Loss of Heterozygosity Analysis of Chromosome 17p13.1-13.3 and Its Correlation with Clinical Outcome in Medulloblastomas / 대한소아혈액종양학회지

PURPOSE: Cytogenetic studies molecular genetic studies, including loss of heterozygosity (LOH) studies, have shown that deletions on the short arm of chromosome 17 (17p) distal to TP53 locus are the most common genetic events in medulloblastoma, and that these occur in 30 to 50% of medulloblastomas. We examined the occurrences and frequencies of allelic deletions on chromosome 17p13.1-13.3 by LOH analysis to investigate the possible involvement of 17p13.1-13.3 in medulloblastoma development. We also performed survival analysis to determine whether LOH analysis of 17p13.1-13.3 can be used to predict prognosis in medulloblastoma. METHOD: LOH was analyzed by polymerase chain reaction (PCR) on chromosome 17p13.1-13.3 using 3 microsatellite markers, TP53 on 17p13.1, D17S796 on 17p13.1-13.2 and D17S1574 on 17p13.3, in 17 medulloblastoma DNAs extracted from archival tissue specimens (cases 1~15) or fresh frozen tissue specimens (cases 16 and 17). RESULTS: Allelic deletions were detected in 5 of 17 informative cases (29%) on TP53, 8 of 17 informative cases (47%) on D17S796, and 4 of 17 informative cases (24%) on D17S1574. Overall, 9 of 17 cases (53%) showed LOH on chromosome 17p13.1-13.3. The 5-year progression free survival (PFS) and 5-year overall survival (OS) rates were identical (59%). The 5-year PFS for 9 medulloblastoma patients with LOH on 17p13.1-13.3 was 56%, and the 5-year PFS for 8 medulloblastoma patients without LOH on 17p13.1-13.3 was 63%. In our survival analysis, we did not find a significant association between survival and LOH on 17p13.1-13.3. CONCLUSION: Our results support the notion that deletions of chromosome 17p13.1-13.3 may be involved in the pathogenesis of medulloblastoma. From survival analysis, we conclude that LOH on chromosome 17p13.1-13.3 may not be a significant predictor of prognosis in medulloblastoma.

Clinical, Electrophysiological and Pathological Characteristics in Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) with Chromosome 17p11.2-p12 Deletion

BACKGROUND: Hereditary neuropathy with liability to pressure palsies (HNPP) is a peripheral nerve disorder characterized by autosomal dominant inheritance, recurrent pressure palsies, reduced motor and sensory conduction velocities and sausage-like swellings (tomacula) of myelin sheaths in nerve biopsy. A 1.5-Mb deletion in chromosome 17p11.2- p12 is present in the majority but not all cases of HNPP. The aim of the present study was to evaluate the clinical, electrophysiological and morphological aspects of HNPP patients associated with chromosome 17p11.2-p12 deletion. METHODS: To detect the presence of the deletion, the DNA of the patients was analyzed with pVAW409R3 (D17S122). An electrophysiological study was done in all patients. Sural nerve biopsy with teasing was done in three patients. RESULTS: DNA analysis and electrophysiological tests revealed the deletion in 8 families and 16 patients. Nerve conduction studies demonstrated diffuse mild to moderate slowing of nerve conduction velocities especially worse over the common entrapment sites, regardless of clinical manifestations. The long duration of compound muscle and nerve action potentials without conduction blocks or dispersion is characteristic of patients with HNPP. The tomacula of myelin sheaths was found on sural nerve teasing. CONCLUSIONS: We report the clinical, electrophysiological and morphological aspects of the Korean HNPP patients associated with chromosome 17p11.2-p12 deletion. (J Korean Neurol Assoc 19(3):251~259, 2001)

Intraoperative Electrophysiological Monitoring during Microvascular Decompression for Hemifacial Spasm and Surgical Outcome

