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. 2014 Aug;51(8):545-52.
doi: 10.1136/jmedgenet-2014-102320. Epub 2014 Jun 16.

High risk of tobacco-related cancers in CDKN2A mutation-positive melanoma families

Hildur Helgadottir  1 , Veronica Höiom  1 , Göran Jönsson  2 , Rainer Tuominen  1 , Christian Ingvar  2 , Ake Borg  2 , Håkan Olsson  2 , Johan Hansson  1
Affiliations
Free PMC article

High risk of tobacco-related cancers in CDKN2A mutation-positive melanoma families

Hildur Helgadottir et al. J Med Genet. 2014 Aug.
Free PMC article

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.

Keywords: Cancer: dermatological; Cancer: head and neck; Cancer: lung; Genetic epidemiology; Genetic screening/counselling.

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Figures

Figure 1
Figure 1
Age-specific cumulative incidence of non-melanoma cancers and for cancers in respiratory and upper digestive tissues (including pancreas) among the cohort of CDKN2A p.Arg112dup carriers (n=120).
See this image and copyright information in PMC

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