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PubMed1987

N-myc oncogene amplification in a patient with IV-S neuroblastoma.

Neuroblastoma (NB) is a tumor usually arising in children and young adults showing different degrees of malignancy. Recently, the presence of N-myc amplification in neuroblasts has been associated with a poor outcome in the late stages of disease (Evans's Stage IV). Until now no amplification of N-myc gene has been observed in Stage IV-S, usually considered to have a favorable prognosis. In this paper we report a case of a child affected by NB Stage IV-S showing mild N-myc gene amplification. The finding of N-myc amplification in our patient shows that such alteration of the N-myc oncogene is not necessarily correlated with a poor prognosis; in this light the role of N-myc amplification in the neoplastic process should be reconsidered.

Abdominal Neoplasms↗

PubMed1990

A comparative analysis of nuclear DNA content and N-myc gene amplification in neuroblastoma.

Nuclear DNA content and N-myc amplification have been found to have prognostic significance in neuroblastoma. To investigate the interrelationships between these two parameters, tumor samples from 18 patients with neuroblastoma were analyzed for both total DNA and N-myc gene content. Quantitative DNA analysis was performed by image analysis. Quantitative Southern blot hybridization was used to determine N-myc gene copy number and to distinguish between low level gene amplification or excess gene copies secondary to aneuploidy. Six of the 18 patients have died. Five of the six had nonaneuploid tumors, but only two of the six exhibited major N-myc amplification. Low-level amplification was detected in one Stage II patient. The authors' results suggest that neuroblastomas with N-myc amplification are a subset of nonaneuploid tumors.

Blotting, Southern↗

PubMed1992

Overexpression of c-myc by amplification of negative promoter domain.

Amplification of myc proto-oncogenes has been reported in many human malignancies, but whether the amplified genes are properly regulated has not been well studied. Transcription factors that control gene expression are of limited abundance, and we have previously shown (Johnston, R.N., and Kucey, B.L. (1988) Science 242, 1551-1554) that amplified heat shock promoter sequences can compete with natural heat shock genes for these factors, resulting in heat shock gene disregulation. To establish whether protooncogenes may also be disregulated in this manner, a previously identified negative regulatory domain from the human c-myc promoter was amplified by up to 800-fold in Chinese hamster ovary cells. The amplified cells showed up to a 14-fold increase in hamster c-myc transcript abundance when compared with controls and also displayed reduced doubling times, enhanced incorporation of tritiated thymidine, elevated growth in soft agar, and a fusiform morphology, consistent with an elevation in the degree of cellular transformation. We infer that overexpression of endogenous hamster c-myc genes in the experimental cells was elicited in trans by sequestration of an inhibitory factor or complex that bound to excess nonfunctional human c-myc promoter domains. The transcriptional inhibitory activity we detect is consistent with anti-oncogene function.

Animals↗

PubMed2025

Molecular features influencing clinical outcome of advanced HER2-positive gastric cancer receiving trastuzumab plus chemotherapy.

BACKGROUND: Less than half of the human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) patients respond to trastuzumab plus chemotherapy, and the outcomes are unsatisfactory. Understanding the underlying mechanisms remains crucial for identifying patients who are more likely to benefit from treatment. PATIENTS AND METHODS: We performed targeted DNA sequencing on paired pre-treatment and progressive tumour tissues from 22 HER2-positive advanced GC patients undergoing first-line treatment with trastuzumab and chemotherapy. Clinicopathological and genomic characteristics were assessed for the correlation with clinical outcomes. RESULTS: A performance status (PS) of 0-1 was associated with improved progression-free survival (PFS) and overall survival (OS) than a PS of 2. Poorly differentiated tumours exhibited shorter PFS than moderate or moderate-poor ones. Pre-treatment amplification of MYC or TOP2A gene was association with increased PFS, and suggested a potential benefit for OS. Patients with higher tumour mutation burden (TMB) experienced significantly worse PFS, while higher chromosome instability (CIN) appeared to be correlated with longer PFS. Compared to non-responders, responders had a higher CIN but similar TMB and intratumoural heterogeneity (ITH). PS and MYC amplification emerged as independent factors related to PFS according to multivariate survival analysis. Additionally, after treatment, TMB significantly increased in non-responders, while CIN significantly decreased in responders. CONCLUSIONS: Pre-treatment MYC amplification and PS were independently associated with clinical outcomes in HER2-positive advanced GC patients treated with first-line trastuzumab plus chemotherapy. Dynamic post-treatment changes in TMB and CIS provide valuable insights into the relationship between therapeutic response and distinct evolutionary trajectories.

