Examination of intraductal papillary mucinous neoplasms of pancreas and their association with extrapancreatic malignancies

Abstract

The primary objective of the thesis is to assess the prevalence and the incidence of extrapancreatic malignancies (EPMs) in a cohort of Italian patients diagnosed with intraductal papillary mucinous neoplasms (IMPNs) of pancreas, and to identify the risk factors for their occurrence. The secondary objective is to assess an association between pancreatic IPMN and selected single nucleotide polymorphisms (SNPs) within 8q24 region of human genome. The tertiary objective of the thesis is to assess whether patients with pancreatic IPMNs have an increased propensity to develop colorectal adenomas. Methods: In order to meet the objectives three separate studies were conducted: the hospital-based multicentric study, the genetic association study and the colonoscopic case-control study. The hospital-based multicentric study was conducted in Italy from January 2010 to January 2011 in eight participating centers. Three hundred ninety IPMN cases were included in the study and screened for EPMs. EPMs were grouped according to time of their diagnosis as previous, synchronous (both prevalent) and metachronous (incident). The distribution of demographics, medical history and lifestyle habits was assessed among cases. The observed/expected (O/E) ratio of prevalent EPMs was calculated. The genetic association study was performed on 117 IPMN cases and 231 age and gender matched controls. Cases were enrolled at the Digestive Endoscopy Unit, Policlinico Agostino Gemelli, Rome, Italy with either a prevalent or incident IPMN diagnosis, diagnosed from January 2010 to June 2011. Status of selected SNPs (rs6983267, rs6993464, rs7014346, rs10505477) was determined using a StepOne Realtime PCR system (Applied Biosystems) and TaqMan SNP Genotyping Assay ™ 40X. Unconditional multiple logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of selected SNPs and IPMNs... Primarni cilj doktorske disertacije je utvrditi prevalenciju i incidenciju ekstrapankreasnih maligniteta (EPM) u kohorti italijanskih pacijenata sa intraduktalnim papilarnim mucinoznim neoplazmama (IPMN) pankreasa i identifikovati faktore rizika za njihov nastanak. Sekundarni cilj doktroske disertacije je utvrditi da li je prisustvo IPMN udruženo sa prisustvom odabranih genetskih “single-nucleotide” polimorfizama (SNP) u 8q24 regionu humanog genoma. Tercijarni cilj doktorske disertacije je utvrditi da li pacijenti sa IPMN imaju značajno više kolorektalih adenoma u odnosu na opštu populaciju. Metode: Kako bi se ispunili navedeni ciljevi doktorske disertacije sprovedene su tri odvojene studije: multicentrična bolnička studija, studija genetske asocijacije i kolonoskopska studija slučajeva i kontrola. Multicentrična bolnička studija sprovedena je u osam bolničkih centara u Italiji u period od janura 2010 do januara 2011. Tri stotine devedeset pacijenata sa IPMN uključeni su u studiju i ispitani na prisustvo EPM. EPM su u odnosu na vreme otkrivanja grupisani na prethodne i sinhrone (koji zajedno čine prevalentne) i metahrone. Dobijeni podatci iskorišćeni su kako bi se izračunao odnos otkrivenih i očekivanih EPM (O/E odnos). Pacijenti sa i bez EPM su upoređeni u odnosu na demografske karakteristike, životne navike i prethodnu istoriju bolesti. Studija genetske asocijacije sprovedena je na 177 IPMN slučajeva i 231 kontrola uparenih po polu i starosti. Novotkriveni slučajevi IPMN, kao i oni koji su imali zakazane kontrolne preglede u Službi za digestivnu endoskopiju Poliklinike Agostino Gemelli, Rim, Italija u period od januara 2010 do juna 2011 uključeni su u studiju. Status odabranih SNP (rs6983267, rs6993464, rs7014346, rs10505477) određivan je uz pomoć “StepOne Real-time PCR” (Applied Biosystems) i “TaqMan SNP Genotyping Assay ™ 40X” sistema. Bezuslovni multivarijantni logisticki regresioni model je korisćen za procenu odnosa šansi (OR) i 95%-og intervala poverenja (95% CI) asocijacije odabranih SNP sa IPMN.