High-Throughput Mutation Profiling in Intraductal Papillary Mucinous Neoplasm (IPMN)

Abstract

Of the 22 screened tumor-related genes, only K-ras, p53, and PIK3CA mutations were found in IPMN. K-ras mutations are more prevalent in invasive than premalignant IPMN. The variable coexistence of mutations in the invasive cancer and in the adjacent precursor cells may point to the heterogeneous nature of this tumor.

Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas.

“…Previous reports found activating PIK3CA mutations in three of 14 (21%) ITPNs [12,18]. Two different groups identified PIK3CA mutations in 11% (4/36) and 9% (2/21) of IPMNs, respectively [5,16]; it is noteworthy that the missense hot-spot mutation H1047R in exon 20 was found in four of six invasive cancers. In our series, PIK3CA mutations were absent in both ITPNs and IPMNs; given the good quality of sequences we obtained, this discrepancy is possibly due to the small number of cases analysed by each of the three studies.…”

“…The mutations we found in IDH1, NRAS and CTNNB1 arose in known hotspots for these genes. Although PTEN mutations have not been previously reported in IPMNs or ITPNs [12], loss of PTEN expression in IPMNs has been reported [35], and mutations in PIK3CA, another gene in this pathway, also occur in a small percentage of cases [5,16,35]. The pathogenetic role of CDKN2A/P16 and SMAD4 was further investigated by immunohistochemical analysis.…”

“…TP53, CDKN2A/p16 and SMAD4 mutations and/or loss of expression are generally found in higher-grade lesions [13][14][15]. IPMNs are genetically heterogeneous [16], and different patterns of genetic alterations have been reported in the different morphological subtypes of IPMNs: Mohri et al [4] reported KRAS mutations as more prevalent in gastric-type than intestinal-type IPMN [4]; Xiao et al [17] identified KRAS and BRAF mutations and abnormal p53 immunolabelling in the oncocytic type, but less frequently than in the pancreatobiliary IPMN. Yamaguchi et al [18] analysed 15 gastric-type IPMNs, pyloric gland variant, which showed frequent mutations in GNAS and KRAS (60% and 80%, respectively).…”

The genetic classification of pancreatic neoplasia

“…As mentioned, somatic KRAS mutations occur in a high proportion of IPMNs, with higher incidence in gastric and pancreatobiliary subtypes and the associated tubular adenocarcinomas [85][86][87][88]. Somatic TP53 mutations are almost exclusively found in areas of high-grade dysplasia or invasion, which indicates that this mutation is a relatively late event in carcinogenesis [88][89][90][91]. Most noninvasive IPMNs show intact expression of the tumor suppressor gene SMAD4, whereas SMAD4 loss can be seen in invasive carcinomas arising in association with IPMNs, again suggesting that SMAD4 is targeted late in neoplastic progression [92,93].…”

“…The four most frequently involved genes in PDA play a role in IPMNs too. As mentioned, somatic KRAS mutations occur in a high proportion of IPMNs, with higher incidence in gastric and pancreatobiliary subtypes and the associated tubular adenocarcinomas [85][86][87][88]. Somatic TP53 mutations are almost exclusively found in areas of high-grade dysplasia or invasion, which indicates that this mutation is a relatively late event in carcinogenesis [88][89][90][91].…”