In this series, a subset of the IPNBs presented as multifocal lesions (biliary papillomatosis), but only the largest neoplastic foci were analysed. The present authors have previously shown that IPMNs can be heterogeneous with regard to GNAS mutations,9 and this study’s failure to examine multiple selleck chem synchronous lesions may have produced false negatives. The authors find this possibility less likely as GNAS mutations would confer a growth advantage to the index lesion and thus there is a high likelihood that the index lesion will be the most prominent neoplastic focus in a multifocal IPNB. Another caveat may be that the activating hotspot mutation in IPNBs is not at GNAS codon 201, but, rather, at codon 227, which was not examined in the current study.

However, based on the data that GNAS mutations in epithelial neoplasms (including IPMNs) are always restricted to codon 201,9,35,42 the authors find this possibility unlikely. Finally, the issue of assay sensitivity, which is always a concern in a ��negative�� study of this nature, should be addressed. The PCR/ligation assay used herein can detect a single mutant GNAS molecule amongst 200 wild-type templates (0.5% lower limit of detection)9 and has been successfully used for identifying mutant GNAS in highly biologically heterogeneous pancreatic cyst fluid samples. Thus, the present authors consider it quite unlikely that false negative results have been obtained using microdissected tumour tissue (with neoplastic cellularity of >80%).

In conclusion, GNAS codon 201 mutation, a newly discovered ��mountain�� in the genetic landscape of IPMNs, is an uncommon alteration in IPNBs, despite the morphologic similarities between the two lesions arising at embryologically related sites. Additionally, KRAS mutations are also less common in IPNBs than in IPMNs. Based on the present series, it can be assumed that the signalling pathways involved in the pathogenesis of IPNBs are distinct from those in IPMNs. Larger, more comprehensive sequencing studies should help to elucidate the genetic landscape of IPNBs. Acknowledgments This study was supported by the National Institutes of Health (P50CA062924, P01CA134292), the Sol Goldman Pancreatic Cancer Research Center, the Michael Rolfe Foundation for Pancreatic Cancer Research and by a fellowship grant from German Cancer Aid (Deutsche Krebshilfe eV) to HM.

Conflicts of interest None declared. Supporting information Additional supporting information may be found in the online version of this article: Table S1. Detailed clinical and histopathologic data for the study population. Table S2. Oligonucleotides used for sensitivepolymerase chain reaction ligation method for detecting GNASand KRAS mutations. Click here to view.(135K, doc) Please note: Wiley-Blackwell are not responsible GSK-3 for the content or functionality of any supporting materials supplied by the authors.