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Insufficiency of phosphatase and tensin homolog (PTEN) occurs in numerous tumor types and has been implicated as a resistance mechanism to receptor tyrosine kinase-targeted therapies in human cancer. In this study, we have performed a comprehensive molecular and immunohistochemical characterization of PTEN in 58 imatinib-naive and 54 imatinib-treated gastrointestinal stromal tumors (GISTs). The findings were correlated with clinicopathological data. At the genomic level, PTEN was affected mainly by mono-allelic loss, which was significantly less frequent in imatinib-naive vs imatinib-resistant tumors (9% vs 39%, P

Introduction Synovial sarcoma (SynSa) is an aggressive mesenchymal tumor, comprising approximately 10% of all soft tissue sarcomas. Over half of SynSa patients develop metastasis or local recurrence, but the underlying molecular mechanisms of the aggressive clinical behavior remain poorly characterized. Materials and methods Sixty-four frozen tumor specimens from 54 SynSa patients were subjected to array comparative genomic hybridization (aCGH) and gene expression profiling. The examined set of tumor specimens included 16 primary tumors from untreated patients who did not develop metastasis/local recurrence (SynSa1 group), 26 primary tumors from untreated patients who developed metastases or local recurrence during follow-up (SynSa2 group), and 22 metachronous metastatic/recurrent SynSa tumors (SynSa3 group). Results AURKA and KIF18A, which play important roles in various mitotic events, were the two most up-regulated genes in SynSa2 and SynSa3 groups compared to the SynSa1 group. Expression profiles of SynSa2 and SynSa3 tumors did not show any significant differences. Analysis of genomic index (GI) based on aCGH profiles demonstrated that the SynSa1 group consisted of tumors with significantly less complex genomes compared to SynSa2 and SynSa3 groups. There was no significant difference in genome complexity between SynSa2 and SynSa3 tumors. Conclusions Primary SynSa tumors from patients who develop metastases or local recurrence share common molecular features with metastatic/recurrent tumors. Presented data suggest that the aggressive clinical SynSa behavior is determined early in tumorigenesis and might be related to impaired regulation of mitotic mechanisms. This article is part of a Directed Issue entitled: Rare Cancers.

The cholecystokinin 2 receptor (CCK2R/CCKBR) is expressed in gastrointestinal stromal tumours (GISTs). We sought to investigate the role of CCK2R in GIST pathogenesis. Molecular characterization of CCK2R was performed on a heterogeneous cohort of 50 GISTs. In addition, CCK2R expression was evaluated by immunohistochemistry (IHC), using tissue microarray (TMA) containing 292 GISTs, two cases of hyperplasia of interstitial Cajal's cells (ICC) and six gastric microscopic GISTs. Mono-allelic loss of the CCK2R/11p15 allele was identified in 13.7% of GISTs, having no impact on the level of CCK2R transcript expression. No CCK2R mutations were found. The CCK2Ri4sv, CCK2R splice variant with retention of intron 4 was detected in six of 20 tumours analysed. Wild-type CCK2R transcripts were commonly expressed (57.1% of cases) and this expression was highly correlated with gastric primary site of GISTs (p < 0.001). At the protein level, expression of CCK2R in incidental ICC hyperplasia and early stages of gastric GIST development was documented, and its gastric association was confirmed on GIST-TMA by IHC. To explore the in vivo effect of CCK2R activation on tumour growth, gastrin versus placebo was administered intraperitoneally in nude mice carrying human GIST xenografts. The tumour volume was followed for 10 weeks. The effect of this stimulation on tumour cell proliferation/apoptosis was assessed by IHC and KIT/PKC-θ signalling was evaluated by western blotting (WB). In vivo experiments showed a two-fold increase in the volume of tumours which were exposed to gastrin in comparison with non-exposed controls (p = 0.03), with a significant increase in mitotic activity (p = 0.04) and Ki-67 proliferation index (p = 0.008). By WB, gastrin stimulation resulted in hyper-activation of KIT and PKC-θ kinases, and in evident PI3K-AKT pathway over-activation. Our results indicate a promoting role of CCK2R on GIST tumourigenesis, particularly in tumours of gastric origin.

Synovial sarcoma (SS) is an aggressive type of tumor, comprising approximately 10 % of soft tissue sarcomas. Over 90 % of SS cases are characterized by the t(X;18)(p11.2;q11.2) translocation, which results mainly in the formation of oncogenic SS18-SSX1 or SS18-SSX2 fusions. In a typical SS18-SSX fusion transcript, exon 10 of SS18 is fused to exon 6 of SSX1/2. However, several variant fusion transcripts have been already described. In the present study, we examined the fusion transcript type in a series of 40 primary untreated SS tumor specimens using reverse transcription polymerase chain reaction and fluorescence in situ hybridization assay. We detected SS18-SSX1 transcript in 22 (55 %) patients and SS18-SSX2 transcript in 17 (42.5 %) patients, while in one patient, none of SS18-SSX1/2 fusion transcripts were identified. Among the cases under study, two tumors carried novel SS18-SSX1 and SS18-SSX2 variant translocations that were allegedly created by an alternative splicing, and in additional case, an unusual translocation variant previously described by other group was found. Our data suggest that alternative splicing may play an important role in novel fusion transcript formation, and additionally we show that it may be a recurrent event in SS. Furthermore, we describe the first case of a complex rearrangement possibly linking SS to REPS2 gene.