer, Hansen, Thomas Van Overeem, Brok, Jesper Sune, Grønskov, Karen, Tumer, Asuman Z, Ahlborn, Lise Barlebo, Schmiegelow, Kjeld, and Wadt, Karin A W
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- 2023
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25. Ciliary Neurotrophic Factor Potentiates the beta-Cell Inhibitory Effect of IL-1 beta in Rat Pancreatic Islets Associated With Increased Nitric Oxide Synthesis and Increased Expression of Inducible Nitric Oxide Synthase
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Wadt, Karin A. W., Larsen, Claus M., Andersen, Henrik U., Nielsen, Karin, Karlsen, Allan E., and Mandrup-Poulsen, Thomas
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- 1998
26. Putative new childhood leukemia cancer predisposition syndrome caused by germline bi-allelic missense mutations in DDX41
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Diness, Birgitte R., primary, Risom, Lotte, additional, Frandsen, Thomas L., additional, Hansen, Bente, additional, Andersen, Mette K., additional, Schmiegelow, Kjeld, additional, and Wadt, Karin A. W., additional
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- 2018
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27. Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families
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Taylor, Nicholas J, Mitra, Nandita, Goldstein, Alisa M, Tucker, Margaret A, Avril, Marie-Françoise, Azizi, Esther, Bergman, Wilma, Bishop, D Timothy, Bressac-de Paillerets, Brigitte, Bruno, William, Calista, Donato, Cannon-Albright, Lisa A, Cuellar, Francisco, Cust, Anne E, Demenais, Florence, Elder, David E, Gerdes, Anne-Marie, Ghiorzo, Paola, Grazziotin, Thais C, Hansson, Johan, Harland, Mark, Hayward, Nicholas K, Hocevar, Marko, Höiom, Veronica, Ingvar, Christian, Landi, Maria Teresa, Landman, Gilles, Larre-Borges, Alejandra, Leachman, Sancy A, Mann, Graham J, Nagore, Eduardo, Olsson, Håkan, Palmer, Jane M, Perić, Barbara, Pjanova, Dace, Pritchard, Antonia, Puig, Susana, van der Stoep, Nienke, Wadt, Karin A W, Whitaker, Linda, Yang, Xiaohong R, Newton Bishop, Julia A, Gruis, Nelleke A, Kanetsky, Peter A, Taylor, Nicholas J, Mitra, Nandita, Goldstein, Alisa M, Tucker, Margaret A, Avril, Marie-Françoise, Azizi, Esther, Bergman, Wilma, Bishop, D Timothy, Bressac-de Paillerets, Brigitte, Bruno, William, Calista, Donato, Cannon-Albright, Lisa A, Cuellar, Francisco, Cust, Anne E, Demenais, Florence, Elder, David E, Gerdes, Anne-Marie, Ghiorzo, Paola, Grazziotin, Thais C, Hansson, Johan, Harland, Mark, Hayward, Nicholas K, Hocevar, Marko, Höiom, Veronica, Ingvar, Christian, Landi, Maria Teresa, Landman, Gilles, Larre-Borges, Alejandra, Leachman, Sancy A, Mann, Graham J, Nagore, Eduardo, Olsson, Håkan, Palmer, Jane M, Perić, Barbara, Pjanova, Dace, Pritchard, Antonia, Puig, Susana, van der Stoep, Nienke, Wadt, Karin A W, Whitaker, Linda, Yang, Xiaohong R, Newton Bishop, Julia A, Gruis, Nelleke A, and Kanetsky, Peter A
- Abstract
Germline mutations in CDKN2A are frequently identified among melanoma kindreds and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2A mutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2A mutation carriage and 2-mm, 5-mm, and atypical nevus counts among blood-related members of melanoma families. Compared with individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (odds ratio = 1.64; 95% confidence interval = 1.18-2.28) nevi but not 2-mm nevi (odds ratio = 1.06; 95% confidence interval = 0.92-1.21) or 5-mm nevi (odds ratio = 1.26; 95% confidence interval = 0.94-1.70). Stratification by case status showed more pronounced positive associations among non-case family members, who were nearly three times (odds ratio = 2.91; 95% confidence interval = 1.75-4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results support the hypothesis that unidentified nevogenic genes are co-inherited with CDKN2A and may influence carcinogenesis.
