Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase.

High-frequency point mutations of genes encoding histones have been identified recently as novel drivers in a number of tumors. Specifically, the H3K36M/I mutations were shown to be oncogenic in chondroblastomas and undifferentiated sarcomas by inhibiting H3K36 methyltransferases, including SETD2. Here we report the crystal structures of the SETD2 catalytic domain bound to H3K36M or H3K36I peptides with SAH (S-adenosylhomocysteine). In the complex structure, the catalytic domain adopts an open conformation, with the K36M/I peptide snuggly positioned in a newly formed substrate channel. Our structural and biochemical data reveal the molecular basis underying oncohistone recognition by and inhibition of SETD2.

Expression of cyclooxygenase-2 in chondroblastoma: immunohistochemical analysis with special emphasis on local inflammatory reaction.

To investigate the frequency and mechanism of the peritumoral inflammatory reaction in chondroblastoma, we evaluated the relationship between clinicoradiological findings and immunohistochemical expression of cyclooxygenase-2 (COX-2) in excised tumors. Twenty-one cases of chondroblastoma were studied. Imaging analysis was performed with radiographs and T1- and T2-weighted magnetic resonance images in all cases and with computed tomography scan and bone scintigraphy in some cases. Immunohistochemical study for COX-2 was carried out using formalin-fixed paraffin-embedded tissues. Periosteal reaction was observed in 6 cases (29%) and bone marrow edema in 15 cases (71%). Soft-tissue edema, joint effusion, and synovitis were found in 10 cases (48%), in 7 cases (33%), and in 9 cases (43%), respectively. Immunohistochemical expression of COX-2 in chondroblastoma cells was found in 15 of 21 cases (71%). The intensity of COX-2 immunoreactivity was correlated statistically with the presence of periosteal reaction, bone-marrow edema, soft-tissue edema, and synovitis. Our results indicate that activation of eicosanoid synthesis by COX-2 expression in the tumor itself is probably an important factor, inducing peritumoral inflammatory changes in chondroblastomas.

Metastatic chondroblastoma with elevated creatine kinase and paraneoplastic neurologic autoimmunity.

A 17-year-old girl presented with chondroblastoma of the fibula and pulmonary metastases. Serum creatine kinase (CK) was elevated for a decade preoperatively and fell to near normal after tumor excision. An episode of aseptic meningitis 3 months later led to serologic detection of three antibody markers of paraneoplastic neurologic autoimmunity that in adult patients are characteristic of thymoma and lung carcinoma: muscle-type acetylcholine receptor (AChR) autoantibody (Ab), type 2 Purkinje cell cytoplasmic Ab (PCA-2), and collapsin response-mediator protein-5-IgG (CRMP-5-IgG). Locally recurrent chondroblastoma was excised 1 year later. Serum CK was elevated, CRMP-5-IgG was positive, PCA-2 was lower, and AChR Ab was undetectable. Three years after diagnosis she has stable pulmonary metastases, with elevated CK, higher PCA-2, positive CRMP-5-IgG, and undetectable AChR Ab. The association of metastatic chondroblastoma, elevated CK, and an evolving profile of paraneoplastic autoantibodies reveals a previously unrecognized immunobiologic dimension of chondroblastoma.

Elevation of serum alkaline phosphatase in clear cell chondrosarcoma of bone.

BACKGROUND: Clear cell chondrosarcoma is a rare bone tumor, which is sometimes misdiagnosed as a different bone neoplasm. MATERIALS AND METHODS: The files of 6 patients with clear cell chondrosarcomas were reviewed. Histological slides, radiographic studies, and pre- and post-operative serum alkaline phosphatase (ALP) levels were evaluated. Molecular and histochemical analyses of ALP were documented in one case of clear cell chondrosarcoma. RESULTS: Pre-operative serum ALP levels were elevated in 3 patients, and were normal in another 3 patients. After removal of the tumors, the enzyme levels decreased in all patients and returned to normal in 3 patients, who had pre-operative high ALP levels. Enzyme histochemical and molecular analyses demonstrated that the tumor produced ALP. CONCLUSION: Clear cell chondrosarcoma produces ALP, which can be used as a tumor marker in diagnosis and follow-up.