Succinate Dehydrogenase Subunit B (SDHB) Gene Mutations In Paediatric Metastatic Paraganglioma: A Report Of Two Cases

Poster PresentationBackground: Paragangliomas and pheochromocytomas are catecholamine-releasing neuroendocrine tumors that occur rarely in the paediatric population. Mutations in cancer susceptibility genes can be identified in up to 40% of paediatric cases. Germline mutations in the succinate dehydrogenase subunit B (SDHB) gene in particular, are associated with extra-adrenal paraganglioma with high rate of metastasis and young age at presentation. Methods: Patients with metastatic paraganglioma diagnosed below the age of 18 years were identified from the Hong Kong Paediatric Haematology and Oncology Study Group database. With informed consent, peripheral blood was obtained from the subjects for extraction of DNA, PCR and direct DNA sequencing of all the 8 exons and splice sites of the SDHB were performed to test for germline mutation. Results: Two patients were identified and recruited for testing. Patient 1 was a 12-year-old boy diagnosed with subhepatic paraganglioma. The patient underwent adjuvant chemotherapy (gemcitabine, docetaxol, avastin) followed by en-bloc tumour resection. At the age of 15, MIBG-avid metastatic lesions at the L3-4 vertebrae were detected in surveillance scan and subtotal spondylectomy was performed. Urine HVA/VMA were normal all along. Family history was unremarkable. Further immunohistochemistry demonstrated loss of SDHB staining in the tumour cells. Sequencing of the SDHB gene revealed a novel heterozygous mutation, c.415C>T (p.Leu139Phe) that was not present in 150 normal controls. Sequencing of SDHC, SDHD, and VHL genes showed wild-type sequence. Patient 2 was a 13 year-old girl with negative family history who suffered from subhepatic paraganglioma and right adrenal phaeochromocytoma with metastasis to the right scapula and skull bone. Debulking surgery was performed for the abdominal primaries and curettage to the right shoulder metastasis. Three courses of 131-I-MIBG therapy were given with response. The patient subsequently developed left adrenal phaeochromocytoma and was treated surgically. Nevertheless, she relapsed at the age of 22 with metastasis at the intraabdominal nodes as well as lumbar vertebrae and was then managed with palliation. Sequencing of the SDHB gene confirmed the presence of a known pathogenic heterozygous mutation, c.572G>A (p.Cys191Tyr)

Receptor-type tyrosine-protein phosphatase kappa promoter hypermethylation correlates with unfavorable prognosis in nasal NK/T-cell lymphoma patients treated with SMILE regimen

Poster Presentation: no. IP-1One of the main characteristics of nasal NK/T-cell lymphoma (NKTCL) is the constitutive activation of signal transducer and activator of transcription 3 (STAT3) and frequent deletions on chromosome 6q. Tyrosine phosphorylation at Tyr705 is required for STAT3 to bind to specific DNA target sites. Here we first investigated whether receptor-type tyrosine-protein phosphatase kappa (PTPRK), the only protein tyrosine phosphatase at 6q that contains a STAT3-specifying motif, negatively regulates STAT3 activation in NKTCL. We found a strong in vivo correlation between low PTPRK expression and high nuclear phospho-STAT3Tyr705 levels in NKTCL primary tumors and showed that PTPRK binds to STAT3 and directly dephosphorylates phospho-STAT3 at Tyr705 and regulates the levels of phospho-STAT3Tyr705 in NKTCL. Further studies showed that monoallelic deletion and promoter hypermethylation causes underexpression of PTPRK mRNA in NKTCL, and methylation of PTPRK promoter significantly correlates with higher IPI (p<0.001) and with inferior overall survival (p=0.049) in NKTCL patients treated with the steroid-dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) regimen. Altogether, our findings show that PTPRK underexpression leads to STAT3 activation and contributes to NKTCL pathogenesis and that methylation of the PTPRK promoter correlates with a severe clinical course and worse prognosis in NKTCL patients treated with the SMILE protocol