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- 2017
28. Phenotypic and Histopathological Tumor Characteristics According to CDKN2A Mutation Status among Affected Members of Melanoma Families
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Taylor, Nicholas J, Handorf, Elizabeth A, Mitra, Nandita, Avril, Marie-Françoise, Azizi, Esther, Bergman, Wilma, Bianchi-Scarrà, Giovanna, Bishop, D Timothy, Bressac-de Paillerets, Brigitte, Calista, Donato, Cannon-Albright, Lisa A, Cuellar, Francisco, Cust, Anne E, Demenais, Florence, Elder, David E, Friedman, Eitan, Gerdes, Anne-Marie, Ghiorzo, Paola, Goldstein, Alisa M, Grazziotin, Thais C, Hansson, Johan, Hayward, Nicholas K, Hocevar, Marko, Höiom, Veronica, Holland, Elizabeth A, Ingvar, Christian, Landi, Maria Teresa, Landman, Gilles, Larre-Borges, Alejandra, Leachman, Sancy A, Mann, Graham J, Nagore, Eduardo, Olsson, Håkan, Palmer, Jane, Perić, Barbara, Pjanova, Dace, Puig, Susana, Schmid, Helen, van der Stoep, Nienke, Tucker, Margaret A, Wadt, Karin A W, Whitaker, Linda, Yang, Xiaohong R, Newton Bishop, Julia A, Gruis, Nelleke A, Kanetsky, Peter A, Taylor, Nicholas J, Handorf, Elizabeth A, Mitra, Nandita, Avril, Marie-Françoise, Azizi, Esther, Bergman, Wilma, Bianchi-Scarrà, Giovanna, Bishop, D Timothy, Bressac-de Paillerets, Brigitte, Calista, Donato, Cannon-Albright, Lisa A, Cuellar, Francisco, Cust, Anne E, Demenais, Florence, Elder, David E, Friedman, Eitan, Gerdes, Anne-Marie, Ghiorzo, Paola, Goldstein, Alisa M, Grazziotin, Thais C, Hansson, Johan, Hayward, Nicholas K, Hocevar, Marko, Höiom, Veronica, Holland, Elizabeth A, Ingvar, Christian, Landi, Maria Teresa, Landman, Gilles, Larre-Borges, Alejandra, Leachman, Sancy A, Mann, Graham J, Nagore, Eduardo, Olsson, Håkan, Palmer, Jane, Perić, Barbara, Pjanova, Dace, Puig, Susana, Schmid, Helen, van der Stoep, Nienke, Tucker, Margaret A, Wadt, Karin A W, Whitaker, Linda, Yang, Xiaohong R, Newton Bishop, Julia A, Gruis, Nelleke A, and Kanetsky, Peter A
- Published
- 2016
29. Molecular Characterization of Melanoma Cases in Denmark Suspected of Genetic Predisposition
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Wadt, Karin A. W., Aoude, Lauren G., Krogh, Lotte, Sunde, Lone, Bojesen, Anders, Gronskov, Karen, Wartacz, Nine, Ek, Jakob, Tolstrup-Andersen, Morten, Klarskov-Andersen, Mette, Borg, Ake, Heegaard, Steffen, Kiilgaard, Jens Folke, Hansen, Thomas V. O., Klein, Kerenaftali, Jonsson, Goran, Drzewiecki, Krzysztof T., Duno, Morten, Hayward, Nicholas K., Gerdes, Anne-Marie, Wadt, Karin A. W., Aoude, Lauren G., Krogh, Lotte, Sunde, Lone, Bojesen, Anders, Gronskov, Karen, Wartacz, Nine, Ek, Jakob, Tolstrup-Andersen, Morten, Klarskov-Andersen, Mette, Borg, Ake, Heegaard, Steffen, Kiilgaard, Jens Folke, Hansen, Thomas V. O., Klein, Kerenaftali, Jonsson, Goran, Drzewiecki, Krzysztof T., Duno, Morten, Hayward, Nicholas K., and Gerdes, Anne-Marie
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- 2015
30. Germline RAD51B truncating mutation in a family with cutaneous melanoma
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Wadt, Karin A W, Aoude, Lauren G, Golmard, Lisa, Hansen, Thomas V O, Sastre-Garau, Xavier, Hayward, Nicholas K, Gerdes, Anne-Marie, Wadt, Karin A W, Aoude, Lauren G, Golmard, Lisa, Hansen, Thomas V O, Sastre-Garau, Xavier, Hayward, Nicholas K, and Gerdes, Anne-Marie
- Abstract
Known melanoma predisposition genes only account for around 40% of high-density melanoma families. Other rare mutations are likely to play a role in melanoma predisposition. RAD51B plays an important role in DNA repair through homologous recombination, and inactivation of RAD51B has been implicated in tumorigenesis. Thus RAD51B is a good candidate melanoma susceptibility gene, and previously, a germline splicing mutation in RAD51B has been identified in a family with early-onset breast cancer. In order to find genetic variants associated with melanoma predisposition, whole-exome sequencing was carried out on blood samples from a three-case cutaneous melanoma family. We identified a novel germline RAD51B nonsense mutation, and we demonstrate reduced expression of RAD51B in melanoma cells indicating inactivation of RAD51B. This is only the second report of a germline truncating RAD51B mutation. While this case report is consistent with melanoma being part of the RAD51B cancer spectrum further population-based screening of large case-control sample series will be needed to definitively establish if this is the case.
