Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome

Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87% of enchondromas (benign cartilage tumors) and in 70% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81%) subjects with Ollier disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, which will enable functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation

Myoepithelioma of bone with a novel FUS-POU5F1 fusion gene

AimsMyoepithelial tumours of soft tissue are rare lesions with a broad morphological and clinical spectrum. Previous studies have found EWSR1 rearrangements in approximately half of all cases and PBX1, ZNF44 and POU5F1 have been identified as recurrent fusion partners. In bone, only a small number of myoepithelial tumours have been described. We investigated an intraosseous myoepithelioma of the sacrum in a 54-year-old man without EWSR1 rearrangement for the presence of other fusion genes. Methods and resultsG-banding analysis, SNP-array and fluorescence in situ hybridisation suggested rearrangement of the FUS and POU5F1 genes. RT-PCR confirmed a chimeric in-frame transcript fusing FUS exon 5 to POU5F1 exon 2. The clinical course after en bloc resection was without recurrence or metastasis over a period of 87months. ConclusionWe report a novel FUS-POU5F1 fusion gene in an intraosseous myoepithelioma of the sacrum. This case highlights that FUS can replace EWSR1 as the N-terminal transactivator in oncogenic fusion genes in myoepithelial tumours, similar to that which has previously been demonstrated in other tumour entities. Thus, in addition to EWSR1, also FUS needs to be considered as a potential fusion partner in the molecular work up of myoepithelial tumours

Fusion genes in angiomatoid fibrous histiocytoma

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor of low malignant potential and uncertain differentiation. Only three genetically investigated cases of AFH have been reported. Two of them displayed a FUS-ATF1 fusion gene and one showed an EWSR1-ATF1 chimera. Using RT-PCR analysis, we have identified the EWSR1-ATF1 fusion transcript, and delineated the genomic breakpoints, in two new cases of AFH. Previously, the EWSR1-ATF1 fusion protein has been suggested to activate expression of the MITF-M transcript, and therefore the expression pattern of the MITF gene was studied. The MITF-M transcript was not detected in either AFH, in line with the finding that the co-activator SOX10 was not expressed. Thus, of the five AFH that have been molecularly analyzed to date, two have displayed a FUS-ATF1 fusion gene and three have shown an EWSR1-ATF1 chimera. There is no apparent correlation between the type of fusion gene and clinicopathologic features. Nonetheless, RT-PCR for these fusion transcripts remains a valuable diagnostic adjunct in the distinction between AFH and other soft tissue tumors or metastases that may simulate it

Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis

BACKGROUND & AIMS: Gain-of-function mutations in the KIT receptor tyrosine kinase gene and rare mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene are important events in gastrointestinal stromal tumor (GIST) development. Different mutations are reportedly associated with distinctive phenotypes and possibly clinical behavior. We investigated the correlation among mutation type, phenotype, and clinical course in a preimatinib, population-based series of GIST with long-term follow-up. METHODS: Genomic DNA from 177 GIST patients was analyzed for KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 mutations using denaturating high-performance liquid chromatography and bidirectional sequencing. RESULTS: KIT exon 11 mutations were detected in 101 of 177 GIST (61 deletions, 23 missense mutations, and 17 duplications); wild-type (WT) KIT and PDGFRA were detected in 63; KIT exon 9 and exon 17 mutations in 6 and 1, respectively; and PDGFRA exons 12 and 18 mutations in 3 each. GIST >5 cm vs GIST </=1 cm had mutations in 73% and 33%, respectively. KIT exon 11 deletions were significantly associated with a higher proportion of high risk or overtly malignant groups compared with WT GIST. KIT exon 11 deletions adversely affected outcome. KIT exon 11 duplications and exon 9 mutations were found exclusively in gastric and small intestinal GIST, respectively. CONCLUSIONS: KIT exon 11 deletion is an independent adverse prognostic factor in patients with GIST