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 IDH1 (R132C and R132H) or IDH2 (R172S) mutations in 87% of enchondromas, benign cartilage tumors, and in 70% of spindle cell hemangiomas, benign vascular lesions. In total, 35 of 43 (81%) patients with Ollier disease and 10 of 13 (77%) patients with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of sixteen patients displayed identical mutations in separate lesions. Immunohistochemistry for mutant R132H IDH1 protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors are associated with hypermethylation and downregulation of expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, enabling functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation.

Hepatocyte nuclear factor 6 (HNF-6) is the prototype of a new class of cut homeodomain transcription factors. During mouse development, HNF-6 is expressed in the epithelial cells that are precursors of the exocrine and endocrine pancreatic cells. We have investigated the role of HNF-6 in pancreas differentiation by inactivating its gene in the mouse. In hnf6 ؊/؊ embryos, the exocrine pancreas appeared to be normal but endocrine cell differentiation was impaired. The expression of neurogenin 3 (Ngn-3), a transcription factor that is essential for determination of endocrine cell precursors, was almost abolished. Consistent with this, we demonstrated that HNF-6 binds to and stimulates the ngn3 gene promoter. At birth, only a few endocrine cells were found and the islets of Langerhans were missing. Later, the number of endocrine cells increased and islets appeared. However, the architecture of the islets was perturbed, and their ␤ cells were deficient in glucose transporter 2 expression. Adult hnf6 ؊/؊ mice were diabetic. Taken together, our data demonstrate that HNF-6 controls pancreatic endocrine differentiation at the precursor stage and identify HNF-6 as the first positive regulator of the proendocrine gene ngn3 in the pancreas. They also suggest that HNF-6 is a candidate gene for diabetes mellitus in humans.The pancreas contains exocrine cells that produce digestive enzymes, ducts through which these enzymes transit to the gut, and endocrine cells, organized in islets of Langerhans, that produce insulin, glucagon, somatostatin, and pancreatic polypeptide (PP). The pancreas arises from the primitive gut epithelium as a dorsal bud and a ventral bud, which later fuse to form a single organ (reviewed in reference 29). The pancreatic epithelium, surrounded by mesenchyme, then proliferates and branches into multiple evaginations. During the initial stage of pancreas development (embryonic day 9.5 [e9.5] to approximately e14.5 in the mouse), the pancreatic epithelium consists mainly of cells that are the precursors of the acinar, ductal, and endocrine cells (29). Starting at e9.5, early glucagon-expressing cells are found in the epithelium. Around e12, glucagon cells are found both within the epithelium and in small clusters that are distinct from the epithelium. The fate of these clusters is unknown. Starting around e14.5 to e15, a wave of differentiation is associated with an increase in the synthesis of digestive enzymes and hormones, ultimately resulting in the formation of the acini, ducts, and islets of Langerhans around e18 to e19. The insulin-expressing cells (␤ cells) are then in the core of the islets, and the cells expressing glucagon (␣ cells), somatostatin (␦ cells), and PP are located at their periphery (reviewed in references 29 and 32).A number of transcription factors are involved in endocrine pancreas development (reviewed in references 8 and 25). They belong to the class of basic helix-loop-helix factors (Ngn-3, NeuroD/Beta2, and Hes-1) or are homeoproteins of the LIM (Isl-1), paired-box (Pax-4 and ...

Somatic mutations in TEK, the gene encoding endothelial cell tyrosine kinase receptor TIE2, cause more than half of sporadically occurring unifocal venous malformations (VMs). Here, we report that somatic mutations in PIK3CA, the gene encoding the catalytic p110α subunit of PI3K, cause 54% (27 out of 50) of VMs with no detected TEK mutation. The hotspot mutations c.1624G>A, c.1633G>A, and c.3140A>G (p.Glu542Lys, p.Glu545Lys, and p.His1047Arg), frequent in PIK3CA-associated cancers, overgrowth syndromes, and lymphatic malformation (LM), account for >92% of individuals who carry mutations. Like VM-causative mutations in TEK, the PIK3CA mutations cause chronic activation of AKT, dysregulation of certain important angiogenic factors, and abnormal endothelial cell morphology when expressed in human umbilical vein endothelial cells (HUVECs). The p110α-specific inhibitor BYL719 restores all abnormal phenotypes tested, in PIK3CA- as well as TEK-mutant HUVECs, demonstrating that they operate via the same pathogenic pathways. Nevertheless, significant genotype-phenotype correlations in lesion localization and histology are observed between individuals with mutations in PIK3CA versus TEK, pointing to gene-specific effects.