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- 2015
31. High accuracy of family history of melanoma in Danish melanoma cases
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Wadt, Karin A W, Drzewiecki, Krzysztof T, Gerdes, Anne-Marie, Wadt, Karin A W, Drzewiecki, Krzysztof T, and Gerdes, Anne-Marie
- Abstract
The incidence of melanoma in Denmark has immensely increased over the last 10 years making Denmark a high risk country for melanoma. In the last two decades multiple public campaigns have sought to increase the awareness of melanoma. Family history of melanoma is a known major risk factor but previous studies have shown that self-reported family history of melanoma is highly inaccurate. These studies are 15 years old and we wanted to examine if a higher awareness of melanoma has increased the accuracy of self-reported family history of melanoma. We examined the family history of 181 melanoma probands who reported 199 cases of melanoma in relatives, of which 135 cases where in first degree relatives. We confirmed the diagnosis of melanoma in 77 % of all relatives, and in 83 % of first degree relatives. In 181 probands we validated the negative family history of melanoma in 748 first degree relatives and found only 1 case of melanoma which was not reported in a 3 case melanoma family. Melanoma patients in Denmark report family history of melanoma in first and second degree relatives with a high level of accuracy with a true positive predictive value between 77 and 87 %. In 99 % of probands reporting a negative family history of melanoma in first degree relatives this information is correct. In clinical practice we recommend that melanoma diagnosis in relatives should be verified if possible, but even unverified reported melanoma cases in relatives should be included in the indication of genetic testing and assessment of melanoma risk in the family., The incidence of melanoma in Denmark has immensely increased over the last 10 years making Denmark a high risk country for melanoma. In the last two decades multiple public campaigns have sought to increase the awareness of melanoma. Family history of melanoma is a known major risk factor but previous studies have shown that self-reported family history of melanoma is highly inaccurate. These studies are 15 years old and we wanted to examine if a higher awareness of melanoma has increased the accuracy of self-reported family history of melanoma. We examined the family history of 181 melanoma probands who reported 199 cases of melanoma in relatives, of which 135 cases where in first degree relatives. We confirmed the diagnosis of melanoma in 77% of all relatives, and in 83% of first degree relatives. In 181 probands we validated the negative family history of melanoma in 748 first degree relatives and found only 1 case of melanoma which was not reported in a 3 case melanoma family. Melanoma patients in Denmark report family history of melanoma in first and second degree relatives with a high level of accuracy with a true positive predictive value between 77 and 87%. In 99% of probands reporting a negative family history of melanoma in first degree relatives this information is correct. In clinical practice we recommend that melanoma diagnosis in relatives should be verified if possible, but even unverified reported melanoma cases in relatives should be included in the indication of genetic testing and assessment of melanoma risk in the family.
