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PubMed2003

Localised and unresectable neuroblastoma in infants: excellent outcome with low-dose primary chemotherapy.

The purpose of this study was to evaluate the efficacy of low-dose chemotherapy in infants with localised and unresectable neuroblastoma (NB). All consecutive infants with localised NB and no N-myc amplification were eligible in the SFOP-NBL 94 study. Primary tumour was deemed as unresectable according to imaging data showing any risk of immediate resection. Diagnostic procedures and staging were conducted according to INSS recommendations. For children, provided that they had no threatening symptom (i.e. vital risk or dumb-bell NB with neurologic deficit), chemotherapy consisted in low-dose cyclophosphamide (5 mg(-1)kg day(-1) x 5 days) and vincristine (0.05 mg kg(-1) at day 1)-CV and repeated one to three times every 2 weeks until surgical excision can be safely performed. No postoperative treatment was given. Between January 1995 and December 1999, 134 consecutive infants with localised NB were registered in the study, of whom 39 had an unresectable NB without N-myc amplification. Among them 28 had no threatening symptom and received CV according to the protocol. Objective response was observed in 14 (50%) and the other 14 were given second-line chemotherapy because of no response. Surgery was attempted in 38 patients including 14 after CV alone, leading to complete resection in 23. Relapses occurred in four patients all local. Survival and event-free survival were 100 and 90+/-5% with a median follow-up of 55 months (range 33-93). In conclusion primary low-dose chemotherapy without anthracyclines is efficient in about half of the infants presenting with an unresectable NB and no N-myc amplification, allowing excellent survival rates without jeopardising their long-term outcome even for nonresponding patients who received standard regimen.

Antineoplastic Agents↗

PubMed1994

Overexpression of c-myc precedes amplification of the gene encoding dihydrofolate reductase.

An experimentally inducible model system was generated in which Chinese hamster ovary cells (CHO-9) were stably transfected with an inducible c-myc cDNA. The induction of c-myc in these transfectants is followed by the enhanced binding of c-Myc/Max-containing protein complexes to 5'flanking E-box sequences of the gene encoding dihydrofolate reductase (DHFR). Moreover, DHFR is transiently amplified. The inappropriate overproduction of the oncoprotein, therefore, seems to plays a role in induced DHFR amplification.

Animals↗

PubMed1999

Utility of fluorescence in situ hybridization in pancreatic ductal adenocarcinoma.

Often the diagnosis of pancreas cancer needs to be established from limited cytology specimens or small biopsies. Most ductal adenocarcinomas are histologically well to moderately differentiated and mimicked closely by pancreatitis, and therefore the microscopic diagnosis can be difficult. In addition, there appears to be significant heterogeneity in the outcome of the patients with pancreatic cancer, which cannot be predicted accurately by current prognosticators such as the grade and stage of the tumor. Therefore, there is need for methods that can be used as adjuncts to routine diagnostic and prognostic parameters. This study was designed to test the utility of the fluorescent in situ hybridization (FISH) method in identifying the molecular alterations, particularly the ones that have been detected with relatively high frequency in pancreas cancer. Formalin-fixed and paraffin-embedded tissues of 10 cases were enumerated for chromosome 7, 8, 17, 18, and 20 copy numbers by using alpha-satellite probes, and for c-myc by using a gene-specific probe. The number of signals per nucleus (reflecting chromosomal copy number and status of c-myc amplification) were counted in more than two areas containing 50-500 cells. Because of tumor heterogeneity, monosomy (loss of one chromosome copy) was defined arbitrarily as one signal in >25% of nuclei. C-myc amplification was defined as more than two gene copies in >20% of the cells. The most frequent signal losses were found in chromosomes 8 (four of 10 cases) and chromosome 17 (four of 10), followed by 20 (three of 10) and 18 (two of 10). No loss of chromosome 7 was detected. In contrast, gains in chromosome copy number were identified in only one of 10 tumors, which showed gain of both chromosome 7 and 18. Amplification of c-myc gene was detected in two of 10 cases, but neither of the two had aneuploidy for chromosome 8, where the c-myc gene is located. In addition, loss in c-myc signal was observed in one case that also showed loss of chromosome 8 copy number. FISH can be used to detect chromosomal changes in pancreatic cancer; abundance of lytic enzymes in this organ is not an impediment for the applicability of this technique. Therefore it can potentially be used in the future as an adjunct to the conventional diagnostic and prognostic markers. This study confirms that loss of chromosomes, particularly chromosomes 17 and 18, which carry the p53 and DCC genes, are common in pancreas cancer. Chromosome 20 is also frequently lost. In addition, in this study, alterations of chromosome 8, which is seen commonly in prostatic adenocarcinoma but has not been previously documented in pancreatic cancer, also was detected in five of 10 tumors. Furthermore, amplification of the c-myc gene, which is located in chromosome 8, was found in the two of the remaining five cases. Further studies are needed to confirm this high incidence of chromosome 8 and c-myc alterations and their possible role in the pathogenesis of pancreatic adenocarcinoma.

