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PubMed1991

[Amplification of L-myc oncogene in malignant meningioma. Case report].

Amplification of L-myc oncogene was noticed in a malignant meningioma originating from the right sphenoidal wing of a 54-year-old female. The patient underwent three surgical resections plus radiotherapy over a period of 11 years and then the growth rate of the tumor became much greater with a severely invasive appearance. Using Southern blot hybridization, L-myc amplification was examined on the specimen resected at the fourth operation. As a result, approximately five-fold amplification was confirmed, which has not been previously reported except for that in a small cell carcinoma of the lung. This result may suggest that L-myc amplification is responsible to some extent for the malignant transformation in this meningioma.

Female↗

PubMed1989

Establishment and characterization of a human neuroblastoma cell line.

A continuous human cell line RN-GA was established from a stage-III primary neuroblastoma prior to therapy. Light and electron microscopic analysis of the biopsy showed morphological features typical of neuroectodermal origin. Relative cellular DNA content and N-myc oncogene copy number were also analyzed in the biopsy tissue: the tumor cells presented a near-diploid genome with N-myc amplification. The derived tumor cell line expressed distinctive ultrastructural, cytogenetic and immunological markers of neuroblastoma. Moreover, cells from the culture could be serially transplanted into splenectomized-irradiated nude mice, where they formed a progressively growing solid tumor. Surprisingly, the cells in culture did not show any N-myc amplification, while they retained a near-diploid DNA content. We propose that several techniques (electron microscopy, oncogene analysis, flow cytometry, cytogenetics, tissue culture, cell antigen immunodetection) should be used to establish a firm diagnosis and a correct clinical grading of this tumor. The establishment of this continuous cell line should be valuable as an experimental in vitro system for further studies of neuroblastoma biology and morphology.

Adrenal Gland Neoplasms↗

PubMed1997

Application of fluorescence in situ hybridization to detect N-myc (MYCN) gene amplification on paraffin-embedded tissue sections of neuroblastomas.

Fluorescence in situ hybridization (FISH) was applied to neuroblastoma for detection of N-myc (MYCN) oncogene amplification, and the results were compared with Southern blot analysis (Southern). In nine neuroblastomas (formalin-fixed paraffin-embedded tissues were available in seven cases including two cases with touch preparations, and two cell lines), all five cases with N-myc amplification detected by Southern had cells with multiple N-myc signals by FISH, and three cases showed no N-myc amplification either by Southern or FISH procedure. One case, not examined by Southern, showed amplified signals of N-myc by FISH. These data indicate that FISH results for N-myc amplification have close correlation with Southern blot analysis. The chromosome 2-specific repetitive DNA probe was also applied for the analysis of ploidy by FISH. Six cases with N-myc amplification by Southern and/or FISH had diploid tumors and two cases without amplified N-myc showed aneuploidy. The remaining one case consisted of heterogeneous elements showing diploidy in undifferentiated tissue and both aneuploidy (ganglionic cells) and diploidy (Schwann cells) in differentiated area. We conclude that FISH is a practical, useful and reliable method over Southern especially for analysis of N-myc amplification in neuroblastoma, and simultaneous cohybridization with a specific chromosome probe is of great value in predicting the prognosis of patients.

Blotting, Southern↗

PubMed1996

Comparison of fluorescent in situ hybridization (FISH) and the polymerase chain reaction (PCR) for detection of residual neuroblastoma cells.

Residual neuroblastoma (NB) cells in bone marrow or peripheral progenitor hematopoietic cells harvests may be a source of relapse after autologous transplantation in patients with high stage neuroblastoma. Therefore a sensitive method for detecting minimal residual disease (MRD) in the harvested product is important so that an appropriate purging techniques can be applied and optimized. We report on the detection of NB cells by fluorescence in situ hybridization (FISH) for N-myc amplification and compare the sensitivity of FISH with a semiquantitative polymerase chain reaction (PCR) assay. As a model of MRD we used the neuroblastoma cell line IMR-32 diluted with normal peripheral blood lymphocytes. We were able to detect a single NB cell in 1000 normal mononuclear cells by FISH. The PCR method, using ethidium-bromide-stained gels, required at least 10% NB cells to be present for detection of an amplified band of the N-myc oncogene. Thus, FISH is ten to one hundred times more sensitive in detection of N-myc amplification than a differential PCR and thus it is the method of choice for detection of MRD in NB patients.