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- 2015
32. Molecular characterization of melanoma cases in denmark suspected of genetic predisposition.
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Wadt, Karin A W, Aoude, Lauren G, Krogh, Lotte, Sunde, Lone, Bojesen, Anders, Grønskov, Karen, Wartacz, Nine, Ek, Jakob, Tolstrup-Andersen, Morten, Klarskov-Andersen, Mette, Borg, Åke, Heegaard, Steffen, Kiilgaard, Jens F, Hansen, Thomas V O, Klein, Kerenaftali, Jönsson, Göran B, Drzewiecki, Krzysztof T, Dunø, Morten, Hayward, Nicholas K, Gerdes, Anne-Marie, Wadt, Karin A W, Aoude, Lauren G, Krogh, Lotte, Sunde, Lone, Bojesen, Anders, Grønskov, Karen, Wartacz, Nine, Ek, Jakob, Tolstrup-Andersen, Morten, Klarskov-Andersen, Mette, Borg, Åke, Heegaard, Steffen, Kiilgaard, Jens F, Hansen, Thomas V O, Klein, Kerenaftali, Jönsson, Göran B, Drzewiecki, Krzysztof T, Dunø, Morten, Hayward, Nicholas K, and Gerdes, Anne-Marie
- Abstract
Both environmental and host factors influence risk of cutaneous melanoma (CM), and worldwide, the incidence varies depending on constitutional determinants of skin type and pigmentation, latitude, and patterns of sun exposure. We performed genetic analysis of CDKN2A, CDK4, BAP1, MC1R, and MITFp.E318K in Danish high-risk melanoma cases and found CDKN2A germline mutations in 11.3% of CM families with three or more affected individuals, including four previously undescribed mutations. Rare mutations were also seen in CDK4 and BAP1, while MC1R variants were common, occurring at more than twice the frequency compared to Danish controls. The MITF p.E318K variant similarly occurred at an approximately three-fold higher frequency in melanoma cases than controls. To conclude, we propose that mutation screening of CDKN2A and CDK4 in Denmark should predominantly be performed in families with at least 3 cases of CM. In addition, we recommend that testing of BAP1 should not be conducted routinely in CM families but should be reserved for families with CM and uveal melanoma, or mesothelioma.
