Irrelevance of microsatellite instability in the epidemiology of sporadic pancreatic ductal adenocarcinoma.

Luigi Laghi,Alberto Malesci,Paolo Bianchi,Samantha Bersani,Ilona Gräntzdörffer,Massimo Roncalli,Giona Turri,Anna Brecht,Aldo Scarpa,Marco Montorsi,Gianluca Basso,Christoph Röcken,Claudio Bassi,Guido Schumacher,Alessandro Zerbi,Stefania Beghelli,Antonino Spinelli,Giuseppe Celesti,Giuseppe Di ,P Neuhaus

doi:10.1371/journal.pone.0046002

Abstract

Background and AimsPancreatic cancer risk is increased in Lynch syndrome (LS) patients with mismatch repair gene defects predisposing to colonic and extracolonic cancers with microsatellite instability (MSI). However, the frequency of MSI pancreatic cancers has never been ascertained in consecutive, unselected clinical series, and their contribution to the sporadic and inherited burden of pancreatic cancer remains to be established. Aims of the study were to determine the prevalence of MSI in surgically resected pancreatic cancers in a multicentric, retrospective study, and to assess the occurrence of pancreatic cancer in LS.MethodsMS-status was screened by a panel of 5 mononucleotide repeats (Bat26, Bat25, NR-21, NR-24 and NR-27) in 338 consecutive pancreatic ductal adenocarcinoma (PDAC), resected at two Italian and one German referral centres. The personal history of pancreatic cancer was assessed in an independent set of 58 probands with LS and in 138 first degree relatives who had cancers.ResultsOnly one PDAC (0.3%) showed MSI. This was a medullary type cancer, with hMLH1-deficiency, and no identified germ-line mutation but methylation of hMLH1. Pancreatic cancer occurred in 5 (2.5%) LS patients. Histological sampling was available for 2 cases, revealing PDAC in one case and an ampullary cancer in the other one.ConclusionsMSI prevalence is negligible in sporadic, resected PDAC. Differently, the prevalence of pancreatic cancer is 2.5% in LS patients, and cancers other than PDAC may be encountered in this setting. Surveillance for pancreatic cancer should be advised in LS mutation carriers at referral centers.

Highlights

Despite ranking fourth for incidence, pancreatic ductal adenocarcinoma (PDAC) has the first mortality rate among gastrointestinal cancers [1]
The risk of developing PDAC increases in inherited predispositions to colorectal cancer, namely the PeutzJegers and the Lynch syndrome (LS, or Hereditary Non-Polyposis Hereditary Colorectal Cancer) [2,3]
LS is caused by germ-line mutations in one of the mismatch repair (MMR) genes hMLH1, hMSH2, and, less frequently, hMSH6 or PMS2

Summary

Introduction

Despite ranking fourth for incidence, pancreatic ductal adenocarcinoma (PDAC) has the first mortality rate among gastrointestinal cancers [1]. The risk of developing PDAC increases in inherited predispositions to colorectal cancer, namely the PeutzJegers and the Lynch syndrome (LS, or Hereditary Non-Polyposis Hereditary Colorectal Cancer) [2,3]. Cancers with MMR defects, whether arising in LS patients or sporadically, due to somatic hMLH1 hypermethylation, typically show the molecular phenotype of microsatellite instability (MSI) [4]. MSI prevalence approaches 10% in colorectal cancer, LS accounting for one third of the cases and hMLH1 hypermethylation for the remaining part [4,5]. Pancreatic cancer risk is increased in Lynch syndrome (LS) patients with mismatch repair gene defects predisposing to colonic and extracolonic cancers with microsatellite instability (MSI). Aims of the study were to determine the prevalence of MSI in surgically resected pancreatic cancers in a multicentric, retrospective study, and to assess the occurrence of pancreatic cancer in LS

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Results

Conclusion