DNA, Neoplasm↗

PubMed1988

Increase in copy number of N-myc in retinoblastomas in comparison with chromosome abnormality.

N-myc oncogene amplification was studied in tumor tissue DNA from Japanese retinoblastoma patients, taking into consideration their uni- or bilateral disease form, their family history, and any chromosome abnormalities. Of the 23 cases examined, seven (30%) showed a 1.9- to 2.3-fold amplification of N-myc. No correlation was found between N-myc amplification and either tumor form or family history. Two of three cases having double minute bodies in their tumors showed N-myc amplification. In two tumors with 13q deletions, one produced in the host with constitutional 13q--abnormality showed no N-myc amplification, and the other one produced in the host with normal karyotype showed an N-myc amplification. These results indicate N-myc amplification is independent of the known genetic background in retinoblastoma patients.

Child↗

PubMed1995

Differential expression of pleiotrophin and midkine in advanced neuroblastomas.

Pleiotrophin (PTN) and midkine (MK) are members of a new family of neurotrophic factors whose expression is developmentally regulated. PTN also transforms NIH 3T3 cells, and MK is mitogenic to certain cell lines. Neuroblastomas are tumors derived from neural crest cells, and recent studies have revealed that the biology of these tumors is at least partly regulated by neurotrophic factors and their receptors. To examine the expression of PTN and MK in neuroblastoma, we analyzed their mRNA expression in 72 primary neuroblastomas and 11 neuroblastoma cell lines as well as other tissues and cell lines. PTN is highly expressed in favorable neuroblastomas (stages I, II, and IV-S, n = 44), whereas it is expressed at a significantly lower level in advanced tumors (stages III and IV, n = 28, P = 0.003). PTN is not expressed in either aggressive neuroblastomas with N-myc amplification or in neuroblastoma cell lines. Moreover, the expression pattern of PTN was similar to that of TRK-A, the high affinity receptor for nerve growth factor, in that it is correlated with a favorable prognosis (P < 0.004). In contrast, MK is highly expressed in almost all primary neuroblastomas and cell lines and showed no correlation with disease stage or N-myc amplification. These results suggest that differential expression of PTN and MK may have an important role in regulating growth and differentiation of neuroblastomas.

3T3 Cells↗

PubMed1988

Nuclear oncogene amplification or rearrangement is not involved in human colorectal malignancies.

We have examined 44 cases of human colonic and rectal carcinomas for structural rearrangement and amplification of c-myc, N-myc, L-myc, c-myb and p53 oncogenes. DNA hybridization showed evidence of c-myc amplification in only one of the samples tested. In addition, the same tumour also showed a rearrangement immediately 3' to the c-myc locus. No rearrangement could be found at the c-myc locus in the other 43 cases. Moreover, our molecular analysis of N-myc, L-myc, c-myb and p53 genes indicated no relevant alteration of the copy number and/or genomic structure of these nuclear oncogenes. Thus, at least in human colorectal malignancies, it is unlikely that nuclear oncogene structural alterations and/or amplification plays a major role in tumour induction or progression.

Adenocarcinoma↗

PubMed2001

Improved survival of children with advanced neuroblastoma treated by intensified therapy including myeloablative chemotherapy with stem cell transplantation: a retrospective analysis from the Tohoku Neuroblastoma Study Group.

