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PubMed1996

[Molecular biology markers of neuroblastoma as the basis for a therapy concept].

Molecular biological markers that influence prognosis should be considered in the optimization of therapy for disseminated forms of neuroblastoma. Some of these markers include: N-myc amplification, deletion of 1p36, ploidy, and trk expression. Neuroblastoma without N-myc amplification and high trk expression show a favorable outcome and would enable a more gentle chemotherapy treatment. Neuroblastomas with N-myc amplification and lack of trk expression behave extremely unfavorably and require an even more intensive treatment.

Adult↗

PubMed2002

Double minute chromosomes in acute myeloid leukemia and myelodysplastic syndrome: identification of new amplification regions by fluorescence in situ hybridization and spectral karyotyping.

Double minute chromosomes (dmin) are small chromatin bodies consisting of genes amplified in an extrachromosomal location. dmins are uncommon in hematologic malignancies; they are seen primarily in acute myeloid leukemia, with amplification of the MYC oncogene or, less frequently, the MLL transcription factor. Nine patients with hematologic malignancies with dmin were seen at the Roswell Park Cancer Institute between 1985 and 2000; eight had acute myeloid leukemia and one a myelodysplastic syndrome. Fluorescence in situ hybridization (FISH) demonstrated MYC amplification on dmin in four patients, but MLL amplification was not seen. Spectral karyotyping showed that the dmin derived from chromosome 11 in one patient and from chromosome 19 in two others without MYC or MLL amplification; derivation from these chromosomes was confirmed by FISH with chromosome paint probes. The dmin of chromosome 11 origin hybridized to a bacterial artificial chromosome (BAC) RP11-112M22 that maps to 11q24.3 and is predicted to contain ETS1 and other markers, including D11S11351 and D11S4091. The dmin of chromosome 19 origin in one patient hybridized to BACs RP11-46I12 and RP11-110J19; in the other patient, these clones did not hybridize with the dmin, but were found to be amplified on a marker chromosome that was derived from chromosome 19 in that patient's cells. These BACs have been mapped to 19q12-19q13.1 and 19q11-19q13.1, respectively, and are predicted to contain the markers D19S409 and D19S919 and the gene for ubiquinol-cytochrome C reductase, Rieske iron-sulfur polypeptide1 (UQCRFS1). dmin originating from chromosome 19 have not been reported previously in hematologic malignancies.

Adult↗

PubMed1996

Detection of c-myc oncogene amplification in a CML blastic phase patient with double minute chromosomes.

Double minute chromosomes (dmin) are relatively rare in leukemias. Cytogenetic analysis of blood cells from a woman with blastic phase chronic myelogenous leukemia (BC-CML) showed numerous dmin chromosomes and complex abnormalities including a Philadelphia (ph(1))-chromosome. Oncogene amplification in hematopoietic malignancies is also rare. Using PCR, we retrospectively investigated the extent of c-myc gene amplification in DNA extracted from stored blood smears from the patient. To qualify the PCR products, the beta-globin gene was used as the internal reference gene and it was co-amplified with the c-myc gene. The extent of amplified c-myc was about 6.8-fold. This finding suggests that the c-myc gene was amplified in dmin and that the gene amplification contributes to the progression to acute leukemia or rapid growth of leukemic cells.

Base Sequence↗

PubMed1990

N-myc gene amplification in neuroblastoma is associated with altered phosphorylation of a proliferation related polypeptide (Op18).

We have recently identified and cloned the gene for a cytosolic polypeptide, designated oncoprotein 18 (Op18), which is expressed in acute lymphocytic leukemia and some solid tumors including neuroblastoma. Op18 is phosphorylated upon treatment of lymphoid cells with phorbol myristate acetate. We have proposed that unphosphorylated Op18 plays a role in cellular proliferation, and that its phosphorylated forms, namely Op18a and Op18b, are associated with diminished cell proliferation. In this study, we report that in neuroblastoma tumors, the phosphorylation of Op18 was substantially diminished with increasing N-myc gene copy number. Treatment of the neuroblastoma cell line SMS-KCNR, which contains 75 copies of the N-myc gene, with retinoic acid for ten days resulted in an increase in Op18 phosphorylation. Our findings provide evidence for distinct patterns of Op18 phosphorylation in neuroblastoma tumors with and without N-myc gene amplification.

Cell Division↗

PubMed2002

Comparative genomic hybridization detects an increased number of chromosomal alterations in large cell/anaplastic medulloblastomas.

