Prospective risk of cancer and the influence of tobacco use in carriers of the p16-Leiden germline variant

Abstract

The p16-Leiden germline variant in the CDKN2A gene is associated with a high risk of melanoma and pancreatic cancer. The aims of this study were to assess the risk of developing other cancers and to determine whether tobacco use would alter cancer risk in carriers of such a variant. We therefore prospectively evaluated individuals with a p16-Leiden germline variant, participating in a pancreatic surveillance programme, for the occurrence of cancer (n = 150). Tobacco use was assessed at the start of the surveillance programme. We found a significantly increased risk for melanoma (relative risk (RR) 41.3; 95% confidence interval (CI) 22.9-74.6) and pancreatic cancer (RR 80.8;. In addition, increased risks were found for cancers of the lip, mouth and pharynx (RR 18.8;.2) and respiratory tumours (RR 4.56; 95% CI 1.71-12.1). Current smokers developed significantly more cancers of the lip, mouth and pharynx, respiratory system and pancreas compared with former and never-smokers. In conclusion, this study shows that carriers of a p16-Leiden variant have an increased risk of developing various types of cancer, and smoking significantly increases the risk of frequently occurring cancers. Smoking cessation should be an integral part of the management of p16-Leiden variant carriers. European Journal of Human Genetics (2015) 23, 711-714; doi:10.1038/ejhg.2014; published online 17 September 2014 INTRODUCTIONFamilial atypical multiple mole melanoma (FAMMM) syndrome is an autosomal dominant tumour syndrome characterized by the development of melanoma and dysplastic naevi of the skin. Up to 40% of FAMMM families harbour a germline variant in the CDKN2A gene, making it the most frequently involved gene in FAMMM syndrome. 1 More than 65 different variants in the CDKN2A gene have been identified worldwide. 2 In the Netherlands, the p16-Leiden variant, a 19-base-pair deletion (c.225_243del19; RefSeq NM_000077.4), is the most common CDKN2A germline variant. 3 In a previous study, 4 we demonstrated that carriers of such a variant have an increased risk of developing pancreatic cancer (15-20% lifetime risk). Since then a large cohort of patients is under pancreatic surveillance. 5 Several studies reported an increased risk of tumours other than melanoma and pancreatic cancers for various CDKN2A germline variants. [6][7][8][9][10] However, these studies have used a variety of methodological approaches and some have been limited by inclusion of heterogeneous groups or by failure to determine individual mutation status. In addition, the influence of environmental factors (for example, smoking) on the phenotypic variability in FAMMM syndrome is yet to be elucidated.In the present study, we analysed the prospective risk of cancer in a unique cohort of individuals with the same CDKN2A germline variant (p16-Leiden). In addition, we examined the association between a personal history of smoking and the development of cancer. PATIENTS AND METHODS Patient cohortIndividuals were included in this study on the basis of carrier status for the p16-L...

Predictors for oral cancer in Brazil

“…The oral cancers are generally grouped together in epidemiological studies because they share similar risk factors 11,[15][16][17][18][19] .…”

Phenotypic and Histopathological Tumor Characteristics According to CDKN2A Mutation Status among Affected Members of Melanoma Families

“…Pathogenic germline mutations at CDKN2A have been associated with malignancies other than melanoma, including: breast and pancreatic cancers (Borg et al 2000, Goldstein et al 2006, de Snoo et al 2008, Ghiorzo et al 2012, Potrony et al 2014), smoking-related cancers of the head and neck, lung cancer, and gastroesophageal carcinomas (Helgadottir et al 2014, Potjer et al 2015), as well as central nervous system tumors (Petronzelli et al 2001, Pasmant et al 2007). Moreover, there is recent evidence to suggest that familial melanoma cases who are wildtype for CDKN2A are not at increased risk for non-melanoma cancers in contrast to pathogenic mutation carriers (Helgadottir et al 2014).…”

Multigene panel sequencing of established and candidate melanoma susceptibility genes in a large cohort of Dutch non‐CDKN2A/CDK4 melanoma families

“…Carriers of this mutation show not only a markedly increased risk for (multiple) cutaneous melanomas, but also for other cancers, especially pancreatic cancer and cancers of the upper respiratory tract (larynx, pharynx, oral cavity). 7,8 CDKN2A is an unusual gene in that it encodes two distinct proteins, p16INK4a and the alternatively spliced p14ARF, both of which are tumor-suppressors that act in two distinct pathways. The p16-retinoblastoma(Rb)-pathway controls cellcycle G1-phase exit, while the p14ARF-p53 pathway induces cell cycle arrest or apoptosis.…”