In the hospitals of the Tohoku Neuroblastoma Study Group (TNBSG), treatment for children with advanced neuroblastoma (NB) was intensified in the mid-1990's with the introduction of myeloablative therapy (MT) with stem cell transplantation (SCT) including the use of autologous peripheral blood stem cells (PBSC) and bone marrow transplantation (BMT). In this report, we examined whether the intensified therapy improved the outcome of children with advanced NB (age> 12 months) who were diagnosed between 1991 and 1997. Patients were 36 children (23 boys and 13 girls) with an average age of 3.4 years (range; 1 to 14 years). Six of them had stage III disease, and the other 30 had stage IV. They were treated initially with induction chemotherapy, surgery, and post-operative chemoradiotherapy, after which 17 of them continued further chemotherapy and the other 19 received MT/SCT (18 with PBSCT and 1 with BMT). Progression-free survival (PFS) rate at seven years from diagnosis was 43.5% for all patients, 66.7% for stage III patients and 38.2% for stage IV patients. The difference between stage III and IV patients was not significant. Among the 30 patients with stage IV disease, PFS at seven years was significantly higher in the 19 patients who received MT/SCT (55.6%) than in the 11 patients who did not receive it (12.5%). There was no difference in clinical and biological risk factors between these two groups, except for the proportion of patients with favorable response to initial therapy (36% and 80% for patients without and with MT/SCT, respectively). Furthermore, the proportion of patients with N-myc amplification was significantly higher in patients with progressive disease (PD) after MT/SCT than in those in CR after MT/SCT. The results of this retrospective study of children with advanced NB suggest that therapy intensification involving MT/SCT might result in lengthened survival time for patients with stage IV disease, and that post-transplant PD remains a risk for patients with high levels of N-myc amplification.

Antineoplastic Agents↗

PubMed2001

Cytogenetic and histopathologic studies of congenital supratentorial primitive neuroectodermal tumors: a case report.

Primitive neuroectodermal tumors (PNET) represent about 25% of primary central nervous system tumors in childhood, but congenital PNETs are rare. Cytogenetic studies and studies on molecular pathology have identified several genetic alterations in medulloblastoma, but molecular investigations on supratentorial PNETs are infrequent. We present a male newborn with a large congenital PNET of the right cerebral hemisphere and the molecular analysis of the tumor. Tumor tissue was investigated by routine histology and immunohistochemistry. Fluorescence in-situ hybridization was carried out on native tumor tissue to investigate deletions on chromosome 17p and to analyze c-Myc or N-Myc amplifications. Histologic examination revealed a primitive neuroectodermal tumor with massive extension covering almost the entire right hemisphere. Genetic analysis of the native tumor tissue of our patient excluded a deletion of chromosome 17p. An amplification of the c-Myc or N-Myc oncogene was absent using fluorescence in-situ hybridization. Despite unremarkable genetic analysis in our case prognosis was poor, suggesting that there are additional, yet unknown constitutional genetic aberrations in the pathogenesis of congenital supratentorial PNET.

Biomarkers, Tumor↗

PubMed2001

The inhibitor of apoptosis protein survivin is associated with high-risk behavior of neuroblastoma.