We correlate chromosomal changes in medulloblastomas with histologic subtype, reporting the analysis of 33 medulloblastoma specimens by comparative genomic hybridization, and a subset by fluorescence in situ hybridization. Of the 33 tumors, 5 were desmoplastic/nodular, 10 were histologically classic, and 18 were large cell/anaplastic. Chromosomal gains and losses were more common in anaplastic medulloblastomas than in non-anaplastic ones. We identified 4 medulloblastomas with c-myc amplification and 5 medulloblastomas with N-myc amplification; all 9 were of the large cell/anaplastic subtype. Additional regions with high level gains included 2q14-22, 3p23, 5p14-pter, 8q24, 9p22-23, 10p12-pter, 12q24, 12p11-12, 17p11-12, and Xp11. The majority of these high level gains occurred in anaplastic cases. We also found loss of chromosome 17p in 7 large cell/anaplastic cases but no nonanaplastic medulloblastomas. Finally, we detected a significantly increased overall number of chromosomal alterations in large cell/anaplastic medulloblastomas (6.8/case) compared to non-anaplastic ones (3.3/case). These findings support an association between myc oncogene amplification, 17p loss, and large cell/anaplastic histology.

Adolescent↗

PubMed1997

N-Myc gene amplification is a major prognostic factor in localized neuroblastoma: results of the French NBL 90 study. Neuroblastoma Study Group of the Société Francaise d'Oncologie Pédiatrique.

PURPOSE: To assess the relevance of N-Myc gene amplification (NMA) as a prognostic factor in localized neuroblastoma (NB) and to evaluate whether less intensive adjuvant treatment is advisable in infants without NMA. PATIENTS AND METHODS: Assessment of NBs included clinical and imaging data to allow tumor-node-metastasis (TNM) staging, biologic determinations (N-Myc gene analysis), and standard histology and work-up to eliminate metastatic spread (metaiodobenzylguanidine [MIBG] scintigraphy and extensive bone marrow staging). Resectability was defined according to imaging findings. Chemotherapy was indicated in children older than 1 year at diagnosis who had postoperative residual disease or lymph node (LN) involvement, in infants with NMA, or as primary treatment in children with an unresectable NB, including dumbbell tumors. Radiotherapy was recommended in children older than 1 who presented with persistent gross residual disease at the end of therapy. RESULTS: Between 1990 and 1994, 316 consecutive children who presented with a localized NB were registered in the NBL 90 study. The median age was 12 months, and 42 patients had dumbbell tumors (13%). NMA was found in 22 of 225 assessable children (10%) and correlated with adverse prognostic indicators such as age older than 1 year, an abdominal primary tumor, a large tumor (T3), and unresectability. Among 186 children who had primary excision, five died of surgery-related complications. Primary chemotherapy was given to 130 patients, which allowed removal of the tumor in all but four. The 5-year overall survival (OS) and event-free survival (EFS) rates were, respectively, 91% and 84% with a median follow-up time of 36 months. The outcome of infants and older children was similar (P = .2). EFS of patients with resectable tumors was slightly better than with unresectable primary tumors (EFS, 89% v 78%; P = .02). In dumbbell NBs, neurologic recovery was achieved in 74% of cases that presented with symptoms, and initial laminectomy was avoided in 75% of children. In a univariate analysis, large tumors, high neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) levels, positive LNs, macroscopic residue, and NMA adversely influenced outcome. In the multivariate analysis, NMA was the most powerful unfavorable predictive indicator: OS and EFS rates for these children were 36% and 32%, compared with 98% and 90% in nonamplified tumors (P < .001). CONCLUSION: Our data confirm the overall good prognosis of localized NBs, even when unresectable. NMA is the most relevant adverse prognostic factor in localized NBs, and more intensive treatment should be investigated in these patients. Prospective studies of other biologic factors are warranted to tailor therapy more accurately. The EFS of children who underwent primary surgery was excellent, and further justifies elimination of adjuvant treatment provided they have no NMA. Despite the elimination of postoperative therapy, infants with non-NMA tumors have an excellent outcome, which suggests that initial chemotherapy can be further reduced in case of unresectable NBs.

Adolescent↗

PubMed1993

N-myc oncogene and urinary catecholamines in children with neuroblastoma.

