Molecular, morphological and survival analysis of 177 resected pancreatic ductal adenocarcinomas (PDACs): Identification of prognostic subtypes

Anna Melissa Schlitter,Volker Endris,Katja Steiger,Bo Kong,Jörg Kleeff,Günter Klöppel,Ivonne Regel,Christoph W Michalski,Nicole Pfarr,Angela Segler,Irene Esposito,Markus Bettstetter,Carsten Jäger,Björn Konukiewitz

doi:10.1038/srep41064

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has generally a poor prognosis, but recent data suggest that there are molecular subtypes differing in clinical outcome. This study examines the association between histopathologic heterogeneity, genetic profile, and survival. Tumor histology from 177 resected PDAC patients with follow-up data was subclassified according to predominant growth pattern, and four key genes were analyzed. PDACs were classified as conventional (51%), combined with a predominant component (41%), variants and special carcinomas (8%). Patients with combined PDACs and a dominant cribriform component survived longer than patients with conventional or other combined PDACs. Genetic alterations in at least two out of four genes were found in 95% of the patients (KRAS 93%, TP53 79%, CDKN2A/p16 75%, SMAD4 37%). Patients with less than four mutations survived significantly longer (p = 0.04) than those with alterations in all four genes. Patients with either wildtype KRAS or CDKN2A/p16 lived significantly longer than those with alterations in these genes (p = 0.018 and p = 0.006, respectively). Our data suggest that the number of altered genes, the mutational status of KRAS and certain morphological subtypes correlate with the outcome of patients with PDAC. Future pathology reporting of PDAC should therefore include the KRAS status and a detailed morphological description.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor with dismal prognosis
By analyzing the expression profile of primary PDACs, and human and mouse PDAC cell lines, Collisson recently identified molecular subtypes of PDAC that differed in clinical outcome and drug response[11]
Other studies revealed an association between expression as well as mutational status of key tumor suppressor and oncogenes and patient survival[16,19]

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor with dismal prognosis. It was reported that intact KRAS and the number of mutations in key genes may have prognostic value in PDAC patients[12,13,14,15,16]. It is unclear so far, whether there are genotype-phenotype correlations that are based on the identification of PDACs with special growth patterns or morphological variants with better survival than classical PDACs, beyond the established pathological parameters of staging and grading[17]. The presented findings show that, according to the analyzed parameters, prognostic relevant subtypes of PDAC can be identified

Methods

Results

Conclusion