BACKGROUND/PURPOSE: Apoptotic factors inducing or preventing cell death may intrinsically govern the behavior of some tumors. Survivin is a recently described member of the inhibitor of apoptosis protein (IAP) family, that is expressed in a cell cycle-dependent manner and is found in tumors of unfavorable histology. This study examines the presence of several apoptotic factors, including survivin, in neuroblastoma (NB) tumors. Clues to survivin's function in NB are provided by examining its association with behavior and cell dynamics in tumors and cell lines. METHODS: Expression of a panel of apoptosis factors were quantified in 15 NB and related tumors before chemotherapy and in 3 NB cell lines (NB7, NB10, and NB16). Survivin and other apoptotic factors, as well N-myc amplification in primary tumors was correlated with recurrent disease and outcome. Proliferation rate, apoptosis assays, cell cycle analysis, and drug- or immune-mediated cell death were assessed in cell lines and evaluated in the context of differential survivin and apoptosis gene expression. RESULTS: All 7 tumors that went on to recur expressed survivin, whereas expression was absent in all 8 tumors that went into remission. N-myc was amplified in 4 (57.1%) of the 7 recurrent tumors. Of the 8 tumors that were cured, Fas was expressed in 3 (38%), TRAIL-R1 in 6 (75%) and tumor necrosis factor (TNF)-R1 in 8 (100%), whereas these pro-apoptotic receptors were present in only 1 (14%), 1 (14%), and 4 (57%) of the 7 tumors that went on to recur, respectively. Of the 3 cell lines, NB10 expressed the least survivin, displayed the lowest proliferation index, and had the fewest number of cells in the G2/M (mitotic) phase of the cell cycle. Furthermore, NB10 also was most sensitive to TNF-related apoptosis-inducing ligand (TRAIL) or etoposide-induced cell death. CONCLUSIONS: In primary NB tumors, survivin expression was associated with tumors of high risk and unfavorable prognosis, whereas pro-apoptotic receptor expression was more abundant in tumors of favorable prognosis. In this small series, survivin expression appeared to be more predictive of recurrent disease than N-myc amplification. In cell lines, survivin expression was cell cycle dependent, and its expression was associated with greater proliferation rates and greater resistance to drug- or immune-mediated cell death. Survivin expression may become a useful prognostic marker in NB and could be a potential target for the treatment of this tumor. J Pediatr Surg 36:1785-1791.

Apoptosis↗

PubMed1996

Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma.

BACKGROUND: Neuroblastoma is a childhood tumor derived from cells of the neural crest, with a widely variable outcome. Differences in the behavior and prognosis of the tumor suggest that neuroblastoma can be divided into several biologic subgroups. We evaluated the most frequent genetic abnormalities in neuroblastoma to determine their prognostic value. METHODS: We used Southern blot analysis to study the allelic loss of chromosomes 1p, 4p, 11q, and 14q, the duplication of chromosome 17q, and the amplification of the N-myc oncogene in 89 neuroblastomas. We also determined the nuclear DNA content of the tumor cells. RESULTS: Allelic loss of chromosome 1p, N-myc amplification, and extra copies of chromosome 17q were significantly associated with unfavorable outcome. In a multivariate analysis, loss of chromosome 1p was the most powerful prognostic factor. It provided strong prognostic information when it was included in multivariate models containing the prognostic factors of age and stage or serum ferritin level and stage. Among the patients with stage I, II, or IVS disease, the mean (+/- SD) three-year event-free survival was 100 percent in those without allelic loss of chromosome 1p and 34 +/- 15 percent in those with such loss; the rates of three-year event-free survival among the patients with stage III and stage IV disease were 53 +/- 10 percent and 0 percent, respectively. CONCLUSIONS: The loss of chromosome 1p is a strong prognostic factor in patients with neuroblastoma, independently of age and stage. It reliably identifies patients at high risk in stages I, II, and IVS, which are otherwise clinically favorable. More intensive therapy may be considered in these patients. Patients in stages III and IV with allelic loss of chromosome 1p have a very poor outlook, whereas those without such loss are at moderate risk.

Blotting, Southern↗

PubMed1996

Evaluation of patients with advanced neuroblastoma surviving more than 5 years after initiation of an intensive Japanese protocol: a report from the Study Group of Japan for Treatment of Advanced Neuroblastoma.

