Novel CDKN2A mutations in Austrian melanoma patients. Issue 5 (October 2015)

• Record Type: Journal Article
• Authors: Burgstaller-Muehlbacher, Sebastian; Marko, Martha; Müller, Christoph; Wendt, Judith; Pehamberger, Hubert; Okamoto, Ichiro
• Is Part Of: Melanoma research. Volume 25:Issue 5(2015)
• Publication Date: 2015-10
• Subjects: Melanoma -- Periodicals; Melanoma -- Periodicals; Melanomen; 616.99477
• DOI: 10.1097/CMR.0000000000000179
• Languages: English
• ISSNs: 0960-8931

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <p> <italic>CDKN2A</italic> is the most prominent familial melanoma gene, with mutations occurring in up to 40% of the families. Numerous mutations in the gene are known, several of them representing regional founder mutations. We sought to determine, for the first time, germline mutations in <italic>CDKN2A</italic> in Austria to identify novel mutations. In total, 700 individuals (136 patients with a positive family history and 164 with at least two primary melanomas as the high-risk groups; 200 with single primary melanomas; and 200 healthy individuals as the control groups) were Sanger sequenced for <italic>CDKN2A</italic> exon 1α, 1β, and 2. The 136 patients with affected relatives were also sequenced for <italic>CDK4</italic> exon 2. We found the disease-associated mutations p.R24P (8×), p.N71T (1×), p.G101W (1×), and p.V126D (1×) in the group with affected relatives and p.R24P (2×) in the group with several primary melanomas. Furthermore, we discovered four mutations of unknown significance, two of which were novel: p.A34V and c.151−4 G>C, respectively. Computational effect prediction suggested p.A34V as conferring a high risk for melanoma, whereas c.151−4 G>C, although being predicted as a splice site mutation by MutationTaster, could not functionally be confirmed to alter splicing. Moreover, computational effect prediction confirmed accumulation of high-penetrance mutations in high-risk groups, whereas mutations of unknown significance were distributed across all groups. p.R24P is the most common high-risk mutation in Austria. In addition, we discovered two new mutations in Austrian melanoma patients, p.A34V and c.151−4 G>C, respectively.</p> </sec> </abstract>