Purpose: Conjunctival melanoma is a rare but potentially deadly tumor of the eye. Despite effective local therapies, recurrence and metastasis remain frequent. Once the tumor has metastasized, treatment options are limited and the prognosis is poor. To date, little is known of the genetic alterations in conjunctival melanomas.Experimental Design: We conducted genetic analysis of 78 conjunctival melanomas, to our knowledge the largest cohort reported to date. An oncogene hotspot array was run on 38 samples, screening for a panel of known cancer-relevant mutations. Thirty tumors were analyzed for genome-wide copy number alterations (CNA) using array-based comparative genomic hybridization. Sanger sequencing of selected target mutations was conducted in all samples.Results: BRAF mutations were identified in 23 of 78 (29%) tumors. NRAS mutations, previously not recognized as relevant in conjunctival melanoma, were detected in 14 of 78 (18%) tumors. We found CNAs affecting various chromosomes distributed across the genome in a pattern reminiscent of cutaneous and mucosal melanoma but differing markedly from uveal melanoma.Conclusions: The presence of NRAS or BRAF mutations in a mutually exclusive pattern in roughly half (47%) of conjunctival melanomas and the pattern of CNAs argue for conjunctival melanoma being closely related to cutaneous and mucosal melanoma but entirely distinct from uveal melanoma. Patients with metastatic conjunctival melanoma should be considered for therapeutic modalities available for metastatic cutaneous and mucosal melanoma including clinical trials of novel agents.

Dedifferentiation in TC is accompanied by GLUT1 upregulation and increased proliferation. PDTC was found to be intermediate between DTC and ATC in terms of GLUT1 expression and F-18 FDG or I-124 uptake, suggesting that the flip-flop phenomenon occurs at a dedifferentiation stage in between. Furthermore, the results suggest that F-18 FDG PET/CT is an important imaging modality for ATC and PDTC.

We report a mouse model of multiple osteochondromas (MO), an autosomal dominant disease in humans, also known as multiple hereditary exostoses (MHE or HME) and characterized by the formation of cartilage-capped osseous growths projecting from the metaphyses of endochondral bones. The pathogenesis of these osteochondromas has remained unclear. (MHE or HME), is an autosomal dominant disorder characterized by shortened long bones and multiple cartilage-capped bony projections from the metaphyses of endochondral bones that develop during statural growth (1). In 0.5-3% of patients with MO, an osteochondroma eventually transforms into a chondrosarcoma (2). MO has been linked to loss-of-function mutations in the EXT1 (8q24.1) (3) and EXT2 (11p11-p12) (4) genes (5).EXT1 and EXT2 encode ubiquitously expressed type II transmembrane glycosyltransferases (6), which localize to the endoplasmic reticulum and Golgi complex (7). The two genes act in hetero-oligomeric complexes performing the N-acetylglucosamine and D-glucuronic acid transferase activities required for the synthesis of heparan sulfate (HS) chains on proteoglycans (PGs) (8). Besides their expected structural function, HSPGs have been shown to regulate ligand distribution and/or receptor binding of many signaling systems including the hedgehog, Wnt, and fibroblast growth factor families (9).Whereas many theories on the pathogenesis of osteochondromas in the setting of MO have been proposed, each hinges on two central questions. (i) Is the cellular origin of an osteochondroma a chondrocyte of the growth plate or a cell from the juxtaposed perichondrium/periosteum? (ii) Is an osteochondroma the result of haploinsufficiency-dependent misregulation of signals controlling growth plate maturation or of clonally occurring second mutations in the EXT genes (10) as has been shown for other genetically inherited tumor susceptibililty syndromes (11)?Second mutations in or cytogenetic loss of the wild-type allele of EXT1 or EXT2 have been detected, but only in a subset of osteochondromas, leaving the pathogenetic role of loss of heterozygosity (LOH) unestablished (12-16).In mice, deletion of Ext1 or Ext2 results in a lack of HS biosynthesis; homozygous embryos die between E6.5 and E9.5 due to failure in mesoderm formation. Mice heterozygous for loss of Ext1 or Ext2 survive and are fertile. Small, solitary, osteochondromalike structures on ribs have been detected in 30% of heterozygous Ext2 +/− mice. However, unlike humans with MO, heterozygosity for neither Ext1 nor Ext2 disruption has led to shortened long bones or frequent development of larger osteochondromas on other endochondral bones (17,18). Here we demonstrate that clonal, homozygous inactivation of Ext1 in chondrocytes at low prevalence results in frequent osteochondromas on the apendicular skeleton, mimicking the human MO phenotype. ResultsStrategy to Model Loss of Heterozygosity. Exon 2 of Ext1 codes for highly conserved amino acids of the catalytic center (100% amino acid homology between mouse and human). Missen...