Adenocarcinoma↗

PubMedDate not supplied

Chromosome 8 numerical aberration and C-MYC copy number gain in bladder cancer are linked to stage and grade.

Chromosome 8 aberration and c-myc amplification have been suggested as playing important roles in the development of different human cancers. Using fluorescence in situ hybridization (FISH), chromosome 8 polysomy and c-myc amplification can be detected in cells from bladder cancer. We investigated the correlation of chromosome 8 polysomy, c-myc gene alteration and p53 deletion with histopathological parameters. Twenty-four tumors obtained from patients with bladder cancer were analyzed by interphase cytogenetics using FISH with chromosome 8 and 17 centromere probes together with an YAC clone covering the c-myc locus and three cosmid DNA probes covering the p53 locus. Chromosome 8 polysomy was found in 12 tumors. The average copy number of chromosome 8 centromere signals were significantly higher in high grade and stage, cancers. Also the c-myc copy gain and p53 deletion were significantly correlated with grade as well as stage (p<0.05, in both cases). Both polysomy 8 and c-myc copy gain were significantly correlated with p53 deletions (p<0.01) and DNA ploidy (p<0.001). On the contrary there was no significant correlation between c-myc protein over-expression and c-myc gene amplification. These results may indicate that alteration of chromosomal regions on 8q and 17p, including c-myc and p53 genes, may be linked to progression of bladder cancer.

Carcinoma, Transitional Cell↗

PubMed2006

Medulloblastoma: histopathologic and molecular markers of anaplasia and biologic behavior.

Large cell/anaplastic (LC/A) medulloblastoma (MB) is a recently recognized variant of medulloblastoma known to be associated with an advanced stage and a poor prognosis. Although Eberhart et al. suggested histopathologic grading of medulloblastoma in 2002, no consensus has been reached in terms of determining the criteria of an LC/A variant, and its biological behavior continues to be the subject of debate. We retrospectively analyzed 74 cases (range 0.25-15 years) of MB clinicopathologically using the criteria established by Eberhart et al. The LC/A variant was identified in 16 cases (22% of MB cases), five of which showed a poor outcome. Most LC/A variant cases revealed synaptophysin immunoexpression (75%), but no epidermal growth factor receptor (EGFR) expression. Expression of synaptophysin, NeuN, GFAP, p53, c-erbB2, and EGFR did not differ in LC/A and non-LC/A variants. Seven of the 74 cases of medulloblastoma showed erbB2 amplification by FISH, four of which were LC/A variants. N-myc amplification was observed in only one LC/A variant, but no c-myc amplification was found. In patients younger than 10 years, the LC/A variant showed a significantly poorer outcome than the non-LC/A variant (P = 0.02), while no difference was found in older patients. Multivariate analysis revealed only metastasis on MRI and p53 expression, but not anaplasia as unfavorable prognostic factors. Our study suggests that prognostic implications of anaplasia in medulloblastoma are uncertain, and that the reproducibility of the histopathologic criteria of the LC/A variant should be reassessed before they can be applied in practical use.

Adolescent↗

PubMed2006

MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors.

