title: High risk of tobacco-related cancers in CDKN2A mutation-positive melanoma families.
abstract: BACKGROUND
  Germline mutations in the tumour suppressor gene CDKN2A occur in 5-20% of familial melanoma cases. A single founder mutation, p.Arg112dup, accounts for the majority of CDKN2A mutations in Swedish carriers. In a national program, carriers of p.Arg112dup mutation have been identified. The aim of this study was to assess cancer risks in p.Arg112dup carriers and their first degree relatives (FDRs) and second degree relatives (SDRs).
  
  
  METHODS
  In this prospective cohort study, cancer diagnoses in carriers (n=120), non-carriers (n=111), carriers' FDRs (n=275) and SDRs (n=321) and controls (n=3976) were obtained from the Swedish Cancer Registry. Relative risks (RRs) for cancers were calculated (number of cancers/person years). Two-sided 95% CIs were calculated for all RRs.
  
  
  RESULTS
  In carriers prospective RR for non-melanoma cancers was 5.0 (95% CI 3.7 to 7.3), for pancreatic cancer 43.8 (95% CI 13.8 to 139.0), for cancers in upper digestive tissues 17.1 (95% CI 6.3 to 46.5), and in respiratory tissues 15.6 (5.4 to 46.0). In FDRs and SDRs RRs were significantly elevated for cancers in pancreas, respiratory and upper digestive tissues. In ever-smoking carriers compared with never-smoking carriers, the odds ratio (OR) of cancers in pancreas, respiratory or upper digestive tissues was 9.3 (95% CI 1.9 to 44.7).
  
  
  CONCLUSIONS
  CDKN2A p.Arg112dup mutation carriers from melanoma-prone families and their FDRs and SDRs have elevated risk for pancreatic, lung, head and neck and gastro-oesophageal carcinomas. These cancers were mainly seen in ever-smoking carriers. Germline CDKN2A mutations may confer an increased sensitivity to carcinogens in tobacco smoke. CDKN2A mutation carriers should be counselled to abstain from smoking.
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Hildur
authors.initials: H
authors.lastname: Helgadottir
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Veronica
authors.initials: V
authors.lastname: Höiom
authors.affiliation: Department of Oncology, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Jönsson
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Rainer
authors.initials: R
authors.lastname: Tuominen
authors.affiliation: Department of Oncology, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Ingvar
authors.affiliation: Department of Oncology, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Ake
authors.initials: A
authors.lastname: Borg
authors.affiliation: Department of Oncology, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Olsson
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Hansson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D011446:Prospective Studies; D012306:Risk; D012907:Smoking / Q000453:epidemiology*; D055815:Young Adult
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16
keywords: Cancer: dermatological; Cancer: head and neck; Cancer: lung; Genetic epidemiology; Genetic screening/counselling