BACKGROUND: Hereditary neuropathy with liability to pressure palsies (HNPP) is a peripheral nerve disorder characterized by autosomal dominant inheritance, recurrent pressure palsies, reduced motor and sensory conduction velocities and sausage-like swellings (tomacula) of myelin sheaths in nerve biopsy. A 1.5-Mb deletion in chromosome 17p11.2- p12 is present in the majority but not all cases of HNPP. The aim of the present study was to evaluate the clinical, electrophysiological and morphological aspects of HNPP patients associated with chromosome 17p11.2-p12 deletion. METHODS: To detect the presence of the deletion, the DNA of the patients was analyzed with pVAW409R3 (D17S122). An electrophysiological study was done in all patients. Sural nerve biopsy with teasing was done in three patients. RESULTS: DNA analysis and electrophysiological tests revealed the deletion in 8 families and 16 patients. Nerve conduction studies demonstrated diffuse mild to moderate slowing of nerve conduction velocities especially worse over the common entrapment sites, regardless of clinical manifestations. The long duration of compound muscle and nerve action potentials without conduction blocks or dispersion is characteristic of patients with HNPP. The tomacula of myelin sheaths was found on sural nerve teasing. CONCLUSIONS: We report the clinical, electrophysiological and morphological aspects of the Korean HNPP patients associated with chromosome 17p11.2-p12 deletion. (J Korean Neurol Assoc 19(3):251~259, 2001)

Loss of Heterozygosity Studies on Chromosome 9, 22 and 17p in 12 Various Pediatric Brain Tumors / 대한소아혈액종양학회지

PURPOSE: The normal function of tumor suppressor genes is thought to be related to their ability to regulate cell proliferation and the loss of such function presumably leads to malignant transformation by releasing the transformed cells from growth regulation. One approach to identify these tumor suppressor genes is by loss of heterozygosity (LOH) studies. The rationale of these studies is that the mutation of one allelic copy of a tumor suppressor gene followed by the loss of the remaining wild type allele will result in the total loss of the function of the tumor suppressor gene. Chromosomal loci with frequent LOH in malignant tumors is likely to contain tumor suppressor genes. We want to identify deletions of putative tumor suppressor gene loci in pediatric brain tumors by polymerase chain reaction (PCR)-based LOH studies using microsatellite polymorphic markers of chromosome 9, 22 and 17p as most frequent cytogenetic abnormalities involve chromosome 17p, 22 and 9 in pediatric brain tumors. MATERIAL AND METHOD: Blood and tumor samples were obtained from 12 pediatric brain tumor patients who were operated at Texas Children's Cancer Center from April 1996 to January 1997. The 12 tumors consist of 5 cases of medulloblastomas, 4 cases of juvenile pilocytic astrocytomas, and 1 case each of ependymoma, atypical teratoid rhabdoid tumor and desmoplastic infantile ganglioglioma. Genomic DNA extracted from blood and tumor tissues were amplified by PCR using [gamma-32P]ATP endlabeled primer pairs for the microsatellite polymorphic markers on chromosome 9, 22 and 17p which were D9S171, D9S169, D9S168, D9S165, D9S156, D9S110, D9S146, D9S971, D9S757,D9S176, D9S2105, D9S177, D9S2127, D9S1849, D9S1817, D22S303, D22S33, D22S315, D22S275, D22S299, D22S301, TOP1P2, PDGFB, D22S274, D22S304, D17S1866, D17S1810, D17S796, D17S1566 and D17S1574. The PCR products were separated by electrophoresis in a denaturing 6% polyacrylamide gel and exposed on X-ray films to analyze LOH. RESULTS: 1) There was no evidence of LOH on chromosome 9 in all 12 pediatric brain tumors. 2) Among 12 pediatric brain tumors, only one allelic loss on chromosome 22 (D22S274 : 22q13.31-22q13.33) was observed in an atypical teratoid rhabdoid tumor. 3) LOH for loci on chromosome 17p were detected in 6 cases (50%) of 12 various pediatric brain tumors including 4 cases of medulloblastomas and 1 case each of ependymoma and atypical teratoid rhabdoid tumor. Among 5 cases of medulloblastomas, 4 cases(80%) showed LOH on at least one of 5 markers of chromosome 17p. 4) There was no allelic loss on chromosome 9, 22 and 17p in juvenile pilocytic astrocytomas. CONCLUSION: Our data indicate that there may be a putative tumor suppressor gene located on chromosome 22q13.3 associated with tumorigenesis of atypical teratoid rhabdoid tumor, and other putative tumor suppressor genes located on chromosome 17p13.1-17p13.3 associated with tumorigenesis of medulloblastoma, ependymoma and atypical teratoid rhabdoid tumor. But we need to collect more pediatric brain tumor samples to be studied and allelotype the suggested LOH region in detail.