{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,4]],"date-time":"2025-05-04T00:37:49Z","timestamp":1746319069253,"version":"3.37.3"},"reference-count":39,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2020,7,23]],"date-time":"2020-07-23T00:00:00Z","timestamp":1595462400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["PP00P3_157448"],"award-info":[{"award-number":["PP00P3_157448"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008017","name":"Institut Gustave-Roussy","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008017","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acad Dermatol Venereol"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant genetic disorder. It is commonly caused by mutations in <jats:italic>PTCH1<\/jats:italic> and chiefly characterized by multiple basal cell carcinomas (BCCs) developing prior to the age of 30\u00a0years. In rare cases, NBCCS presents with a late onset of BCC development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To investigate BCC tumorigenesis in two brothers, who showed characteristic features of NBCCS but developed their first BCCs only after the age of 40\u00a0years. Two other siblings did not show signs of NBCCS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We obtained blood samples from four siblings and nine BCCs from the two brothers with NBCCS. Whole exome sequencing and RNA sequencing revealed loss of heterozygosity (LOH) of <jats:italic>PTCH1<\/jats:italic> in eight out of nine tumours that consistently involved the same haplotype on chromosome 9. This haplotype contained a germinal splice site mutation in <jats:italic>PTCH1<\/jats:italic> (NM_001083605:exon9:c.763\u20106C&gt;A). Analysis of germline DNA confirmed segregation of this mutation with the disease. All BCCs harboured additional somatic loss\u2010of\u2010function (LoF) mutations in the remaining <jats:italic>PTCH1<\/jats:italic> allele which are not typically seen in other cases of NBCCS. This suggests a hypomorphic nature of the germinal <jats:italic>PTCH1<\/jats:italic> mutation in this family. Furthermore, all BCCs had a similar tumour mutational burden compared to BCCs of unrelated NBCCS patients while harbouring a higher number of damaging <jats:italic>PTCH1<\/jats:italic> mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our data suggest that a sequence of three genetic hits leads to the late development of BCCs in two brothers with NBCCS: a hypomorphic germline mutation, followed by somatic LOH and additional mutations that complete <jats:italic>PTCH1<\/jats:italic> inactivation. These genetic events are in line with the late occurrence of the first BCC and with the higher number of damaging <jats:italic>PTCH1<\/jats:italic> mutations compared to usual cases of NBCCS.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jdv.16767","type":"journal-article","created":{"date-parts":[[2020,6,21]],"date-time":"2020-06-21T18:49:55Z","timestamp":1592765395000},"page":"396-402","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Genomic profiling of late\u2010onset basal cell carcinomas from two brothers with nevoid basal cell carcinoma syndrome"],"prefix":"10.1111","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5185-7520","authenticated-orcid":false,"given":"O.","family":"Hasan Ali","sequence":"first","affiliation":[{"name":"Department of Dermatology University Hospital Zurich Zurich Switzerland"},{"name":"Institute of Immunobiology Kantonsspital St. Gallen St. Gallen 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