This paper reports the analysis of N-myc amplification, urinary vanillylmandelic acid (VMA), and norepinephrine (NE) excretion and survival in 22 children with neuroblastoma and 7 with ganglio-neuroblastoma. Five patients had N-myc amplification (from 30 to more than 200 copies), all of whom had advanced-stage disease. The urinary excretion of VMA was normal in all of them, only one showed increased NE excretion. All patients with stage C-D disease and one copy of N-myc had increased VMA urinary excretion and increased (9/14) or normal (5/14) NE urinary excretion. All patients with stage A or B disease had one copy of N-myc. Half of them showed increased VMA urinary levels, while only 3/10 showed increased NE urinary values. Comparison of cumulative survival curves in relation to N-myc amplification and to VMA and NE urinary excretion showed a clear parallelism. Amplification of N-myc corresponded to normal VMA and NE urinary excretion, and was associated with the worst prognosis (P < 0.01), while increased VMA and/or NE excretion was found in patients with only one copy of N-myc.

Child↗

PubMed1995

Allelic loss of chromosome 1 and additional chromosome 17 material are both unfavourable prognostic markers in neuroblastoma.

In neuroblastoma, N-myc amplification and loss of heterozygosity for the short arm of chromosome 1 (LOH 1p) are common genetic abnormalities. We have recently shown that the presence of additional material of the long arm of chromosome 17 (add.17q) also occurs relatively frequently. In the present study, we analyzed a series of 55 tumors for LOH 1p, N-myc amplification and add.17q, using Southern blot analysis with polymorphic DNA probes of pairs of tumor and constitutional DNA. We determined the correlation of these parameters with clinical variables, such as age, stage, serum lactate dehydrogenase (LDH) and ferritin and also with outcome. LOH 1p occurred in 20 out of 55 cases (36%) and was found more often in stage III/IV tumors and in the older age group, although both correlations were not statistically significant. N-myc amplification was only demonstrated in 12 tumors with concomitant LOH 1p and was not present in the 35 cases without LOH 1p. Add.17q was found in 20/53 (38%) informative cases. LOH 1p was shown to be the most significant predictor of a poor outcome (P < 0.00001), independent of age and stage. LOH 1p is also of prognostic value in those cases without N-myc amplification, indicating a stronger prognostic value for LOH 1p. Add.17q was also associated with an unfavourable prognosis, although this was less significantly then with LOH 1p (P = 0.00004).

Alleles↗

PubMed1989

Modification of myc gene amplification in human somatic cell hybrids.

In order to study whether cell fusion would modify the DNA copy number of an amplified oncogene, somatic cell hybrids were made between the human neuroepithelioma cell line MCIXC and HeLaCOT human adenocarcinoma cells. MCIXC contains approximately 21 copies of the c-myc oncogene and HeLaCOT contains approximately 5 copies relative to the control. All hybrid clones investigated displayed a marked decrease in the number of copies of c-myc DNA (an average of 5 copies), while the level of c-myc RNA in the hybrids was similar to that found in both parents. All eight hybrid clones were found to be completely nontumorigenic even though both parent cells formed tumors in 100% of the nude mice treated by injection. This loss of oncogene amplification in the hybrids was shown not to be due to either heterogeneity of c-myc amplification in the MCIXC parent or segregation of a copy of the chromosome 22 from the hybrids. This loss most likely resulted from the breakdown of a homogeneously staining region (containing the amplified gene copies) into double minutes, which were subsequently lost from the cells. The HeLaCOT cell line was also fused to the human neuroblastoma BE(2)C, which contains approximately 123 copies of the N-myc oncogene relative to control. Ten hybrid clones were found to contain an average of 47 copies of N-myc DNA, significantly less than the 91 copies predicted had no loss occurred. These BE(2)C x HeLaCOT hybrids expressed on average about 15% the N-myc RNA seen in the BE(2)C parent and, as with the MCIXC x HeLaCOT hybrids, were found to be completely nontumorigenic. However, upon passage in culture, one BE(2)C x HeLaCOT hybrid eventually became tumorigenic. This hybrid also displayed reduced copies of N-myc DNA in comparison to its parent hybrid but surprisingly showed a 2-fold increase in N-myc RNA. Thus, the expression of N-myc, but not the amplification state of either myc gene, appears to correlate with the tumorigenicity of the cells.

Blotting, Southern↗

PubMed1998

Moderate amplifications of the c-myc gene correlate with molecular and clinicopathological parameters in colorectal cancer.