To determine whether integration of human papillomavirus (HPV) DNA sequences could lead to the deregulation of genes implied in oncogenesis, we analysed the HPV integration sites in a series of nine cell lines derived from invasive genital carcinomas. Using in situ hybridization, HPV16 or 18 sequences were found at chromosome band 8q24, the localization of MYC, in IC1, IC2, IC3, IC6 and CAC-1 cells and at other sites in IC4, IC5, IC7 and IC8 cells. We then localized viral sequences at the molecular level and searched for alterations of MYC structure and expression in these cells. MYC genomic status and viral integration sites were also analysed in primary tumors from which IC1, IC2, IC3 and IC6 cells were derived. In IC1, IC2 and CAC-1 cells, HPV DNA was located within 58 kb of MYC, downstream, upstream, or within MYC. In IC3 and IC6 cells, HPV DNA was located 400-500 kb upstream of MYC. Amplification studies showed that, in IC1, IC2 and IC3, viral and MYC sequences were co-amplified in an amplicon between less than 50 and 800 kb in size. MYC amplification was also observed in primary tumors, indicating that this genetic alteration, together with viral insertion at the MYC locus, had already taken place in vivo. MYC was not amplified in the other cell lines. MYC mRNA and protein overexpression was observed in the five cell lines in which the HPV DNA was inserted close to the MYC locus, but in none of the lines where the insertion had occurred at other sites. MYC activation, triggered by the insertion of HPV DNA sequences, can be an important genetic event in cervical oncogenesis.

Carcinoma↗

PubMedDate not supplied

c-erbB-2 overexpression may be used as an independent prognostic factor for breast cancer patients.

Insight into correlations between specific gene amplification and the clinical behavior of tumors may provide new prognostic tools High c-erbB-2 expression is an early feature in some breast tumors, whereas c-myc may be involved in the development of neoplasia. After an initial flurry of excitement about their prognostic significance, controversy has arisen about their independent importance. In an attempt to solve this problem, we decided to study c-erbB-2 and c-myc amplification and overexpression in 62 unselected breast carcinomas. This was done in order to correlate them statistically with one another, as well as with other prognostic parameters. A positive correlation was discovered between c-erbB-2 amplification and overexpression (P = 0.02); however, the correlations between c-erbB-2 amplification and c-myc amplification and overexpression (P = 0.06 and P = 0.095 respectively) were found to be negative. In addition, no correlation was found to exist between c-erbB-2 amplification and Cathepsin-D, steroid receptors, node status and menopausal status, as well as between c-erbB-2 overexpression and Cathepsin-D, node invasiveness, tumor status, grade or menopausal status. In conclusion, the c-erbB-2 overexpression has positive correlation with only a few other prognostic parameters, and therefore can be used as an independent prognostic factor.

Breast Neoplasms↗

PubMed2002

Neuroblastoma: a single institution's experience with 128 children and an evaluation of clinical and biological prognostic factors.

Between 1985 and 1999, 128 children with neuroblastoma were treated at the Royal Alexandra Hospital for Children. The objective of this retrospective study was to report on a single institution's experience with neuroblastoma and to evaluate clinical and biological prognostic factors using univariate and multivariate assessment. Fifty-two percent presented with localized disease, 41% had stage IV disease, and 7% had stage IVs disease. The 5-year overall survival rate was 65%. Significant prognostic factors in univariate analysis included stage, site, histology, N-myc amplification, neuron-specific enolase (NSE), lactate dehydrogenase (LDH), and urinary dopamine. In multivariate assessment, the adjusted hazard ratio was 3.5 (95 %CI 1.4-8.5) for N-myc amplification, 8.7 (95% CI 3.0-25) for NSE > 300 ng/mL, and 3.6 (95% CI 1.3-10) for-LDH > 3000 U/L. This study confirmed that survival was heavily influenced by closely interrelated clinical and biological factors. Prospective studies including more recently identified molecular prognostic factors are warranted to predict the biological heterogeneity of neuroblastoma.

Adrenal Gland Neoplasms↗

PubMed1997

Correlation between morphologic and nonmorphologic prognostic markers of neuroblastoma.