Humans↗

PubMed1990

Heterogenous amplification of myc family oncogenes in small cell lung carcinoma.

One hundred forty-two foci of small cell lung carcinoma (SCLC) from 47 patients were examined for amplification of myc family oncogenes (c-myc, N-myc, and L-myc), by dot blot hybridization using formalin-fixed and paraffin-embedded materials which were resected surgically or obtained at autopsy. Some selected patients were also examined by in situ hybridization. Amplification of myc family genes was detected in 11 patients (23.4%) (c-myc in one, N-myc in five, and L-myc in five). Two of the 11 patients (one with N-myc and one with L-myc) had heterogenously amplified clones. In the patient with N-myc amplification, amplification was detected in metastatic tumors in the pancreas, lung, and pleura, but not in the liver and lymph node metastases. In the primary tumor, areas with and without N-myc amplification were seen. In the patient with L-myc amplification, although amplification was not detected in the surgically resected primary lesion, mediastinal lymph node metastatic lesions obtained at autopsy showed L-myc gene amplification. These two cases, together with previously reported evidence, suggest that myc gene amplification plays an important role in malignant progression, rather than development, of SCLC. In Stage III and IV groups, patients with over ten-fold myc gene amplification were suggested to survive for a shorter time than patients without such amplification (P = 0.06).

Aged↗

PubMed1989

Clinical value of N-myc oncogene amplification in 52 patients with neuroblastoma included in recent therapeutic protocols.

Southern blot analysis of neuroblastoma (NB) cell DNA from 52 patients (58 samples) allowed the detection of an N-myc amplification on three of the 13 BM samples and three of 13 tumor samples at diagnosis, on two of 17 tumor samples taken after induction therapy, on three of seven BM samples and two of the five local tumor samples taken after relapse. N-myc was amplified in two of the 15 patients with stage I to III NB and in 10 of the 36 patients with stage IV neuroblastoma over 1 year of age. Conclusions from the analysis are as follows: first tumor samples obtained on previously treated patients are histologically modified and detection of N-myc amplification is not accurate; consequently N-myc amplification must be defined at diagnosis. Surgical biopsies of the primary tumors can, however, be delayed and malignant cells obtained by ultrasound-guided punctures or analyzed on bone marrow samples if they represent more than 50% of the total population. Second, any attempt to define the prognostic value must be performed on a group of patients treated with a new aggressive protocol of chemotherapy; it will require a multiparametric analysis including, in particular, results of an extensive clinical staging at diagnosis and histological criteria.

Child↗

PubMed1994

c-myc oncogene amplification and cytometric DNA ploidy pattern as prognostic factors in musculoskeletal neoplasms.

The relationship between c-myc oncogene amplification in neoplastic cells as determined by means of Southern-blot analysis, and their nuclear DNA content as assessed by combined flow and image cytometry, was investigated in fresh tumor specimens from 33 patients with musculoskeletal neoplasms. Amplification, without rearrangement of the c-myc proto-oncogene, was detected in 4 out of 7 bone sarcomas and in 6 out of 26 soft-tissue sarcomas, but in none of 3 benign giant-cell bone tumors. Among the 10 cases with c-myc amplification, 2 were found to be cytometrically DNA diploid, 2 DNA tetraploid, and 6 DNA aneuploid. Conversely, there were 10 tumors displaying extremely aneuploid DNA patterns without c-myc oncogene amplification. Thus, there was no relationship between c-myc amplification and DNA ploidy; neither did the percentage of S-phase cells, as determined by means of image cytometry, correlate significantly with the occurrence of c-myc amplification. A surprising sex-bias was observed; all 6 cases of c-myc-amplified soft-tissue sarcomas occurred in females, whereas none of the 11 males with such sarcomas showed this amplification. When the clinical follow-up data of the patients were scrutinized, it was found that the DNA ploidy pattern of the neoplastic cell nuclei, in combination with the S-phase values, as well as the occurrence of c-myc amplification, yielded prognostic information, being statistically significant 2 years after the diagnosis.

Adolescent↗

PubMed1994

Amplification of N-myc gene and increase of urinary VMA and HVA in patients with neuroblastic tumors.

