PMID- 24935963 OWN - NLM STAT- MEDLINE DCOM- 20150330 LR - 20220129 IS - 1468-6244 (Electronic) IS - 0022-2593 (Print) IS - 0022-2593 (Linking) VI - 51 IP - 8 DP - 2014 Aug TI - High risk of tobacco-related cancers in CDKN2A mutation-positive melanoma families. PG - 545-52 LID - 10.1136/jmedgenet-2014-102320 [doi] AB - 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. CI - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions. FAU - Helgadottir, Hildur AU - Helgadottir H AD - Department of Oncology and Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. FAU - Hoiom, Veronica AU - Hoiom V AD - Department of Oncology and Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. FAU - Jonsson, Goran AU - Jonsson G AD - Department of Oncology, Lund University and Skane University Hospital, Lund, Sweden. FAU - Tuominen, Rainer AU - Tuominen R AD - Department of Oncology and Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. FAU - Ingvar, Christian AU - Ingvar C AD - Department of Oncology, Lund University and Skane University Hospital, Lund, Sweden. FAU - Borg, Ake AU - Borg A AD - Department of Oncology, Lund University and Skane University Hospital, Lund, Sweden. FAU - Olsson, Hakan AU - Olsson H AD - Department of Oncology, Lund University and Skane University Hospital, Lund, Sweden. FAU - Hansson, Johan AU - Hansson J AD - Department of Oncology and Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. LA - eng GR - 294576/ERC_/European Research Council/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140616 PL - England TA - J Med Genet JT - Journal of medical genetics JID - 2985087R RN - 0 (Cyclin-Dependent Kinase Inhibitor p16) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Aged, 80 and over MH - Child MH - Child, Preschool MH - Cyclin-Dependent Kinase Inhibitor p16/*genetics MH - Female MH - Genetic Predisposition to Disease/genetics MH - Humans MH - Male MH - Middle Aged MH - Mutation/genetics MH - Neoplasms/*epidemiology/*genetics MH - Prospective Studies MH - Risk MH - Smoking/*epidemiology MH - Young Adult PMC - PMC4112445 OTO - NOTNLM OT - Cancer: dermatological OT - Cancer: head and neck OT - Cancer: lung OT - Genetic epidemiology OT - Genetic screening/counselling EDAT- 2014/06/18 06:00 MHDA- 2015/03/31 06:00 CRDT- 2014/06/18 06:00 PHST- 2014/06/18 06:00 [entrez] PHST- 2014/06/18 06:00 [pubmed] PHST- 2015/03/31 06:00 [medline] AID - jmedgenet-2014-102320 [pii] AID - 10.1136/jmedgenet-2014-102320 [doi] PST - ppublish SO - J Med Genet. 2014 Aug;51(8):545-52. doi: 10.1136/jmedgenet-2014-102320. Epub 2014 Jun 16.