C-myc gene activation is a common event in multiple types of neoplasia and has been associated with different cellular processes relevant to the malignant transformation of cancer cells. C-myc gene amplification has been analysed in colorectal carcinomas by means of an innovative DNA fingerprinting method based on the arbitrarily primed PCR. This method requires a low amount of DNA, uses multiple internal controls and appears sensitive and reproducible. Clinicopathological and molecular correlates have been investigated in a series of 70 colorectal carcinomas. The incidence of c-myc amplification was 26%, ranging from two- to fivefold increase in copy number. C-myc amplification occurrence was more frequent in more advanced stages of tumour invasion (P < 0.001) and was associated with mutations in the p53 tumour-suppressor gene (P = 0.048). The presence of c-myc amplification was indicative of a shorter disease-free survival period but, because of its strong association with Dukes' stage, its prognostic value is questionable.

Adult↗

PubMed1992

Biology of neuroblastomas in Japan found by screening.

Between June 1983 and December 1990, cytogenetic analysis was performed on 82 neuroblastoma patients, including 41 patients found by mass screening. The N-myc copy number was determined in 77 of the 82 patients. Patients were classified into three groups: patients found by mass screening (group A) (n = 41), patients found clinically who were under 12 months of age (group B) (n = 12), and patients found clinically who were over 12 months of age (group C) (n = 29). All patients in group A had hyperdiploid (H-2n) or near-triploid (3n) karyotypes; they were all completely free of tumor for 4-84 months after diagnosis, although one patient relapsed and attained complete remission again. Among those in group B, one patient with a stage 4 tumor had a near-diploid Karyotype (2n) and N-myc amplification, and died 18 months after diagnosis. Another patient aged 2 days with a stage 4S tumor had near-diploid karyotype and N-myc amplification, and died 9 months after diagnosis. Tumors in the remaining 18 patients in group B had hyperdiploid or near-triploid karyotypes, they lacked N-myc amplification, and the patients were free of tumor for 12-89 months after diagnosis. All patients in group C except two have near-diploid or hypotetraploid karyotypes, and 21 of 29 patients died within 18 months. One 13-month-old patient (classified in stage 2) and another 7-year-old patient (stage 2) had near-triploid karyotypes and were alive at 74 and 72 months, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Gene Amplification↗

PubMed1996

Tumorigenicity of cerebellar primitive neuro-ectodermal tumors in athymic mice correlates with poor prognosis in children.

The histogenesis of medulloblastoma, also described as a cerebellar primitive neuro-ectodermal tumor (PNET), remains controversial and unresolved. In addition, genetic markers which characterize cerebellar PNETs with poor prognosis in children have not been identified. Since xenografts can be valuable tools for better understanding the genetic events involved in cerebellar PNETs, small fragments of tumor samples from 17 children with newly diagnosed cerebellar PNETs were transplanted s.c. into female athymic Swiss mice. Eleven were non-metastatic and 6 were metastatic PNETs. Eight tumors (47%) were tumorigenic. Histological analysis showed 6 typical medulloblastomas, 1 PNET with melanin pigment and 1 PNET with a rhabdoid phenotype. Wide heterogeneity was observed in tumor growth, with a doubling time ranging from 8 to 81 days after the first passage. Tumorigenicity was correlated with the metastatic phenotype of the tumor (p < 0.001). All the patients but one with a tumorigenic tumor relapsed and died. The survival of patients with a non-tumorigenic PNET (67%) was significantly higher than that of patients with a tumorigenic PNET (13%) (p < 0.02). None of the xenografts or tumors from patients exhibited N-myc-gene alteration. Only one xenograft showed c-myc amplification, with an abnormal 15-kilobase fragment. None of the 17 tumors from patients showed amplification or c-myc-gene rearrangement. In conclusion, tumorigenicity of cerebellar PNETs strongly correlates both with the metastatic phenotype of the tumors and with the disease-free survival of the patients. In addition, genetic events other than c-myc-gene amplification might be involved in cerebellar PNETs with poor prognosis.

Animals↗

PubMed2001

[A functional gene map is required to adapt therapy of metastatic neuroblastoma].

Neuroblastoma is a very common solid tumor which arises in childhood and shows an extreme heterogeneity at the clinical, histological and genetic levels. Besides age and stage, N-myc amplification and 1p deletion are prognostic factors of the disease: in Europe, these genetic markers are used to conduct therapy. In France, N-myc amplification is a factor of bad prognosis which leads, in all forms of the disease including localised forms and metastatic forms of children aged of less than 1 year, to a myeloablative treatment with autologous hematopoietic stem cells transplantation. By contrast, N-myc amplification has no impact on the survival of children aged of more than 1 year with a poor prognosis (30% overall survival, 5 years) but this genetic abnormality is taken into account to treat primary tumor of these patients. In an attempt to find out prognostic factors of these aggressive forms of the disease, various pathways (apoptosis, differentiation angiogenesis, detoxication, immune response) have been recently surveyed, but studies have been carried out on a limited number of genes. Moreover, experimental models of human metastatic neuroblastoma have been obtained in which variations of genes transcript levels involved in these pathways, are observed. The current break-through of cDNA microarrays allows to develop a dynamic transcriptomic scanning of these models as well as of tumors and bone marrows from patients upon conventional chemotherapy. This technology will enable: i) to define molecular entities of the metastatic disease; ii) to apply adapted treatment; iii) to develop new therapeutic strategies.

