Pancreatic cancer-associated gene polymorphisms in a nation-wide cohort of p16-Leiden germline mutation carriers; a case–control study

Potjer et al. BMC Res Notes (2015) 8:264 DOI 10.1186/s13104-015-1235-4 RESEARCH ARTICLE Open Access Pancreatic cancer‑associated gene polymorphisms in a nation‑wide cohort of p16‑Leiden germline mutation carriers; a case–control study Thomas P Potjer1*, Nienke van der Stoep1, Jeanine J Houwing‑Duistermaat2, Ingrid C A W Konings3, Cora M Aalfs4, Peter C van den Akker5, Margreet G Ausems6, Charlotte J Dommering7, Lizet E van der Kolk8, Merel C Maiburg9, Liesbeth Spruijt10, Anja Wagner11, Hans F A Vasen12 and Frederik J Hes1 Abstract Background: The p16-Leiden founder mutation in the CDKN2A gene is the most common cause of Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome in the Netherlands. Individuals with this mutation are at increased risk for developing melanoma of the skin, as well as pancreatic cancer. However, there is a notable interfamilial variabil‑ ity in the occurrence of pancreatic cancer among p16-Leiden families. We aimed to test whether previously identi‑ fied genetic risk factors for pancreatic cancer modify the risk for pancreatic cancer in p16-Leiden germline mutation carriers. Methods: Seven pancreatic cancer-associated SNPs were selected from the literature and were genotyped in a cohort of 185 p16-Leiden germline mutation carriers from 88 families, including 50 cases (median age 55 years) with pancreatic cancer and 135 controls (median age 64 years) without pancreatic cancer. Allelic odds ratios per SNP were calculated. Results: No significant association with pancreatic cancer was found for any of the seven SNPs. Conclusions: Since genetic modifiers for developing melanoma have already been identified in CDKN2A mutation carriers, this study does not exclude that genetic modifiers do not play a role in the individual pancreatic cancer risk in this cohort of p16-Leiden germline mutation carriers. The search for these modifiers should therefore continue, because they can potentially facilitate more targeted pancreatic surveillance programs. Keywords: CDKN2A, p16-Leiden, Germline mutation, FAMMM syndrome, Pancreatic cancer, Modifiers, Single nucleotide polymorphisms Background The melanoma gene CDKN2A produces two important proteins: p16INK4a, which is a cyclin-dependent kinase inhibitor, and p14ARF, which binds the p53-stabilizing protein MDM2 [1]. In the Netherlands, a founder mutation in the CDKN2A gene, a 19-base pair deletion called *Correspondence: 1 Department of Clinical Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands Full list of author information is available at the end of the article p16-Leiden (c.225_243del19; RefSeq NM_000077.4), is the most common cause of Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome [2]. In addition to a marked increased risk of developing melanoma of the skin (70% lifetime risk), these mutation carriers also have a 15–20% lifetime risk of developing pancreatic cancer with a mean age of 58 years at diagnosis [3]. Interestingly, there is a notable interfamilial variability in the occurrence of pancreatic cancer among p16-Leiden families [3]. Therefore, the p16-Leiden mutation might not be the only genetic risk factor in these individuals causing © 2015 Potjer et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Potjer et al. BMC Res Notes (2015) 8:264 an increased susceptibility for pancreatic cancer. Since pancreatic cancer has a very poor prognosis due to late occurrence of symptoms and therefore late detection, surveillance for pancreatic cancer is currently offered to p16-Leiden germline mutation carriers in a research setting to investigate whether pancreatic cancer, or, even more preferable, high-grade precursor lesions can be detected earlier in a potentially still curable stage [4]. By identifying additional genetic risk factors (genetic modifiers) in these individuals, surveillance could possibly be more individualized. In recent years, genome-wide association studies (GWAS) have identified several common risk variants associated with pancreatic cancer [5–7]. In this study, we genotyped a selected number of these variants (SNPs) in a unique cohort of p16-Leiden mutation carriers with and without pancreatic cancer. We hypothesized that these SNPs might modify the risk of pancreatic cancer in these p16-Leiden mutation carriers. Methods Study population and DNA sample collection For this case–control study, only proven carriers of the p16-Leiden germline mutation were included. From all Dutch p16-Leiden mutation carriers, DNA is stored in the Laboratory for Diagnostic Genome Analysis (LDGA) of the Leiden University Medical Center. All p16-Leiden germline mutation carriers diagnosed at the LDGA between the initiation of CDKN2A gene diagnostics at the LDGA in 1998 and January 1st 2014 were eligible for inclusion. Cases were defined as having been diagnosed with exocrine pancreatic cancer at the time of data collection; controls were at least 55 years old on January 1st 2014 or died beyond that age, and were not diagnosed with pancreatic cancer. Individuals who were younger than 55 years or died before this age were excluded from the control group. Medical records were obtained for each individual from the electronic hospital information system of the medical center where this individual initially received genetic counselling by a clinical geneticist for CDKN2A gene diagnostics. Access to these medical records was granted for the (co)authors since they are clinical geneticists working in these medical centers. Additional follow up data was acquired from two ongoing pancreatic surveillance studies (a singlecenter study at Leiden University Medical Center and a multi-center study at Erasmus MC University Medical Center Rotterdam) and from the Netherlands Foundation for the Detection of Hereditary Tumours, a central registration institute for hereditary tumours (FAMMM, amongst others) in the Netherlands. This study was approved by the Ethics Committee of the Leiden University Medical Center, by issuing a declaration of no Page 2 of 5 objection (#P14.148). This is an assessment of the study protocol on due diligence, that is, if it serves the codes of good practice and good conduct. It is not a formal ethical assessment, because the study does not fall within the scope of the Dutch law for medical research on human subjects; the medical records and the DNA were already available and the involved human subjects were not spec (...truncated)