{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T01:57:25Z","timestamp":1790733445471,"version":"4.1.0"},"reference-count":15,"publisher":"American Medical Association (AMA)","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Dermatol"],"published-print":{"date-parts":[[2023,10,1]]},"abstract":"<jats:sec id=\"ab-dbr230012-4\"><jats:title>Importance<\/jats:title><jats:p>Knowledge about the prevalence and tumor types of <jats:italic>CDKN2A<\/jats:italic>-related melanoma-astrocytoma syndrome (MAS) is limited and could improve disease recognition.<\/jats:p><\/jats:sec><jats:sec id=\"ab-dbr230012-5\"><jats:title>Objective<\/jats:title><jats:p>To estimate the prevalence and describe the tumor types of MAS.<\/jats:p><\/jats:sec><jats:sec id=\"ab-dbr230012-6\"><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>This retrospective cohort study analyzed all available MAS cases from medical centers in the US (2 sites) and Europe (2 sites) and from biomedical population genomic databases (UK Biobank [United Kingdom], Geisinger MyCode [US]) between January 1, 1976, and December 31, 2020. Patients with MAS with <jats:italic>CDKN2A<\/jats:italic> germline pathogenic variants and 1 or more neural tumors were included. Data were analyzed from June 1, 2022, to January 31, 2023.<\/jats:p><\/jats:sec><jats:sec id=\"ab-dbr230012-7\"><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>Disease prevalence and tumor frequency.<\/jats:p><\/jats:sec><jats:sec id=\"ab-dbr230012-8\"><jats:title>Results<\/jats:title><jats:p>Prevalence of MAS ranged from 1 in 170\u202f503 (n\u2009=\u20091 case; 95% CI, 1:30\u202f098-1:965\u202f887) in Geisinger MyCode (n\u2009=\u2009170\u202f503; mean [SD] age, 58.9 [19.1] years; 60.6% women; 96.2% White) to 1 in 39\u202f149 (n\u2009=\u200912 cases; 95% CI, 1:22\u202f396-1:68\u202f434) in UK Biobank (n\u2009=\u2009469\u202f789; mean [SD] age, 70.0 [8.0] years; 54.2% women; 94.8% White). Among UK Biobank patients with MAS (n\u2009=\u200912) identified using an unbiased genomic ascertainment approach, brain neoplasms (4 of 12, 33%; 1 glioblastoma, 1 gliosarcoma, 1 astrocytoma, 1 unspecified type) and schwannomas (3 of 12, 25%) were the most common malignant and benign neural tumors, while cutaneous melanoma (2 of 12, 17%) and head and neck squamous cell carcinoma (2 of 12, 17%) were the most common nonneural malignant neoplasms. In a separate case series of 14 patients with MAS from the US and Europe, brain neoplasms (4 of 14, 29%; 2 glioblastomas, 2 unspecified type) and malignant peripheral nerve sheath tumor (2 of 14, 14%) were the most common neural cancers, while cutaneous melanoma (4 of 14, 29%) and sarcomas (2 of 14, 14%; 1 liposarcoma, 1 unspecified type) were the most common nonneural cancers. Cutaneous neurofibromas (7 of 14, 50%) and schwannomas (2 of 14, 14%) were also common. In 1 US family, a father and son with MAS had clinical diagnoses of neurofibromatosis type 1 (NF1). Genetic testing of the son detected a pathogenic <jats:italic>CDKN2A<\/jats:italic> splicing variant (c.151-1G&amp;amp;gt;C) and was negative for <jats:italic>NF1<\/jats:italic> genetic alterations. In UK Biobank, 2 in 150 (1.3%) individuals with clinical NF1 diagnoses had likely pathogenic variants in <jats:italic>CDKN2A<\/jats:italic>, including 1 individual with no detected variants in the <jats:italic>NF1<\/jats:italic> gene.<\/jats:p><\/jats:sec><jats:sec id=\"ab-dbr230012-9\"><jats:title>Conclusions and Relevance<\/jats:title><jats:p>This cohort study estimates the prevalence and describes the tumors of MAS. Additional studies are needed in genetically diverse populations to further define population prevalence and disease phenotypes.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamadermatol.2023.2621","type":"journal-article","created":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T15:00:57Z","timestamp":1692198057000},"page":"1112","source":"Crossref","is-referenced-by-count":15,"title":["Estimated Prevalence, Tumor Spectrum, and Neurofibromatosis Type 1\u2013Like Phenotype of <i>CDKN2A<\/i>-Related Melanoma-Astrocytoma Syndrome"],"prefix":"10.1001","volume":"159","author":[{"given":"Michael R.","family":"Sargen","sequence":"first","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas P.","family":"Potjer","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary E.","family":"Velthuizen","sequence":"additional","affiliation":[{"name":"Division Laboratories, Pharmacy and Biomedical Genetics, Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arelis E.","family":"Martir-Negron","sequence":"additional","affiliation":[{"name":"Miami Cancer Institute, Baptist Health South Florida, Miami"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazmin","family":"Odia","sequence":"additional","affiliation":[{"name":"Miami Cancer Institute, Baptist Health South Florida, Miami"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hildur","family":"Helgadottir","sequence":"additional","affiliation":[{"name":"Department of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica N.","family":"Hatton","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy S.","family":"Haley","sequence":"additional","affiliation":[{"name":"Department of Genomic Health, Geisinger Clinic, Geisinger Health System, Danville, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gretchen","family":"Thone","sequence":"additional","affiliation":[{"name":"Department of Genomic Health, Geisinger Clinic, Geisinger Health System, Danville, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte C.","family":"Widemann","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea M.","family":"Gross","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marielle E.","family":"Yohe","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland"},{"name":"Laboratory of Cell and Developmental Signaling, Center for Cancer Research, Frederick, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosandra N.","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack F.","family":"Shern","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Taylor","family":"Sundby","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esteban","family":"Astiazaran-Symonds","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Arizona College of Medicine, Tucson"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong R.","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Carey","sequence":"additional","affiliation":[{"name":"Department of Genomic Health, Geisinger Clinic, Geisinger Health System, Danville, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret A.","family":"Tucker","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas R.","family":"Stewart","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisa M.","family":"Goldstein","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"2","key":"dbr230012r1","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1136\/jmg.2006.043802","article-title":"Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents.","volume":"44","author":"Goldstein","year":"2007","journal-title":"J Med Genet"},{"issue":"6","key":"dbr230012r2","doi-asserted-by":"publisher","DOI":"10.1093\/jncics\/pkac074","article-title":"Impact of transcript (p16\/p14ARF) alteration on cancer risk in CDKN2A germline pathogenic variant carriers.","volume":"6","author":"Sargen","year":"2022","journal-title":"J Natl Cancer Inst Cancer Spectr"},{"issue":"20","key":"dbr230012r3","doi-asserted-by":"publisher","first-page":"9818","DOI":"10.1158\/0008-5472.CAN-06-0494","article-title":"High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL.","volume":"66","author":"Goldstein","year":"2006","journal-title":"Cancer Res"},{"issue":"8","key":"dbr230012r4","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1136\/jmedgenet-2014-102320","article-title":"High risk of tobacco-related cancers in CDKN2A mutation-positive melanoma families.","volume":"51","author":"Helgadottir","year":"2014","journal-title":"J Med Genet"},{"issue":"12","key":"dbr230012r5","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1093\/jnci\/92.12.1006","article-title":"Genotype-phenotype relationships in US melanoma-prone families with CDKN2A and CDK4 mutations.","volume":"92","author":"Goldstein","year":"2000","journal-title":"J Natl Cancer Inst"},{"issue":"4","key":"dbr230012r6","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1111\/bjd.2016.175.issue-4","article-title":"CDKN2A mutations with p14 loss predisposing to multiple nerve sheath tumours, melanoma, dysplastic naevi and internal malignancies: a case series and review of the literature.","volume":"175","author":"Sargen","year":"2016","journal-title":"Br J Dermatol"},{"issue":"11","key":"dbr230012r7","first-page":"2298","article-title":"Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors.","volume":"58","author":"Bahuau","year":"1998","journal-title":"Cancer Res"},{"issue":"2","key":"dbr230012r8","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2021.0112","article-title":"A genome-first approach to characterize DICER1 pathogenic variant prevalence, penetrance, and phenotype.","volume":"4","author":"Mirshahi","year":"2021","journal-title":"JAMA Netw Open"},{"issue":"7726","key":"dbr230012r9","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","article-title":"The UK Biobank resource with deep phenotyping and genomic data.","volume":"562","author":"Bycroft","year":"2018","journal-title":"Nature"},{"issue":"8","key":"dbr230012r10","doi-asserted-by":"publisher","first-page":"1506","DOI":"10.1038\/s41436-021-01170-5","article-title":"Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation.","volume":"23","author":"Legius","year":"2021","journal-title":"Genet Med"},{"key":"dbr230012r11","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1016\/j.ebiom.2016.04.005","article-title":"Comprehensive RNA analysis of the NF1 gene in classically affected NF1 affected individuals meeting NIH criteria has high sensitivity and mutation negative testing is reassuring in isolated cases with pigmentary features only.","volume":"7","author":"Evans","year":"2016","journal-title":"EBioMedicine"},{"key":"dbr230012r12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.humpath.2017.05.010","article-title":"Histopathologic evaluation of atypical neurofibromatous tumors and their transformation into malignant peripheral nerve sheath tumor in patients with neurofibromatosis 1\u2014a consensus overview.","volume":"67","author":"Miettinen","year":"2017","journal-title":"Hum Pathol"},{"issue":"21","key":"dbr230012r13","doi-asserted-by":"publisher","first-page":"4720","DOI":"10.1158\/0008-5472.CAN-19-1429","article-title":"Cdkn2a loss in a model of neurofibroma demonstrates stepwise tumor progression to atypical neurofibroma and MPNST.","volume":"80","author":"Chaney","year":"2020","journal-title":"Cancer Res"},{"issue":"7","key":"dbr230012r14","doi-asserted-by":"publisher","first-page":"1820","DOI":"10.1016\/j.ajpath.2015.02.023","article-title":"Molecular and genomic alterations in glioblastoma multiforme.","volume":"185","author":"Crespo","year":"2015","journal-title":"Am J Pathol"},{"issue":"1","key":"dbr230012r15","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1038\/s41392-020-0150-x","article-title":"DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer.","volume":"5","author":"Huang","year":"2020","journal-title":"Signal Transduct Target Ther"}],"container-title":["JAMA Dermatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamadermatology\/articlepdf\/2808644\/jamadermatology_sargen_2023_br_230012_1697555574.19053.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T15:09:12Z","timestamp":1697641752000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamadermatology\/fullarticle\/2808644"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,1]]},"references-count":15,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2023,10,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamadermatol.2023.2621","relation":{},"ISSN":["2168-6068"],"issn-type":[{"value":"2168-6068","type":"print"}],"subject":[],"published":{"date-parts":[[2023,10,1]]}}}