In January 1985, a single protocol consisting of cyclophosphamide, vincristine, tetrahydropyranyl adriamycin, and cis-platinum for the treatment of advanced neuroblastoma was begun nationwide in Japan and was found to improve clinical results significantly in terms of 2- or 3-year survival rate. Between January 1985 and December 1988, 113 eligible patients (7 infants younger than 12 months of age with stage IVA disease and 106 patients aged 12 months or older with stage III or IV disease) were enrolled and followed up for 5 years or more after initiation of treatment, as of March 1994. In this study, the usefulness of the protocol for the treatment of advanced neuroblastoma was evaluated with survival rates in relation to age, tumor site, stage, and N-myc amplification for patients surviving more than 5 years after initiation of the protocol. Fifty of the 113 patients were alive 5 years or more after initiation of the treatment, 39 without any episodes of disease recurrence. Fourteen (70%) of 20 patients with stage III, 6 (50%) of 12 with stage IVB, and 24 (30%) of 81 with stage IVA disease were alive and disease-free 5 years after initiation of the protocol. Twenty (56%) of 36 patients without N-myc amplification were alive at 5 years after initiation of the protocol. Only one patient who was alive without evidence of the disease at 5 years had recurrence afterward.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

[Congenital neuroblastomas].

BACKGROUND: We consider congenital neuroblastomas (CN) those detected in pregnancy or at the very first hours of life. Due to perinatal sonography, its incidence has increased in the last years. We present herein our experience in the treatment of this condition and we try to find out any different clinical pattern from those neuroblastomas diagnosed later in life. METHODS: We review the CN treated in our hospital from 1990 to 2003, analyzing diagnosis, localization, tumor staging, N-myc amplification, treatment and evolution. RESULTS: Among the 107 neural tumors managed during this period (89 neuroblastomas, 18 ganglioneuromas), 8 were congenital neuroblastomas (7 girls, 1 boy). Two patients had prenatal diagnosis and 6 tumours were detected in routine exploration or casual findings upon neonatal examination. Six were abdominal, 1 thoracoabdominal and 1 abdominopelvic with dumbbell invasion. Three tumours were classified like stage 1, 1 stage 2, 1 stage 3, 1 stage 4 and 2 stage 4S. Although most of them had unfavorable histology, we didn't find N-myc amplification in any tumor. All patients were operated upon, with preoperative chemotherapy in 2 of them. Resection was complete in 7 out of the 8 tumors. The patient who presented neurological symptoms at birth recovered neither motility nor bladder function after resection. All of them survive after 60+/-53 months of follow-up. CONCLUSIONS: The outcome in this group of neuroblastomas is better that expected, probably because of its abdominal location. On the contrary in dumbbell neuroblastomas, neurological damage at birth seems to be irreversible.

Female↗

PubMed1986

Intragenic pausing and anti-sense transcription within the murine c-myc locus.

We present a detailed analysis of strand-specific transcription in different regions of the murine c-myc locus. In normal and transformed cell lines, RNA polymerase II directed transcription occurs in the sense and anti-sense direction. Three noncontiguous regions show a high level of transcription in the anti-sense orientation: upstream of the first exon, within the first intron and in the 3' part of the gene (intron 2 and exon 3). In a cell line carrying a c-myc amplification (54c12), anti-sense transcription is not uniformly increased throughout the locus and is differentially affected by inhibition of protein synthesis. These results suggest that anti-sense transcription in various parts of the locus is independently regulated. In the sense orientation, transcriptional activity is higher in the first exon than in the rest of the gene indicating that transcription pauses near the 3' end of the first exon. The extent of this intragenic pausing varies among different cell lines and is most severe in cells with a c-myc amplification. Transcription initiation and pausing are both negatively regulated by labile proteins.

Animals↗

PubMed2005

Genetic alterations in B-cell non-Hodgkin's lymphoma.