Neuroblastic tumor cases in our departments were evaluated in terms of the stage of the tumor, N-myc amplification, urinary vanillylamndelic acid (VMA)/homovanillic acid (HVA) and survival rate. Two asymptomatic cases, diagnosed when under a year old by mass screening, had no amplifications of N-myc but showed more than one value of urinary VMA/HVA ratio. The patients are now doing well eight years after complete excision of the neuroblastoma which had originated in the sympathetic ganglion. On the other hand, two other symptomatic cases, operated on at the ages of 3 and 5 years, showed remarkable amplifications with less than one value of urinary VMA/HVA, and died from the tumor soon after partial resection of the neuroblastoma and ganglioneuroblastoma which had originated in the adrenal gland and the sympathetic ganglion, respectively. The present monograph reports our cases and discusses prognostic factors.

Child, Preschool↗

PubMed1997

Polymerase chain reaction compared with dot blotting for the determination of N-myc gene amplification in neuroblastoma.

The magnitude of N-myc amplification (NMA) influences the treatment strategy of localized neuroblastomas. Reliable assays are therefore needed for all types of tumor samples. The aim of this comparative study of 119 tumor samples was to determine whether a polymerase chain reaction (PCR)-based assay could replace the current dot blot assay as a routine and reliable means of determining NMA. The 2 assays exhibited comparable sensitivity and were completely concordant for samples containing at least 20% neuroblastoma cells. In their present state, both assays remain semi-quantitative since an absolute quantification of the N-myc copy number in clinical samples is limited by uncertainty about the amplification level of reference cell lines and by the estimation of the proportion of malignant cells. However, PCR offers several advantages over dot blotting, such as feasibility on minute samples, simplicity, standardization, rapidity and cost effectiveness.

Cost-Benefit Analysis↗

PubMed1997

Low level c-myc gene amplification in gastric cancer detected by dual color fluorescence in situ hybridization analysis.

BACKGROUND AND OBJECTIVES: By using the dual color fluorescence in situ hybridization analysis, the amplification of c-myc gene can be detected in the tumor tissue samples obtained from patients with gastric cancer, and the relationship between the molecular cytogenetic change and the clinical stage or histological type may be clarified. METHOD: The tumor tissue samples were obtained from 21 patients with gastric cancer. Simultaneous detection of signals from the chromosome 8 centromere and c-myc gene in each cell after hybridization with appropriate probes was carried out on 50-200 tumor cells in each case. RESULTS: Chromosome 8 polysomy was found in 10 patients. The average centromere 8 copy number was significantly higher in differentiated (2.7) than in undifferentiated (2.3) types of gastric cancer. However, there was no significant difference in occurrence of polysomy 8 between early and advanced cancer. The relative gain (1.1-1.9) of c-myc copy number was found in all 21 cases. There was no significant difference in the fraction of cells with c-myc gene amplification between early (pT1) and advanced (pT2-4) carcinomas. CONCLUSION: We conclude that the present dual color fluorescence in situ hybridization of gastric cancer may be useful in the evaluation of low level c-myc gene amplification, which is difficult to detect by Southern blotting, and may be applicable to the diagnosis of early gastric cancer.

Adult↗

PubMed1993

Loss of retinoblastoma gene and amplification of N-myc gene in retinoblastoma.

We have analyzed paired samples of genomic DNA from peripheral leukocyte and primary tumor tissue from nine patients with retinoblastoma (RB) and from two RB cell lines, WERI-Rb-1 and Y79, to detect the molecular alterations of the retinoblastoma susceptibility gene (RB-1) and N-myc gene. In Southern analysis, RB-1 deletions in tumor tissues were detected in five patients (56%), one of these revealed a total loss of RB-1. N-myc amplification was found only in one (11.1%) out of nine patients. We also observed a total loss of RB-1 in WERI-Rb-1, and a more than 100-fold amplification of N-myc in Y79. The analysis of the relationship between molecular events and clinical characteristics such as age, sex, tumor laterality did not reveal any specific correlation. These results suggest that genetic backgrounds of RB in Korean patients are quite similar to those of reported cases elsewhere. The high sensitivity of our method in detecting the RB-1 loss indicates that this method can be a useful tool for initially screening a large number of tumors.

Child↗

PubMedDate not supplied

Antiblastic treatment does not affect N-myc gene amplification in neuroblastoma.