Age Factors↗

PubMedDate not supplied

[Risk stratification in medulloblastoma: screening for molecular markers].

BACKGROUND: The present study evaluates molecular markers for patients at risk of poor or no response to medulloblastoma. The aim of the study is to optimize therapy stratification. PATIENTS AND METHODS: 69 snap-frozen medulloblastoma samples were examined. C-MYC amplification was determined by fluorescence in situ hybridisation (FISH) analysis. Methylation specific PCR revealed the level of promoter methylation status of the tumor suppressor genes CASP8 (Caspase 8), TIMP3, CDH1 (E-Cadherin), CDKN2A (p16) and MGMT. Expression of GAS7 was evaluated by RT-PCR. RESULTS: C-MYC amplification: 4/69 tumors displayed high level amplification; 53/69 tumors displayed low level (< 4 copies) or no amplification; 12/69 samples were not predictive. In patients with c-MYC amplification a tendency towards unfavorable outcome was observed (p = 0.3). Promoter methylation status: CASP8: in 36/40 tumors methylated; TIMP3: 1/38 methylated; MGMT 0/44 methylated; CDKN2A: 1/46 methylated; E-cadherin 3/36 methylated; no association between methylation status and clinical outcome. GAS7: Detection of specific RNA in 20/29 medulloblastoma samples. CONCLUSION: No significant association between amplification of c-MYC and clinical outcome was observed. Promoter methylation of tumor suppressor genes is non-randomly distributed with a high level of methylation of CASP8. Recent studies show that silencing of CASP8 by methylation could be overcome by interferon gamma providing a possible therapeutic mechanism. GAS7 was shown to be a marker of mature neuronal cells with potential antitumorigenic capacity in neuronal tumors. In medulloblastoma 20/29 of the tumors examined express GAS7. Therefore a tumor suppressing function of GAS7 is improbable.

Biomarkers, Tumor↗

PubMed2005

Genotype-phenotype relationships in a mouse model for human small-cell lung cancer.

Lung tumors are usually classified into small-cell lung cancer (SCLC) or non-SCLC (NSCLC) depending on their pathological and histological characteristics. SCLC is defined not only by its characteristic neuroendocrine differentiation, aggressiveness, and metastatic potential, but also by a specific set of genetic aberrations, including the loss of the tumor suppressor genes p53 and Rb1 and the amplification of any member of the Myc family of oncogenes. We have previously described a mouse model of SCLC by somatic conditional disruption of Trp53 and Rb1 genes that closely resembles the human condition. Based on the possibility to study early tumor lesions and to culture and subclone progressed tumors and metastases, we discuss here a strategy to define genotype-phenotype relationships that can explain the underlying biology of lung neuroendocrine tumors. We have found that tumors may be constituted by genetically variant cell populations, which might represent different progression stages. Interestingly, we observed L-myc amplification and Ascl-1 expression in those populations showing neuroendocrine differentiation. Non-neuroendocrine cell populations from the same tumors did not show L-myc amplification nor Ascl-1 expression. We propose that this genetic divergence can play a relevant role in the definition of some phenotypic characteristics like metastasis potential or chemoresistance.

Animals↗

PubMed1997

In-111 pentetreotide scintigraphy in patients with neuroblastoma. Comparison with I-131 MIBG, N-Myc oncogene amplification, and patient outcome.