BACKGROUND: Although the patients with diagnosed B-NHL are classified into the same disease stage on the basis of clinical, histopathological, and immunological parameters, they respond significantly different to the applied treatment. This points out the possibility that within the same group of lymphoma there are different diseases at molecular level. For that reason many studies deal with the detection of gene alterations in lymphomas to provide a better framework for diagnosis and treatment of these hematological malignancies. AIM: To define genetic alterations in the B-NHL with highest possibilites for diagnostic purposes and molecular detection of MRD. METHODS: Formalin fixed and paraffin embedded lymph node tissues from 45 patients were examined by different PCR techniques for the presence of IgH and TCR gamma gene rearrangement; K-ras and H-ras mutations; c-myc amplification and bcl-2 translocation. There were 34 cases of B-cell non-Hodgkin's lymphoma (B-NHL), 5 cases of T-cell non-Hodgkin's lymphoma (T-NHL) and 6 cases of chronic lymphadenitis (CL). The mononuclear cell fraction of the peripheral blood of 12 patients with B-NHL was analyzed for the presence of monoclonality at the time of diagnosis and in 3 to 6 months time intervals after an autologous bone marrow transplantation (BMT). RESULTS: The monoclonality of B-lymphocytes, as evidenced by DNA fragment length homogeneity, was detected in 88 % (30/34) of B-NHL, but never in CL, T-NHL, or in normal PBL. Bcl-2 translocation was detected in 7/31 (22.6%) B-NHL specimens, c-myc amplification 9/31 (29%, all were more than doubled), K-ras mutations in 1/31 (3.23%) and H-ras mutations in 2/31 (6.45%) of the examined B-NHL samples. In the case of LC and normal PBL, however, these gene alterations were not detected. All the patients (12) with B-NHL had dominant clone of B-lymphocyte in the peripheral blood at the time of diagnosis while only in 2 of 12 patients MRD was detected 3 or 6 months after BMT. CONCLUSION: Because it is quic and simple, PCR analysis of clonal IgH rearrangements is very useful when diagnostic assistance is required. This technique is also very effecient for tracking minimal residual disease in lymphomas and leukemias and for monitoring clonal evolution in acute and chronic lymphoblastic leukemias and lymphomas. The presence of other genetic alterations, which we detected, should serve as an additional prognostic or predictive factor in the patients with B-NHL.

Gene Rearrangement, gamma-Chain T-Cell Antigen Rec↗

PubMedDate not supplied

[Value of prognostic factors in the Austrian A-NB87 Neuroblastoma Study].

AIMS: A multivariate analysis was performed to evaluate the impact of various prospectively evaluated risk factors. PATIENTS AND METHODS: From January 1987 to December 1993, 120 patients were registered in the study. 108/120 patients were eligible. There were 49 girls and 59 boys with a median age at diagnosis of 14 months (range, 0 to 224 months). Patients were classified according to the Evans classification system. LDH, NSE, Ferritin, N-myc amplification, 1p-deletion and ploidy were evaluated at diagnosis. Treatment intensity was based on the results of primary surgery: surgery only for 22 (20%) stage I and IIA patients (macroscopic residue without lymph node involvement), the 9 IIB patients (8,5%) (macroscopic residue with lymph node involvement) had mild chemotherapy in addition (6 x VCR/CYC) and elective radiation (Rx). Stage III patients were divided into 2 groups: IIIA patients (n = 17/16%) had to have ferritin levels under 300 micrograms/ml, NSE lower than 100 ng/ml and age below 2 years at diagnosis and received 6 alternating cycles of DAMO/ MVDOC. If one of these three criteria was not fulfilled, patients were assigned to the more intensive treatment arm stage IIIB (n = 12/11%), i.e. 9 alternating cycles of DAMO/MVDOC/IPE. Stage IV pts (n = 35/32.5%) received 8 MVDOC/IPE cycles and 20 patients received megatherapy followed by stem cell reinfusion in addition. 13 stage IVs patients (12%) were registered and had elective VCR/CYC and/or liver radiation in case of poor clinical condition. The median observation time is 4.2 years (range, 1 to 7.5). RESULTS: The survival rate at 3 years was excellent for localized disease and stage IVs with survival rates of 100% for stage I/IIA and 92% for stage IVs. Stage IIIA patients had an EFS rate of 81% whereas stage IIB patients achieved only 69%. Stage IV patients reached 51%, however outcome was especially poor for stage IIIB patients (20%) due to treatment related toxicities. The toxic death rate in the study was 13% (2 surgical deaths, 8 infections, 4 multiple organ failures). Univariate analysis demonstrated the following significant unfavorable risk factors: age over 1 year at diagnosis (58/108 pts, p = 0.006), NSE > 100 ng/ml (26/95 pts, p < 0.0001), Ferritin > 300 ng/ml (19/98 pts, p = 0.007), LDH > 300 (400) U/L, 51/87 pts, p = 0.004), presence of N-myc amplification (17/59 pts, p = 0.001), deletion of the short arm of chromosome 1 (19/74 pts, p < 0.0001) and di/tetraploidy (32/72 pts, p = 0.008). The power of these factors was even stronger in patients with localized disease whereas no significant prediction was observed for stage IV patients. Furthermore a significant correlation of the serological (NSE, ferritin, LDH) and biological factors (N-myc, deletion 1p, di/tetraploidy) was detected in this study. Only NSE was identified as an independent prognostic factor (p = 0.018) whereas no independent factor could be identified within the 3 biological parameters due to their high correlations (Kendall's tau for N-myc and deletion 1p:0.7). However, N-myc (p = 0.005) as well as deletion 1p (p = 0.01) were found significantly more important than di/tetraploidy. CONCLUSIONS: Biological classification of neuroblastomas should be mandatory and be the prerequisite for any risk adapted treatment. One serological and 2 biological factors could be a good standard evaluation to identify neuroblastoma patients at risk.

