Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling

Abstract

Germline mutations in CDKN2A have been reported in pancreatic cancer families, but genetic counseling for pancreatic cancer risk has been limited by lack of information on CDKN2A mutation carriers outside of selected pancreatic or melanoma kindreds. Lymphocyte DNA from consecutive, unselected white non-Hispanic patients with pancreatic adenocarcinoma was used to sequence CDKN2A. Frequencies of mutations that alter the coding of p16INK4 or p14ARF were quantified overall and in subgroups. Penetrance and likelihood of carrying mutations by family history were estimated. Among 1537 cases, 9 (0.6%) carried germline mutations in CDKN2A, including three previously unreported mutations. CDKN2A mutation carriers were more likely to have a family history of pancreatic cancer (P¼0.003) or melanoma (P¼0.03), and a personal history of melanoma (P¼0.01). Among cases who reported having a first-degree relative with pancreatic cancer or melanoma, the carrier proportions were 3.3 and 5.3%, respectively. Penetrance for mutation carriers by age 80 was calculated to be 58% for pancreatic cancer (95% confidence interval (CI) 8-86%), and 39% for melanoma (95% CI 0-80). Among cases who ever smoked cigarettes, the risk for pancreatic cancer was higher for carriers compared with non-carriers (HR 25.8, P¼2.1Â10 À13 ), but among nonsmokers, this comparison did not reach statistical significance. Germline mutations in CDKN2A among unselected pancreatic cancer patients are uncommon, although notably penetrant, especially among smokers. Carriers of germline mutations of CDKN2A should be counseled to avoid tobacco use to decrease risk of pancreatic cancer in addition to taking measures to decrease melanoma risk. Keywords: cyclin-dependent kinase inhibitor p16; genes; p16; pancreatic neoplasms INTRODUCTION Pancreatic cancer is associated with very poor survival rates, with long-term survivors limited to those with resected early stage tumors. However, detection of pancreatic cancer at an early stage is challenging, and this mandates identification of high-risk groups to be targeted for prevention and screening intervention.Since first observed by Lynch and Krush in 1968, 1 the incidence of pancreatic cancer has been noted to be increased in many families affected by inherited melanoma syndromes. In genetic analyses of these families, 20-40% of inherited increased melanoma susceptibility can be linked to mutations of the CDKN2A gene (p16/Ink4) located on chromosome 9p21. [2][3][4][5] As a result of the increased incidence of pancreatic cancer in melanoma families with CDKN2A mutations, it was hypothesized that mutations likely also predispose to pancreatic cancer development. 2 Mutations in CDKN2A have subsequently been described in familial pancreatic cancer kindreds, some without melanoma. 3,4 Somatic mutations of CDKN2A are present in up to 95% of pancreatic tumors. 5 These findings provide further support for the premise that CDKN2A mutations have an important role in the development of pancreatic cancer. Clinical findings in mutation carri...

Incidence and Trends of Malignant and Benign Pancreatic Lesions in Yazd, Iran between 2001 and 2011

“…Another contributing factor, cigarette smoking has proven epidemiological correlation with development of pancreatic cancer (Momi (Schenk et al, 2001), type 2 diabetes mellitus, (Huxley et al, 2005) and an abundance of single genetic mutations, genetic loci, and hereditary syndromes (Iacobuzio-Donahue, 2012;Klein, 2012;McWilliams et al, 2011). Hereditary conditions including among others familial breast cancer with BRCA2 mutation (Lucas et al, 2013), Peutz-Jeghers syndrome (van Lier et al, 2010), and Hereditary Nonpolyposis Colorectal Cancer (HNCC) (Holmes and Bordeianou, 2011) have been causally implicated in malignant tumors of the pancreas.…”

Indication for CDKN2A Mutation Analysis in Familial Pancreatic Cancer-Families Without Melanomas

“…Recently, the prevalence of CDKN2A-mutations in a large series of unselected PC cases was studied and this turned out to be low (0.6%). 16 A subanalysis of this series in which only FPC cases were included showed CDKN2A-mutations in 3.3% of cases. The discrepancy between these and our series is not readily explained, although the method of patient selection between our series (gathered from PC family registries) and the latter large series (unselected PC cases) may account for part of the discrepancy.…”

Risk Factors in Pancreatic Cancer

“…Among cases who reported having a first-degree relative with pancreatic cancer or melanoma, the carrier proportions were 3.3 and 5.3%, respectively. Penetrance for mutation carriers by age 80 was calculated to be 58% for pancreatic cancer and the risk of pancreatic cancer in smokers was 25 compared to non-carriers (McWilliams et al, 2011). The onset of pancreatis cancer in a historical cohort of 36 patients from 26 families with FAMM was 65 years old.…”