OBJECTIVE: 1. To evaluate the relative efficacy of In-111 pentetreotide and 1-131 radioiodinated meta-idobenzyl guanidine (MIBG) for detection of primary and metastatic neuroblastoma. 2. To assess the prognostic value of In-111 pentetreotide uptake. METHODS AND MATERIALS: Seven In-111 pentetreotide and seven I-131 MIBG scans were obtained in six patients with stage IV neuroblastoma and 1 with stage III ganglioneuroblastoma. Three scans were obtained at initial staging and four were obtained during therapy. Correlation was made with concomitant computed tomography scans, bone scans, N-myc oncogene amplification, and clinical outcome. RESULTS: Primary tumor was present in six patients and had been resected in 1. In-111 pentetreotide uptake was seen in two of six primary tumors, I-131 MIBG scan was positive in five of six. In-111 pentetreotide scan was positive in two of four patients with bone metastases, I-131 MIBG scan was positive in three of four. Both showed liver metastases in one patient and did not show bone marrow metastases in another. Overall sensitivity for primary or metastatic disease was 57% (four of seven) for In-111 pentetreotide and 86% (six of seven) for MIBG. Correlation between N-myc oncogene and In-111 pentetreotide uptake was seen in four of seven patients. In-111 pentetreotide uptake correlated with the clinical outcome in six patients with more than 1 year follow-up. Two patients with negative In-111 pentetreotide scans had unfavorable outcome. One patient died, and the other had local recurrence 15 months after diagnosis. Four patients with a positive scan are alive without disease on follow-up at 13-31 months after diagnosis. CONCLUSION: In-111 pentetreotide scintigraphy is less sensitive than I-131 MIBG for detecting active neuroblastoma. In-111 pentetreotide uptake on scintigraphy may correlate with the prognosis. However, a larger series of patients is needed for further evaluation.

3-Iodobenzylguanidine↗

PubMedDate not supplied

C-MYC locus amplification as metastasis predictor in intestinal-type gastric adenocarcinomas: CGH study in Brazil.

BACKGROUND: The genetic events involved in gastric cancer, the third most frequent cancer in the world with a high incidence in Pard State, Brazil, remain largely unknown. MATERIALS AND METHODS: Twenty-one primary gastric adenocarcinomas were investigated by comparative genomic hybridization (CGH) and the relationships between genomic abnormalities and histopathological features were evaluated. RESULTS: Eighty-one percent of cases presented DNA copy-number changes. Chromosomal gains were the most frequent finding, losses occurring only in the diffuse type. The main copy-number gains were on chromosome 8, principally on 8q24.1 (8/21 cases), 8p21 (3/21) and 8p23.2-8p12 (2/21). Gain of region 8q24. 1, where C-MYC is located, was the main finding, exclusively in the intestinal type with metastasis. CONCLUSION: C-MYC locus amplification may be predictor of aggressiveness in intestinal-type gastric cancer, playing an important role in its development and progression. Moreover, other genes on 8q24 should be investigated. Gastric adenocarcinomas of differing histopathological features were associated with distinct genetic alterations, supporting the hypothesis that they evolve through distinct genetic pathways.

Adenocarcinoma↗

PubMed1989

Arrangement and expression of integrated adenovirus type 12 DNA in the transformed hamster cell line HA12/7: amplification of Ad12 and c-myc DNAs and evidence for hybrid viral-cellular transcripts.

In the genome of the adenovirus type 12 (Ad12)-transformed hamster cell line HA12/7 about three copies of the viral DNA are fixed by integration. The results of blot-hybridization, molecular cloning, and nucleotide sequencing experiments suggest a model for the arrangement of Ad12 DNA molecules in which the left hand terminus of one of the Ad12 DNA copies is linked to unique hamster DNA. The right hand end of this DNA molecule is fused to an inverted copy of a left terminal approximately 4.3 kb fragment of Ad12 DNA. This ensemble is followed by the second Ad12 DNA copy whose right terminus is again joined to an inverted, supernumerary left terminal approximately 4.3 kb Ad12 DNA fragment. There is a third Ad12 DNA copy whose right terminus is linked to cellular DNA. In this sequence arrangement, the left terminus of Ad12 DNA is overrepresented, as had been shown earlier (S. Stabel, W. Doerfler and R.R. Friis (1980) J. Virol. 36, 22-40). In the presented model, cellular DNA sequences are interspersed in between the three copies of Ad12 DNA. In the left terminus of the integrated Ad12 DNA, transcription of RNA is initiated which extends out into cellular DNA. The interviral DNA junctions are also transcribed. The c-myc gene in cell line HA12/7 is amplified about 10-fold and considerably more c-myc RNA has been identified in the Ad12-transformed cells than in BHK21 or in LSH hamster cells. It has been shown previously that the E1 region of Ad12 DNA is transcribed into mRNA in HA12/7 cells (Ortin et al. (1976) J. Virol. 20, 355-372). It remains to be investigated whether c-myc amplification and expression are related to the transformed phenotype of HA12/7 cells.

Adenoviridae↗