title: Genetic susceptibility to cutaneous melanoma in southern Switzerland: role of CDKN2A, MC1R and MITF.
abstract: BACKGROUND
  Nearly 10% of all cases of cutaneous melanoma (CM) occur in patients with a personal or family history of the disease.
  
  
  OBJECTIVE
  To obtain information about genetic predisposition to CM in Ticino, the southern region of Switzerland, a zone with moderate-to-high CM incidence.
  
  
  METHODS
  We identified germline mutations in highly CM-associated genes (CDKN2A and CDK4) and low/medium-penetrance variants (MC1R and MITF) in patients with multiple primary CMs or individuals with one or more CM and a positive family history for CM or pancreatic cancer among first- or second-degree relatives. Healthy blood donors (n = 146) were included as a control group.
  
  
  RESULTS
  From July 2010 to July 2012, 57 patients (41 pedigrees) were included. Twenty-six were melanoma-prone families (with at least two cases) and 15 had multiple CMs. Pancreatic cancer was found in six families. The CDKN2A mutation p.V126D was identified in seven patients (four families) with a founder effect, whereas CDKN2A A148T was detected in seven cases (five families) and seven healthy donors (odds ratio 2·76, 95% confidence interval 0·83-9·20). At least one MC1R melanoma-associated polymorphism was detected in 32 patients (78%) and 97 healthy donors (66%), with more than one polymorphism in 12 patients (29%) and 25 healthy donors (17%). The MITF variant p.E318K was identified in four patients from three additional pedigrees (7%) and one healthy control (0·7%).
  
  
  CONCLUSIONS
  Inclusion criteria for the Ticino population for genetic assessment should follow the rule of two (two affected individuals in a family or a patient with multiple CMs), as we detected a CDKN2A mutation in almost 10% of our pedigrees (four of 41), MITF p.E318K in 7% (three of 41) and a higher number of MC1R variants than in the control population.
authors.affiliation: Dermatologia Ente Ospedaliero Cantonale (EOC), Ospedale Regionale Bellinzona e Valli, Bellinzona, Switzerland. Cristina.mangas@eoc.ch, cris_mangas@yahoo.es.
authors.forename: C
authors.initials: C
authors.lastname: Mangas
authors.affiliation: Melanoma Unit, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Potrony
authors.affiliation: Dermatologia Ente Ospedaliero Cantonale (EOC), Ospedale Regionale Bellinzona e Valli, Bellinzona, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Mainetti
authors.affiliation: Private Dermatology Practice, Lugano, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Bianchi
authors.affiliation: Private Dermatology Practice, Bellinzona, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Carrozza Merlani
authors.affiliation: Private Dermatology Practice, Chiasso, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Mancarella Eberhardt
authors.affiliation: Private Dermatology Practice, Lugano, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Maspoli-Postizzi
authors.affiliation: Dermatologia Ente Ospedaliero Cantonale (EOC), Ospedale Regionale Bellinzona e Valli, Bellinzona, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Marazza
authors.affiliation: Private Dermatology Practice, Locarno, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Marcollo-Pini
authors.affiliation: Private Dermatology Practice, Lugano, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Pelloni
authors.affiliation: Istituto Oncologico della Svizzera Italiana (IOSI), Ospedale Regionale Bellinzona e Valli, Bellinzona, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Sessa
authors.affiliation: Private Dermatology Practice, Locarno, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Simona
authors.affiliation: Melanoma Unit, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain.|Biochemistry and Molecular Genetics Service, Hospital Clinic of Barcelona, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Puig-Butillé
authors.affiliation: Melanoma Unit, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain.|Biochemistry and Molecular Genetics Service, Hospital Clinic of Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Badenas
authors.affiliation: Melanoma Unit, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Puig
mesh_terms: D000328:Adult; D017668:Age of Onset; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000453:epidemiology / Q000235:genetics*; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics; D012878:Skin Neoplasms / Q000453:epidemiology / Q000235:genetics*; D013557:Switzerland / Q000453:epidemiology
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D009363:Neoplasm Proteins; D044102:Receptor, Melanocortin, Type 1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4