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

Background and Aims: Pancreatic cancer risk is increased in Lynch syndrome (LS) patients with mismatch repair genedefects predisposing to colonic and extracolonic cancers with microsatellite instability (MSI). However, the frequency of MSIpancreatic cancers has never been ascertained in consecutive, unselected clinical series, and their contribution to thesporadic and inherited burden of pancreatic cancer remains to be established. Aims of the study were to determine theprevalence of MSI in surgically resected pancreatic cancers in a multicentric, retrospective study, and to assess theoccurrence of pancreatic cancer in LS.Methods: MS-status was screened by a panel of 5 mononucleotide repeats (Bat26, Bat25, NR-21, NR-24 and NR-27) in 338consecutive pancreatic ductal adenocarcinoma (PDAC), resected at two Italian and one German referral centres. Thepersonal history of pancreatic cancer was assessed in an independent set of 58 probands with LS and in 138 first degreerelatives who had cancers.Results: Only one PDAC (0.3%) showed MSI. This was a medullary type cancer, with hMLH1-deficiency, and no identifiedgerm-line mutation but methylation of hMLH1. Pancreatic cancer occurred in 5 (2.5%) LS patients. Histological sampling wasavailable for 2 cases, revealing PDAC in one case and an ampullary cancer in the other one.Conclusions: MSI prevalence is negligible in sporadic, resected PDAC. Differently, the prevalence of pancreatic cancer is2.5% in LS patients, and cancers other than PDAC may be encountered in this setting. Surveillance for pancreatic cancershould be advised in LS mutation carriers at referral centers.