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- 2015
33. Germline TERT promoter mutations are rare in familial melanoma
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Harland, Mark, primary, Petljak, Mia, additional, Robles-Espinoza, Carla Daniela, additional, Ding, Zhihao, additional, Gruis, Nelleke A., additional, van Doorn, Remco, additional, Pooley, Karen A., additional, Dunning, Alison M., additional, Aoude, Lauren G., additional, Wadt, Karin A. W., additional, Gerdes, Anne-Marie, additional, Brown, Kevin M., additional, Hayward, Nicholas K., additional, Newton-Bishop, Julia A., additional, Adams, David J., additional, and Bishop, D. Timothy, additional
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- 2015
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34. Melanoma genetics
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Read, Jazlyn, primary, Wadt, Karin A W, additional, and Hayward, Nicholas K, additional
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- 2015
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35. Molecular Characterization of Melanoma Cases in Denmark Suspected of Genetic Predisposition
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Wadt, Karin A. W., primary, Aoude, Lauren G., additional, Krogh, Lotte, additional, Sunde, Lone, additional, Bojesen, Anders, additional, Grønskov, Karen, additional, Wartacz, Nine, additional, Ek, Jakob, additional, Tolstrup-Andersen, Morten, additional, Klarskov-Andersen, Mette, additional, Borg, Åke, additional, Heegaard, Steffen, additional, Kiilgaard, Jens F., additional, Hansen, Thomas V. O., additional, Klein, Kerenaftali, additional, Jönsson, Göran, additional, Drzewiecki, Krzysztof T., additional, Dunø, Morten, additional, Hayward, Nicholas K., additional, and Gerdes, Anne-Marie, additional
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- 2015
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36. Novel germline TP53 variant (p.(Phe109Ile)) confers high risk of cancer.
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Byrjalsen A, Stoltze UK, Lautrup C, Christensen LL, Mikkelsen T, Hjalgrim L, Brok JS, Dahl C, Schmiegelow K, Borgwardt L, Diness BR, Hansen TVO, and Wadt KAW
- Abstract
Competing Interests: Competing interests: KAWW has received payment for a lecture to Seagen Denmark Aps. The lecture addressed BRCA gene testing in patients with breast cancer . The remaining authors declare no conflicts of interest.
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- 2024
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37. Genetic counselling legislation and practice in cancer in EU Member States.
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McCrary JM, Van Valckenborgh E, Poirel HA, de Putter R, van Rooij J, Horgan D, Dierks ML, Antonova O, Brunet J, Chirita-Emandi A, Colas C, Dalmas M, Ehrencrona H, Grima C, Janavičius R, Klink B, Koczok K, Krajc M, Lace B, Leitsalu L, Mistrik M, Paneque M, Primorac D, Roetzer KM, Ronez J, Slámová L, Spanou E, Stamatopoulos K, Stoklosa T, Strang-Karlsson S, Szakszon K, Szczałuba K, Turner J, van Dooren MF, van Zelst-Stams WAG, Vassallo LM, Wadt KAW, Žigman T, Ripperger T, Genuardi M, Van den Bulcke M, and Bergmann AK
- Subjects
- Humans, Genetic Testing legislation & jurisprudence, European Union, Genetic Counseling legislation & jurisprudence, Neoplasms genetics
- Abstract
Background: Somatic and germline genetic alterations are significant drivers of cancer. Increasing integration of new technologies which profile these alterations requires timely, equitable and high-quality genetic counselling to facilitate accurate diagnoses and informed decision-making by patients and their families in preventive and clinical settings. This article aims to provide an overview of genetic counselling legislation and practice across European Union (EU) Member States to serve as a foundation for future European recommendations and action., Methods: National legislative databases of all 27 Member States were searched using terms relevant to genetic counselling, translated as appropriate. Interviews with relevant experts from each Member State were conducted to validate legislative search results and provide detailed insights into genetic counselling practice in each country., Results: Genetic counselling is included in national legislative documents of 22 of 27 Member States, with substantial variation in legal mechanisms and prescribed details (i.e. the 'who, what, when and where' of counselling). Practice is similarly varied. Workforce capacity (25 of 27 Member States) and genetic literacy (all Member States) were common reported barriers. Recognition and/or better integration of genetic counsellors and updated legislation and were most commonly noted as the 'most important change' which would improve practice., Conclusions: This review highlights substantial variability in genetic counselling across EU Member States, as well as common barriers notwithstanding this variation. Future recommendations and action should focus on addressing literacy and capacity challenges through legislative, regulatory and/or strategic approaches at EU, national, regional and/or local levels., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Public Health Association.)
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- 2024
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38. TINF2 is a major susceptibility gene in Danish patients with multiple primary melanoma.
