{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T01:09:15Z","timestamp":1788570555458,"version":"build-2803163510"},"reference-count":26,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2015,10,3]],"date-time":"2015-10-03T00:00:00Z","timestamp":1443830400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"SingHealth Foundation Research Grant, Singapore","award":["SHF\/FG426S\/2009"],"award-info":[{"award-number":["SHF\/FG426S\/2009"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Neurofibromatosis type 1 (<jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>1) is a genetic disorder characterized by the development of multiple neurofibromas, cafe\u2010au\u2010lait spots, and Lisch nodules. Individuals with <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>1 are at increased risk of developing various tumors, such as malignant peripheral nerve sheath tumor (<jats:styled-content style=\"fixed-case\">MPNST<\/jats:styled-content>), pheochromocytoma, leukemia, glioma, rhabdomyosarcoma, and breast cancer. Here, we describe the exome sequencing of breast cancer, <jats:styled-content style=\"fixed-case\">MPNST<\/jats:styled-content>, and neurofibroma from a patient with <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>1. We identified a germline mutation in the <jats:italic><jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>1<\/jats:italic> gene which resulted in conversion of leucine to proline at amino acid position 847. In addition, we showed independent somatic <jats:italic><jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>1<\/jats:italic> mutations in all the three tumors (frameshift insertion in breast cancer (p.A985fs), missense mutation in <jats:styled-content style=\"fixed-case\">MPNST<\/jats:styled-content> (p.G23R<jats:bold>)<\/jats:bold>, and inframe deletion in dermal neurofibroma (p.L1876del\u2010Inf)), indicating that a second hit in <jats:italic><jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>1<\/jats:italic> resulting in the loss of function could be important for tumor formation. Each tumor had a distinct genomic profile with mutually exclusive mutations in different genes. Copy number analysis revealed multiple copy number alterations in the breast cancer and the <jats:styled-content style=\"fixed-case\">MPNST<\/jats:styled-content>, but not the benign neurofibroma. Germline loss of chromosome 6q22.33, which harbors two potential tumor suppressor genes, <jats:italic><jats:styled-content style=\"fixed-case\">PTPRK<\/jats:styled-content><\/jats:italic> and <jats:italic><jats:styled-content style=\"fixed-case\">LAMA<\/jats:styled-content>2<\/jats:italic>, was also identified; this may increase tumor predisposition further. In the background of <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>1 syndrome, although second\u2010hit <jats:italic><jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>1<\/jats:italic> mutation is critical in tumorigenesis, different additional mutations are required to drive the formation of different tumors.<\/jats:p>","DOI":"10.1002\/cam4.551","type":"journal-article","created":{"date-parts":[[2015,10,3]],"date-time":"2015-10-03T10:02:52Z","timestamp":1443866572000},"page":"1871-1878","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Whole\u2010exome sequencing of breast cancer, malignant peripheral nerve sheath tumor and neurofibroma from a patient with neurofibromatosis type 1"],"prefix":"10.1002","volume":"4","author":[{"given":"John Richard","family":"McPherson","sequence":"first","affiliation":[{"name":"Division of Neuroscience and Behavioral Disorders Duke\u2010National University of Singapore Graduate Medical School  Singapore 169857 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Choon\u2010Kiat","family":"Ong","sequence":"additional","affiliation":[{"name":"Lymphoma Genomic Translational Research Laboratory Division of Medical Oncology National Cancer Centre Singapore 11 Hospital Drive Singapore 169610 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cedric Chuan\u2010Young","family":"Ng","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Epigenome Division of Medical Sciences National Cancer Centre Singapore 11 Hospital Drive Singapore 169610 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikneswari","family":"Rajasegaran","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Epigenome Division of Medical Sciences National Cancer Centre Singapore 11 Hospital Drive Singapore 169610 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong\u2010Lee","family":"Heng","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Epigenome Division of Medical Sciences National Cancer Centre Singapore 11 Hospital Drive Singapore 169610 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willie Shun\u2010Shing","family":"Yu","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Epigenome Division of Medical Sciences National Cancer Centre Singapore 11 Hospital Drive Singapore 169610 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benita Kiat\u2010Tee","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of General Surgery Singapore General Hospital Outram Road Singapore 169608 Singapore"},{"name":"Division of Surgical Oncology National Cancer Centre Singapore 11 Hospital Drive Singapore 169610 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preetha","family":"Madhukumar","sequence":"additional","affiliation":[{"name":"Department of General Surgery Singapore General Hospital Outram Road Singapore 169608 Singapore"},{"name":"Division of Surgical Oncology National Cancer Centre Singapore 11 Hospital Drive Singapore 169610 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa Ching\u2010Ching","family":"Teo","sequence":"additional","affiliation":[{"name":"Division of Surgical Oncology National Cancer Centre Singapore 11 Hospital Drive Singapore 169610 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Ngeow","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology National Cancer Centre Singapore 11 Hospital Drive Singapore 169610 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aye\u2010Aye","family":"Thike","sequence":"additional","affiliation":[{"name":"Department of Pathology Singapore General Hospital 20 College Road Academia, Level 7, Diagnostics Tower Singapore 169856 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven George","family":"Rozen","sequence":"additional","affiliation":[{"name":"Division of Neuroscience and Behavioral Disorders Duke\u2010National University of Singapore Graduate Medical School  Singapore 169857 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puay\u2010Hoon","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Pathology Singapore General Hospital 20 College Road Academia, Level 7, Diagnostics Tower Singapore 169856 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann\u00a0Siew\u2010Gek","family":"Lee","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology Division of Medical Sciences National Cancer Centre Singapore Singapore Singapore"},{"name":"Office of Clinical &amp; Academic Faculty Affairs Duke\u2010National University of Singapore Graduate Medical School Singapore Singapore"},{"name":"Department of Physiology Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin\u2010Tean","family":"Teh","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Epigenome Division of Medical Sciences National Cancer Centre Singapore 11 Hospital Drive Singapore 169610 Singapore"},{"name":"Laboratory of Cancer Therapeutics Division of Cancer and Stem Cell Biology Duke\u2010National University of Singapore Graduate Medical School 8 College Road Singapore 169857 Singapore"},{"name":"Laboratory of Chromatin Regulation Cancer Science Institute of Singapore 14 Medical Drive Singapore 117599 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoon\u2010Sim","family":"Yap","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology National Cancer Centre Singapore 11 Hospital Drive Singapore 169610 Singapore"},{"name":"Faculty of Health Sciences School of Medicine University of Adelaide Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,10,3]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a010118"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90253-B"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90024-9"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(09)70033-6"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2007.049346"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.35560"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9776(97)90558-0"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.2194"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)65507-1"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.2870030111"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.2870100405"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3095"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3116"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13561"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.2004.019026"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0503224102"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10689-007-9149-5"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2014.141"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0062852"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-013-1421-5"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-11-059881"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2007.12.024"},{"key":"e_1_2_7_25_1","first-page":"436","article-title":"Diverse modes of genomic alterations in hepatocellular carcinoma","volume":"15","author":"Jhunjhunwala S.","year":"2014","journal-title":"Genome Biol."},{"key":"e_1_2_7_26_1","first-page":"889","article-title":"Identification of GABRA1 and LAMA2 as new DNA methylation markers in colorectal cancer","volume":"40","author":"Lee S.","year":"2012","journal-title":"Int. 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