title: Characterization of patients at high risk of melanoma in Austria.
abstract: BACKGROUND
  Risk of melanoma is determined by genetic and exogenous factors. Only a few studies have included both characteristics in a comprehensive multivariable analysis.
  
  
  OBJECTIVE
  To find determinants of patients at high risk of melanoma in Austria, including phenotype, genotype and lifestyle characteristics in comprehensive analyses.
  
  
  METHODS
  In total, 1668 patients with melanoma from the M3 case-control study were studied. Overall, 567 participants were sequenced for CDKN2A, 232 for CDK4, 123 for MITF encoding the variant E318K and 964 for MC1R.
  
  
  RESULTS
  Patients with melanoma with a positive family history (n = 190, 11·6%), multiple primary melanomas (n = 261, 15·7%) and younger age (< 50 years, n = 675, 40·5%) were defined as being at high risk. All other patients with melanoma were defined as the reference group. We found significant differences between those two groups and between the high-risk subgroups (positive family history, multiple primary melanomas and younger age). Pigmentation phenotype was associated with the high-risk group in general (childhood freckling, odds ratio 1·46, P = 0·007; blond/reddish hair colour, odds ratio 1·43, P = 0·011). Patients with a positive family history and patients with early-onset disease were similar regarding both their phenotypic characteristics and external factors. Established high-risk mutations in CDKN2A were found in cases with a positive family history (n = 12) or multiple melanomas (n = 2). Moreover, we found three patients carrying the MITF p.E318K variant, two with a CDK4 variant and seven with nonsynonymous MC1R variants with undescribed biological significance, of which four were predicted as damaging.
  
  
  CONCLUSIONS
  Austrian patients could represent a reservoir for novel genetic variants. Further investigation of populations in Central and Eastern Europe might reveal more novel and disease-relevant variants.
authors.affiliation: Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: C
authors.identifier: http://orcid.org/0000-0002-5031-7255
authors.initials: C
authors.lastname: Müller
authors.affiliation: Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Wendt
authors.affiliation: Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Rauscher
authors.affiliation: The Scripps Research Institute, La Jolla, CA, U.S.A.
authors.forename: S
authors.initials: S
authors.lastname: Burgstaller-Muehlbacher
authors.affiliation: Clinical Institute for Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Sunder-Plassmann
authors.affiliation: Department of Dermatology and Venereology, General Hospital Linz, Linz, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Scheurecker
authors.affiliation: Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Richtig
authors.affiliation: Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: I
authors.initials: I
authors.lastname: Fae
authors.affiliation: Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Fischer
authors.affiliation: Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Pehamberger
authors.affiliation: Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: I
authors.initials: I
authors.lastname: Okamoto
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D001317:Austria / Q000453:epidemiology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008545:Melanoma / Q000453:epidemiology* / Q000235:genetics; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D010375:Pedigree; D012307:Risk Factors; D012878:Skin Neoplasms / Q000453:epidemiology* / Q000235:genetics; D012880:Skin Pigmentation; D013472:Sunlight / Q000009:adverse effects; D055815:Young Adult
chemical_list: D009363:Neoplasm Proteins