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Jensen MR, Jelsig AM, Gerdes AM, Hölmich LR, Kainu KH, Lorentzen HF, Hansen MH, Bak M, Johansson PA, Hayward NK, Van Overeem Hansen T, and Wadt KAW
- Subjects
- Humans, Syndrome, Denmark epidemiology, Telomere-Binding Proteins genetics, Melanoma genetics, Thyroid Neoplasms, Sarcoma, Neoplasms, Multiple Primary
- Abstract
TINF2 encodes the TINF2 protein, which is a subunit in the shelterin complex critical for telomere regulation. Three recent studies have associated six truncating germline variants in TINF2 that have previously been associated with a cancer predisposition syndrome (CPS) caused by elongation of the telomeres. This has added TINF2 to the long telomere syndrome genes, together with other telomere maintenance genes such as ACD , POT1 , TERF2IP , and TERT . We report a clinical study of 102 Danish patients with multiple primary melanoma (MPM) in which a germline truncating variant in TINF2 (p.(Arg265Ter)) was identified in four unrelated participants. The telomere lengths of three variant carriers were >90% percentile. In a routine diagnostic setting, the variant was identified in two more families, including an additional MPM patient and monozygotic twins with thyroid cancer and other cancer types. A total of 10 individuals from six independent families were confirmed carriers, all with cancer history, predominantly melanoma. Our findings suggest a major role of TINF2 in Danish patients with MPM. In addition to melanoma, other cancers in the six families include thyroid, renal, breast, and sarcoma, supporting a CPS in which melanoma, thyroid cancer, and sarcoma predominate. Further studies are needed to establish the full spectrum of associated cancer types and characterize lifetime cancer risk in carriers., Competing Interests: The authors declare no competing interests., (© 2023.)
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- 2023
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39. Novel Genetic Causes of Gastrointestinal Polyposis Syndromes.
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Jelsig AM, Byrjalsen A, Busk Madsen M, Kuhlmann TP, van Overeem Hansen T, Wadt KAW, and Karstensen JG
- Abstract
Hereditary polyposis syndromes are characterized by a large number and/or histopathologically specific polyps in the gastrointestinal tract and a high risk of both colorectal cancer and extracolonic cancer at an early age. While the genes responsible for some of the syndromes, eg, APC in familial adenomatous polyposis and STK11 in Peutz-Jeghers syndrome, have been known for decades, novel genetic causes have recently been detected that have shed light on the broader clinical spectrum of syndromes. Genetic diagnoses are important because they can facilitate a personalized surveillance program. Furthermore, at-risk members of the patient's family can be tested and enrolled in surveillance as needed. In some cases, prenatal diagnostics should be offered. In this paper, we describe the development in germline genetics of the hereditary polyposis syndromes over the last 10-12 years, their clinical characteristics, as well as how to implement genetic analyses in the diagnostic pipeline., Competing Interests: Dr Karin AW Wadt reports personal fees from advisory board meetings with MSD and AstraZeneca, outside the submitted work. The authors report no conflicts of interest in this work., (© 2021 Jelsig et al.)
- Published
- 2021
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40. Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.