Adolescent↗

PubMed1995

Prognostic implications of chromosome 17p deletions in human medulloblastomas.

DNA derived from medulloblastoma biopsies was analyzed to determine if deletions of the 17p region, mutations of the TP53 gene, or amplification of the c-myc, N-myc, EGFR (epidermal growth factor receptor), or MDM2 (murine double-minute-2) genes was indicative of a poor prognosis. Loss of heterozygosity for 17p, observed in 8/28 (29%) paired samples, was associated with a shortened survival period (p = 0.045 by the logrank test). TP53 mutations occurred in 2/46 (4.3%) tumor samples. c-myc Amplification was seen in 3/43 (6.9%) cases, while none of the tumors contained amplified N-myc, EGFR, or MDM2 genes. These results demonstrate that, while only rare medulloblastomas contain TP53 gene mutations or amplification of the c-myc gene, loss of heterozygosity on chromosome 17p is indicative of a significantly worse prognosis among patients with these tumors. Further, these results provide a strong impetus for a prospective analysis of loss of heterozygosity in a cooperative group setting, which would include tumor staging, a selection of treatment modalities, and multivariate analyses.

Adolescent↗

PubMed1996

Clinical relevance of loss heterozygosity of the short arm of chromosome 1 in neuroblastoma: a single-institution study.

Neuroblastoma is characterized by a wide variability of its clinical course, and considerable effort has been made to identify factors determining outcome in this disease. In a series of 82 patients from a single institution, we have investigated the prognostic impact of multiple clinical, biological and genetic parameters. Univariate testing showed that advanced stage of disease, abdominal localization of the primary tumor, elevated urinary dopamine levels, N-myc amplification (NMA) and loss of heterozygosity of chromosome lp (LOH lp) were related to a poor outcome. Most of these parameters were strong indicators of treatment failure in children younger than 12 months of age but none of them, apart from stage, had a significant prognostic impact in patients older than 12 months at diagnosis. Interestingly, the shorter survival time associated with the presence of lp deletions or NMA appears to be more strongly linked to a poorer outcome after relapse or progression than to a shorter progression-free interval. Although different types of LOH lp have been described in neuroblastoma and may be associated with different biological features, as suggested by a different pattern of catecholamine secretion, tumors with LOH lp present an aggressive clinical behavior, regardless of the type of LOH lp. In this study, LOH lp is an indicator of poor prognosis and identifies a larger population at risk than NMA alone.

Chromosomes, Human, Pair 1↗