Morphologic (Shimada classification--SC, original and modified histologic grades--OHG and MHG) and nonmorphologic (serum LDH, 1 p del, DNA index, N-myc copy number, telomerase activity, and expression of MRP, MDR1, and TRK) prognostic markers for NB have been reviewed. The functional role of these nonmorphologic markers in the development and progression of this disease include abnormal cell proliferation, resistance to chemotherapeutic agents, and induction of apoptosis. A statistically significant association between high OHG/MHG (grade 3), DNA index of 1 (diploidy), > 1 copy of N-myc per haploid genome and serum LDH of > or = 1500 IU/1 (p < 0.001 for each) has been described. In SC, undifferentiated histology and high MKI are associated with N-myc amplification. However, a lack of correlation between morphology and N-myc amplification has been found in localized NB. Confirmation of these observations must now be obtained on larger numbers of prospectively studied cases. Data on correlation for various prognostic markers could provide guidelines for identification of subsets of NB having strongly significant, readily determinable, reproducible, and relatively inexpensive prognostic markers that could ultimately be used to design an algorithm for risk-specific therapy.

Biomarkers, Tumor↗

PubMed1993

Human neuroblastoma cell lines that express N-myc without gene amplification.

BACKGROUND: About one half of aggressive neuroblastomas lack N-myc amplification. Cell lines from such tumors are needed to determine the biological basis of aggressive tumor behavior. METHODS: Neuroblastoma cell lines were established from a primary tumor (SMS-LHN) and a bone marrow metastasis (LA-N-6) of two children with Stage IV neuroblastoma. Although both cell lines and their original tumors lacked N-myc genomic amplification, these patients died of progressive disease. RESULTS: SMS-LHN and LA-N-6 can be distinguished from primitive neuroectodermal tumor (PNET) lines by cell surface antigen expression and catecholamine production. Cytogenetic analysis of each cell line revealed unique genetic rearrangements, whereas both lines showed abnormalities involving chromosome 2. Neither cell line contained double-minute chromosomes, homogeneously staining regions, a 1p chromosomal deletion, or t(11;22). The growth rates of these two new lines in vitro and in vivo (as xenografts in nude mice) are slower than N-myc amplified neuroblastoma lines. Both lines express greater amounts of N-myc RNA and protein relative to nonneuroblastoma cell lines (including PNET), although not to the extent of cell lines with N-myc genomic amplification. CONCLUSIONS: The relatively large amount of N-myc expression in these two new cell lines suggests that N-myc expression without amplification could play a role in the pathogenesis of some neuroblastomas. These cell lines should be useful for investigating mechanisms and consequences of N-myc gene activation other than genomic amplification.

Antigens, Neoplasm↗

PubMedDate not supplied

CD44 expression in neuroblastoma and related tumors.

PURPOSE: A retrospective study was conducted to investigate the relationship between CD44 expression in neuroblastoma and related tumors and other known prognostic indicators. MATERIALS AND METHODS: Immunostaining of CD44 was done on surgical specimens of 55 cases (42 patients) of neuroblastoma (NB) and ganglioneuroblastoma (GNB) and nine cases of ganglioneuroma. The percentage of positive tumor cells was scored semiquantitatively (0-4+) by two observers. CD44 expression was then correlated with survival, age, stage, and N-myc amplification. RESULTS: Fifty-seven percent of the patients with NB or GNB had heterogeneous positive staining (2-4+) on their diagnostic specimens. Twenty-four percent of the patients had no staining for CD44, and 19% had 1+ staining. In the 17 cases with N-myc analysis, an inverse relationship was demonstrated between N-myc and CD44 expression by univariate analysis. Lack of expression of CD44 was highly associated with poor survival (p = 0.0002). When assessing the joint effects of age, stage, and CD44 in multivariate analysis, the effect of CD44 remains significant (p = 0.028) and appears to be independent of age and stage. CONCLUSION: Our data suggest a relationship between CD44 and N-myc amplification. Absence or low expression of CD44 correlates with poor survival and may be a biologic marker of tumor aggressiveness. CD44 appears to be an independent prognostic marker and deserves continued investigation in prospective studies of neuroblastoma.

Adolescent↗

PubMed2003

Cytogenetic, spectral karyotyping, fluorescence in situ hybridization, and comparative genomic hybridization characterization of two new secondary leukemia cell lines with 5q deletions, and MYC and MLL amplification.