Gene amplification has been found in the genome of cells growing in vivo and/or in vitro. In cell lines with acquired multidrug resistance gene amplification has been frequently detected. Moreover, extra-copies of cellular oncogenes have been located in tumor cells in vivo; particularly N-myc gene amplification was discovered in advanced stage of neuroblastoma (NB). Neuroblastoma, a tumor of neural origin, has a high incidence in children. N-myc amplification has been demonstrated in untreated patient and a positive significant correlation with the progression of the disease has been established. In this paper we report on four NB patients treated with a polychemotherapeutic protocol and showing N-myc amplification. One patient examined before and after treatment displayed a slight change in N-myc gene copy numbers. It was shown that N-myc gene amplification is not affected by drug activities and that minimal residual of cells bearing N-myc amplification may remain in the tumor mass. N-myc amplification can also cause advantageous cell growth in the presence of drugs. The implications in the pharmacologic management of NB patient showing N-myc gene amplification is discussed.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1997

Quantitation of HER-2/neu and c-myc gene amplification in breast carcinoma using fluorescence in situ hybridization.

HER-2/neu and c-myc amplification or overexpression have been reported to be associated with poor prognosis in breast carcinoma. The prognostic significance, however, remains somewhat controversial, partly because of discrepancies among different methodologies used for detection of the oncogene amplification or overexpression. Fluorescence in situ hybridization (FISH) has recently been shown to be a useful technique for analyzing genetic alterations in interphase nuclei in various tumors. In this study, FISH was used to quantitate HER-2/ neu and c-myc gene amplification in touch preparations of frozen tissue from 100 node-negative breast carcinomas. HER-2/neu amplification was found to be associated with an abnormal DNA index (P < .001) and tumor size (P < .04). Amplification of c-myc was associated with S phase (P < .0003), abnormal DNA index (P < .003), and a negative estrogen receptor status (P < .01). The coamplification of both oncogenes was strongly associated with an abnormal DNA index (P < .0001) and with tumor size (P < .009). The use of FISH for detection of HER-2/neu gene amplification was 92% concordant with immunocytochemistry (ICC) used for detection of overexpression of HER-2/neu protein. Fifteen of the 100 cases were both amplified for HER-2/neu by FISH and positive by ICC analysis. Seven cases without HER-2/neu gene amplification demonstrated HER-2/neu protein overexpression by ICC. One HER-2/neu-amplified case was negative by ICC. Repeat analysis of a subset of cases showed FISH to be a more reproducible method than ICC in the analysis of HER-2/neu in touch preparations of breast carcinoma. FISH is a rapid and reproducible method that allows the accurate measurement of the level of oncogene amplification within interphase nuclei. The use of FISH should provide a more accurate assessment of the prognostic significance of oncogene amplification in breast carcinoma.

Breast Neoplasms↗

PubMed1994

Estradiol receptors in combination with neu or myc oncogene amplifications might define new subtypes of breast cancer.

Amplifications of neu and c-myc were evaluated in 218 and 145 breast cancers (BC), respectively. Oncogene amplifications were determined for the most part by Southern blot. An association between the proportion of nodes affected and the intensity of neu amplification in estadiol receptor negative (ER-) BC was found (P = 0.028), which was confirmed by the multi-factor analysis of variance (P = 0.05). A significantly greater incidence in neu amplifications among BC with metastases was also found (P = 0.031). A strong association (P = 0.01) between the neu and myc amplification was observed. There is a strong association between myc amplification and ER- BC (P < 0.01). It is concluded that (1) the combination ER- with neu amplification might define a new group of more aggressive BC, as is suggested by their associated nodal involvement; (2) the linkage of myc amplifications with ER- BC and high grade of neu amplification might reflect a trait of tumor aggressivity.

Adult↗

PubMed1993

Amplification of N-myc as a prognostic marker for patients with neuroblastoma.

N-myc is amplified between 5 and several hundred-fold frequently in neuroblastomas and, at lower frequency, in other human cancers with neuronal qualities, including retinoblastomas, gliomas, astrocytomas and small cell lung cancers. In neuroblastomas N-myc amplification is significantly correlated with poor prognosis; for other types of tumors such a correlation is difficult to make, due to low incidence of amplification. Amplification is associated with elevated expression, both of mRNA and protein. N-myc encodes two polypeptides of relative masses of 62 and 64 kDa, which are phosphorylated, at least in vitro, by casein kinase II and that are localized in the nucleus. There they can associate in vivo with another protein, Max, through a C-terminal dimerization motif, the leucine zipper. An N-terminal portion of N-myc, referred to as 'Myc-boxes', can substitute for the transcription-activating function of the yeast transcription factor Gal 4, thus raising the possibility that N-myc itself may act as a transcription factor, either alone or in association with other factors.