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Seppälä TT, Dominguez-Valentin M, Crosbie EJ, Engel C, Aretz S, Macrae F, Winship I, Capella G, Thomas H, Hovig E, Nielsen M, Sijmons RH, Bertario L, Bonanni B, Tibiletti MG, Cavestro GM, Mints M, Gluck N, Katz L, Heinimann K, Vaccaro CA, Green K, Lalloo F, Hill J, Schmiegel W, Vangala D, Perne C, Strauß HG, Tecklenburg J, Holinski-Feder E, Steinke-Lange V, Mecklin JP, Plazzer JP, Pineda M, Navarro M, Vida JB, Kariv R, Rosner G, Piñero TA, Pavicic W, Kalfayan P, Ten Broeke SW, Jenkins MA, Sunde L, Bernstein I, Burn J, Greenblatt M, de Vos Tot Nederveen Cappel WH, Della Valle A, Lopez-Koestner F, Alvarez K, Büttner R, Görgens H, Morak M, Holzapfel S, Hüneburg R, von Knebel Doeberitz M, Loeffler M, Redler S, Weitz J, Pylvänäinen K, Renkonen-Sinisalo L, Lepistö A, Hopper JL, Win AK, Lindor NM, Gallinger S, Le Marchand L, Newcomb PA, Figueiredo JC, Thibodeau SN, Therkildsen C, Wadt KAW, Mourits MJE, Ketabi Z, Denton OG, Rødland EA, Vasen H, Neffa F, Esperon P, Tjandra D, Möslein G, Rokkones E, Sampson JR, Evans DG, and Møller P
- Subjects
- Adult, Aged, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Colorectal Neoplasms, Hereditary Nonpolyposis surgery, Cross-Sectional Studies, Databases, Factual, Female, Follow-Up Studies, Genital Neoplasms, Female prevention & control, Humans, Middle Aged, Prognosis, Prospective Studies, Biomarkers, Tumor genetics, Colorectal Neoplasms, Hereditary Nonpolyposis pathology, DNA Mismatch Repair, Heterozygote, Hysterectomy methods, Mutation, Salpingo-oophorectomy methods
- Abstract
Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants., Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years., Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery., Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene- and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syndrome to improve outcomes., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2021
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41. Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families.
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Lacson JCA, Zamani SA, Froes LAR Jr, Mitra N, Qian L, Doyle SH, Azizi E, Balestrini C, Bishop DT, Bruno W, Carlos-Ortega B, Cuellar F, Cust AE, Elder DE, Gerdes AM, Ghiorzo P, Grazziotin TC, Gruis NA, Hansson J, Hočevar M, Höiom V, Holland EA, Ingvar C, Landman G, Larre-Borges A, Mann GJ, Molgo M, Moredo LF, Olsson H, Out-Luiting JJ, Perić B, Pjanova D, Puig S, Salas-Alanis J, Schmid H, Wadt KAW, Newton-Bishop JA, and Kanetsky PA
- Subjects
- Humans, Retrospective Studies, Sunscreening Agents therapeutic use, Melanoma epidemiology, Melanoma prevention & control, Skin Neoplasms epidemiology, Skin Neoplasms prevention & control, Sunburn epidemiology, Sunburn prevention & control
- Abstract
Background: Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited., Methods: Individuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates., Results: A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis., Conclusions: Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families.
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- 2021
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42. Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT.
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Taylor NJ, Mitra N, Qian L, Avril MF, Bishop DT, Bressac-de Paillerets B, Bruno W, Calista D, Cuellar F, Cust AE, Demenais F, Elder DE, Gerdes AM, Ghiorzo P, Goldstein AM, Grazziotin TC, Gruis NA, Hansson J, Harland M, Hayward NK, Hocevar M, Höiom V, Holland EA, Ingvar C, Landi MT, Landman G, Larre-Borges A, Mann GJ, Nagore E, Olsson H, Palmer JM, Perić B, Pjanova D, Pritchard AL, Puig S, Schmid H, van der Stoep N, Tucker MA, Wadt KAW, Yang XR, Newton-Bishop JA, and Kanetsky PA
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- Adolescent, Adult, Aged, Aged, 80 and over, Area Under Curve, Child, Genetic Testing, Germ-Line Mutation, Heterozygote, Humans, Internationality, Middle Aged, Phenotype, Predictive Value of Tests, Probability, ROC Curve, Risk Factors, Young Adult, Cyclin-Dependent Kinase Inhibitor p16 genetics, Genetic Predisposition to Disease, Logistic Models, Melanoma genetics, Pancreatic Neoplasms epidemiology, Pancreatic Neoplasms genetics, Skin Neoplasms genetics
- Abstract
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 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., (Copyright © 2019 American Academy of Dermatology, Inc. All rights reserved.)