Cytogenetic studies of patients with therapy-induced acute myeloid leukemia (t-AML) have demonstrated whole chromosome loss or q-arm deletion of chromosomes 5 and/or 7 in a majority of cases. We have established two cell lines, SAML-1 and SAML-2, from two patients who developed t-AML after radiation and chemotherapy for Hodgkin disease. In both cases, the leukemia cells contained 5q deletions. SAML-1 has 58 chromosomes and numerous abnormalities, including der(1)(1qter-->1p22::5q31-->5qter), der(5)(5pter-->5q22::1p22-->1pter), +8, der(13)i(13)(q10)del(13)(q11q14.1), and t(10;11). Fluorescence in situ hybridization (FISH) with unique sequence probes for the 5q31 region showed loss of IL4, IL5, IRF1, and IL3, and translocation of IL9, DS5S89, EGR1, and CSFIR to 1p. SAML-2 has 45 chromosomes, del(5)(q11.2q31) with a t(12;13)ins(12;5), leading to the proximity of IRF1 and RB1, and complex translocations of chromosomes 8 and 11, resulting in amplification of MYC and MLL. Comparative genomic hybridization and spectral karyotyping were consistent with the G-banding karyotype and FISH analyses. Because a potential tumor suppressor(s) in the 5q31 region has yet to be identified, these cell lines should prove useful in the study of the mechanisms leading to the development of t-AML.

Acute Disease↗

PubMed2025

Targeting the MYC oncogene with a selective bi-steric mTORC1 inhibitor elicits tumor regression in MYC-driven cancers.

The MYC oncogene is causally involved in the pathogenesis of most human cancers. The mTORC1 complex regulates MYC translation through 4EBP1 and S6K. However, agents that selectively target mTORC1 (without affecting mTORC2) have so far failed to reactivate 4EBP1 and, thus, cannot effectively suppress MYC in vivo. In contrast, nonselective inhibitors that block both mTOR complexes can activate 4EBP1, but often lack tolerability and induce immunosuppression. Here, we introduce bi-steric mTORC1-selective inhibitors, including the clinical candidate RMC-5552, which potently reactivate 4EBP1 and decrease MYC protein expression levels. Consequently, suppression of MYC signaling occurs, resulting in tumor growth inhibition through both direct effects on tumor cells and immune activation. RMC-5552 exhibits anti-tumor activity in human patient-derived xenografts models harboring genomic MYC amplifications and reduces MYC protein levels in vivo. Furthermore, bi-steric mTORC1-selective inhibitors enhance the efficacy of immune checkpoint blockade, leading to tumor regression.

Mechanistic Target of Rapamycin Complex 1↗

PubMed1991

High levels of p19/nm23 protein in neuroblastoma are associated with advanced stage disease and with N-myc gene amplification.

The gene encoding a novel protein designated nm23-H1, which was recently identified as identical to the A subunit of nucleotide diphosphate kinase from human erythrocytes, has been proposed to play a role in tumor metastasis suppression. We report that untreated neuroblastoma tumors contain a cellular polypeptide (Mr = 19,000) designated p19, identified in two-dimensional electrophoretic gels, which occurs at significantly higher levels (P = 0.0001) in primary tumors containing amplified N-myc gene. The partial amino acid sequence obtained for p19 is identical to the sequence of the human nm23-H1 protein. An antibody to the A subunit of erythrocyte nucleotide diphosphate kinase reacted exclusively with p19. In this study, significantly higher levels of p19/nm23 occurred in primary neuroblastoma tumors from patients with advanced stages (III and IV) relative to tumors from patients with limited stages (I and II) of the disease. Even among patients with a single copy of the N-myc gene, tumors from patients with stages III and IV had statistically significantly higher levels of p19/nm23 than tumors from patients with stages I and II. Our findings indicate that, in contrast to a proposed role for nm23-H1 as a tumor metastasis suppressor, increased p19/nm23 protein in neuroblastoma is correlated with features of the disease that are associated with aggressive tumors. Therefore, nm23-H1 may have distinct if not opposite roles in different tumors.

Amino Acid Sequence↗

PubMed1992

Prognostic factors in human primary breast cancer: comparison of c-myc and HER2/neu amplification.