Animals↗

PubMed1993

Combined determination of N-myc oncogene amplification and DNA ploidy in neuroblastoma. Complementary prognostic indicators.

BACKGROUND: N-myc gene amplification is a well-established prognostic indicator in neuroblastoma. Flow cytometric analysis of nuclear DNA content has shown that an abnormal nuclear DNA content in neuroblastoma is associated with a better prognosis. Because some patients with N-myc unamplified tumors have a poor prognosis, factors other than N-myc amplification may play a role in determining the clinical behavior of neuroblastoma. In the current study, the authors correlated N-myc gene amplification and flow cytometric nuclear DNA content with respect to prognosis. METHODS: Forty-one patients with neuroblastoma, including 15 screened patients, served as subjects. The copy number of the N-myc gene was determined by Southern blot analysis. DNA ploidy analysis was done on nuclei isolated from formalin-fixed, paraffin-embedded blocks. RESULTS: Of 40 specimens of neuroblastoma, 7 involved tumors containing amplification of the N-myc gene and 33 did not; 13 specimens showed DNA diploidy, and 27 showed DNA aneuploidy (including 4 with DNA tetraploidy). The Kaplan-Meier survival analysis indicated a significantly better prognosis in patients with unamplified N-myc tumors compared with those with N-myc amplified tumors (87.3% versus 28.6%, P < 0.05) and in patients with DNA aneuploid tumors compared with those with DNA diploid tumors (96.3% versus 43.0%, P < 0.001). The difference in the survival of the two extreme combinations, (e.g., 25 with N-myc unamplified and DNA aneuploidy [4 tetraploidy] versus 5 with N-myc amplified and DNA diploidy) was more significant (96.0% versus 20.0%, P < 0.001) than any other combination. CONCLUSION: Evaluations of N-myc gene amplification and DNA ploidy are complementary, and the combined determination of these two factors may be one of the most powerful prognostic indicators in neuroblastoma.

Child, Preschool↗

PubMed1992

Frequent amplification of c-myc in ground squirrel liver tumors associated with past or ongoing infection with a hepadnavirus.

Persistent infection with hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC) in humans. HCC has also been observed in animals chronically infected with two other hepadnaviruses: ground squirrel hepatitis virus (GSHV) and woodchuck hepatitis virus (WHV). A distinctive feature of WHV is the early onset of woodchuck tumors, which may be correlated with a direct role of the virus as an insertional mutagen of myc genes: c-myc, N-myc, and predominantly the woodchuck N-myc2 retroposon. In the present study, we searched for integrated GSHV DNA and genetic alterations of myc genes in ground squirrel HCCs. Viral integration into host DNA was detected in only 3/14 squirrel tumors and did not result in insertional activation of myc genes, despite the presence of a squirrel locus homologous to the woodchuck N-myc2 gene. This suggests that GSHV may differ from WHV in its reduced ability to induce mutagenic integration events. However, the high frequency of c-myc amplification (6/14) observed in ground squirrel HCCs indicates that myc genes might be preferential effectors in the tumorigenic processes associated with rodent hepadnaviruses, a feature not reported so far in HBV-induced carcinogenesis. Together with previous observations, our results suggest that hepadnaviruses, despite close genetic and biological properties, may use different pathways in the genesis of liver cancer.

Animals↗

PubMed1994

Prognostic prediction in neuroblastomas: clinical significance of combined analysis for Ha-ras p21 expression and N-myc gene amplification.

Ha-ras p21 expression and N-myc gene amplification were examined in 69 neuroblastomas and their clinical significance was analyzed retrospectively. Thirty-nine (89%) of forty-four patients who survived for more than 2 years after diagnosis showed high Ha-ras p21 expression, whereas 19 (76%) of 25 patients who died of progressive disease showed low Ha-ras p21 expression in their tumors. Although all 14 patients whose tumors exhibited N-myc gene amplification died of the disease, 11 other patients (56%) who died did not exhibit N-myc gene amplification. When we considered both low Ha-ras p21 expression and N-myc gene amplification as risk factors, 23 (92%) of the 25 patients who died had at least one of the two and thus could have been predicted to be high-risk patients at diagnosis. The combined analysis of the two factors should provide more accurate information pertinent to patient care.

Child, Preschool↗