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- 2019
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43. Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families.
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Taylor NJ, Mitra N, Goldstein AM, Tucker MA, Avril MF, Azizi E, Bergman W, Bishop DT, Bressac-de Paillerets B, Bruno W, Calista D, Cannon-Albright LA, Cuellar F, Cust AE, Demenais F, Elder DE, Gerdes AM, Ghiorzo P, Grazziotin TC, Hansson J, Harland M, Hayward NK, Hocevar M, Höiom V, Ingvar C, Landi MT, Landman G, Larre-Borges A, Leachman SA, Mann GJ, Nagore E, Olsson H, Palmer JM, Perić B, Pjanova D, Pritchard A, Puig S, van der Stoep N, Wadt KAW, Whitaker L, Yang XR, Newton Bishop JA, Gruis NA, and Kanetsky PA
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- Cyclin-Dependent Kinase Inhibitor p16, DNA Mutational Analysis, Family Health, Female, Genotype, Humans, Male, Nevus, Pigmented genetics, Odds Ratio, Phenotype, Registries, Melanoma, Cutaneous Malignant, Cyclin-Dependent Kinase Inhibitor p18 genetics, Germ-Line Mutation, Melanoma genetics, Nevus genetics, Skin Neoplasms genetics
- Abstract
Germline mutations in CDKN2A are frequently identified among melanoma kindreds and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2A mutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2A mutation carriage and 2-mm, 5-mm, and atypical nevus counts among blood-related members of melanoma families. Compared with individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (odds ratio = 1.64; 95% confidence interval = 1.18-2.28) nevi but not 2-mm nevi (odds ratio = 1.06; 95% confidence interval = 0.92-1.21) or 5-mm nevi (odds ratio = 1.26; 95% confidence interval = 0.94-1.70). Stratification by case status showed more pronounced positive associations among non-case family members, who were nearly three times (odds ratio = 2.91; 95% confidence interval = 1.75-4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results support the hypothesis that unidentified nevogenic genes are co-inherited with CDKN2A and may influence carcinogenesis., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2017
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44. Phenotypic and Histopathological Tumor Characteristics According to CDKN2A Mutation Status among Affected Members of Melanoma Families.
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Taylor NJ, Handorf EA, Mitra N, Avril MF, Azizi E, Bergman W, Bianchi-Scarrà G, Bishop DT, Bressac-de Paillerets B, Calista D, Cannon-Albright LA, Cuellar F, Cust AE, Demenais F, Elder DE, Friedman E, Gerdes AM, Ghiorzo P, Goldstein AM, Grazziotin TC, Hansson J, Hayward NK, Hocevar M, Höiom V, Holland EA, Ingvar C, Landi MT, Landman G, Larre-Borges A, Leachman SA, Mann GJ, Nagore E, Olsson H, Palmer J, Perić B, Pjanova D, Puig S, Schmid H, van der Stoep N, Tucker MA, Wadt KAW, Whitaker L, Yang XR, Newton Bishop JA, Gruis NA, and Kanetsky PA
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- Adult, Aged, Biopsy, Needle, Cohort Studies, Cyclin-Dependent Kinase Inhibitor p16, Databases, Factual, Female, Humans, Immunohistochemistry, Incidence, Male, Melanoma epidemiology, Middle Aged, Mutation, Pedigree, Phenotype, Prognosis, Risk Assessment, Skin Neoplasms epidemiology, Melanoma, Cutaneous Malignant, Cyclin-Dependent Kinase Inhibitor p18 genetics, Genetic Predisposition to Disease epidemiology, Melanoma genetics, Melanoma pathology, Skin Neoplasms genetics, Skin Neoplasms pathology
- Abstract
Competing Interests: The authors state no conflict of interest.
- Published
- 2016
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