Amplification of oncogenes in primary tumours may have prognostic and/or therapeutic significance for patients with breast cancer. We have studied HER2/neu and c-myc amplification together with steroid receptors in human primary breast tumours and related the outcome with (relapse-free) survival. A strong inverse correlation was found between HER2/neu amplification and the presence of oestrogen and progesterone receptors. Actuarial 5-years survival showed that breast cancer patients with c-myc amplification in their primary tumours experience a shorter relapse-free survival, especially in node-negative and in receptor-positive tumours, whereas HER2/neu amplification may be of prognostic value for overall survival in receptor-negative tumours. Overall, in our hands, c-myc amplification appeared to be a more potent prognosticator than HER2/neu amplification in human primary breast cancer.

Breast Neoplasms↗

PubMed1998

A novel myeloid cell line, Marimo, derived from therapy-related acute myeloid leukemia during treatment of essential thrombocythemia: consistent chromosomal abnormalities and temporary C-MYC gene amplification.

A novel myeloid leukemia cell line, Marimo, was established from bone marrow cells of a patient with secondary acute myeloid leukemia (AML) that had developed during the treatment of essential thrombocythemia (ET) with busulfan. Karyotype at the ET phase was 46,XX,der(15)t(1;15) (q23;p12-13), but at the blastic phase changed to 44,XX,-5,del(8)(q22), add(17)(p11),+18, psu dic(18;9) (q23;p21) x 2 lacking t(1;15). In Marimo cells, C-MYC gene was temporarily amplified by double-minutes (dmin) but disappeared at 33 months, whereas t(10;14;11)(q22;q32;q13) and t(10;14)(q22;q32) were added in vitro psu dic(18;9) x 2 and add(17)(p11) were consistently found throughout the culture. These results suggest that this AML clone is not derived from ET but rather is therapy-related.

Cell Line↗

PubMedDate not supplied

Expression of type I interferon receptor and its relation with other prognostic factors in human neuroblastoma.

Expression of type I interferon receptor (IFN-R) has been found in several normal tissues and in malignant neoplasms, mainly those with epithelial differentiation. In order to analyze the immunohistochemical expression of type I IFN-R we studied 79 cases of neuroblastoma. Results of expression of type I IFN-R were statistically correlated with histopathology, stage, bcl-2 and PCNA expression, N-myc amplification and apoptosis. We found expression of type I IFN-R in 54/79 cases showing statistical correlation with bcl-2 expression (P=0.017) and favourable histopathology (P=0.015). The overexpression found in ganglion cells suggests that IFN-R could be involved in the pathway of neuroblastoma differentiation. Moreover, the expression of type I IFN-R in stage 4 cases (12/20), even with N-myc amplification (6/8), opens new possibilities for therapeutic management in advanced cases that do not respond to any chemotherapeutic protocol.

Apoptosis↗

PubMed2003

c-myc down-regulation induces apoptosis in human cancer cell lines exposed to RPR-115135 (C31H29NO4), a non-peptidomimetic farnesyltransferase inhibitor.

A therapeutic strategy that relies on the use of c-myc antisense in combination with a farnesyltransferase inhibitor, RPR-115135 (C31H29NO4), was studied in human cancer cell lines carrying different mutations (Ras, p53, myc amplification). Cell proliferation was strongly inhibited by the combination and was observed when c-myc oligo (at a concentration that down-regulates c-myc expression) was followed by RPR-115135. Cell cycle analysis demonstrated an accumulation in G0-G1 phase and a tendency to apoptosis (not detectable in cells treated with a single agent). Morphological examination and DNA fragmentation assays (filter binding and enzyme-linked immunosorbent assay DNA fragmentation) confirmed the induction of apoptosis. Apoptosis was not p53- and/or p21(waf-1)-dependent, and the key effector was caspase activation. The combination induced Bax expression and Bcl-2 inhibition. Down-regulation of c-myc amplification carried out a specific role exclusively when Ras was mutated. Exposure of human proliferating lymphocytes to combination did not result in cytotoxicity, suggesting that mechanisms regulating c-myc gene expression during normal T cell proliferation might not be involved. Because of the high percentage of human tumors overexpressing c-myc mRNA and/or protein and, simultaneously, harboring oncogenic Ras mutants (i.e., colon cancers), interrupting the myc- and Ras-signaling pathway would be one of the major focuses on therapy of these types of tumors.

Alkyl and Aryl Transferases↗