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PubMed1996

Genetic alterations in esophageal cancer and their relevance to etiology and pathogenesis: a review.

Cancer of the esophagus exists in 2 main forms with different etiological and pathological characteristics-squamous cell carcinoma (SCC) and adenocarcinoma (ADC). This review focuses on the occurrence of genetic alterations in SSC and ADC of the esophagus and on their possible implications for the elucidation of the etiology and pathogenesis of these cancers. The most common alterations found in esophageal cancers include allelic losses at chromosomes 3p, 5q, 9p, 9q, 13q, 17p, 17q and 18q, as well as mutations of p53 (mostly missense), Rb (deletions), cyclin DI (amplifications) and c-myc (amplifications). The sequence of occurrence of these alterations with respect to histopathological tumor progression is discussed. Our findings underscore the different etiology and pathogenesis of SCC vs. ADC and suggest that the genetic alterations observed may represent molecular fingerprints of critical risk involved in the development of these 2 cancers.

Adenocarcinoma↗
PubMed1995

Unfavorable DNA ploidy and Ha-ras p21 findings in neuroblastomas detected through mass screening.

BACKGROUND: Urinary mass screening has been available for 6-month-old infants throughout Japan since 1985. It is still controversial as to whether the program contributes to the detection of unfavorable neuroblastomas destined to present clinically when a patient reaches an older age. DNA diploidy and tetraploidy, low expression of Ha-ras p21, and an amplified N-myc gene status relate to an unfavorable prognosis. The authors examined these biologic indicators in neuroblastomas detected by urinary mass screening. PATIENTS AND METHODS: Seventy-eight neuroblastomas detected by mass screening were studied for DNA ploidy using DNA flow cytometry, Ha-ras p21 expression using immunostaining, and N-myc gene copy number using slot-blot or Southern blot hybridization methods. RESULTS: Of 73 tumors with analyzable DNA flow cytometric results, 18 (24.7%) had diploidy (n = 7) or tetraploidy (n = 11). Twenty-eight (40.0%) of 70 tumors examined showed low-to-absent expression of Ha-ras p21. DNA diploid and tetraploid status correlated significantly with the low-to-absent expression of Ha-ras p21 (P = 0.00021). Fourteen (20.0%) of the 70 patients had both of these two unfavorable prognostic markers. N-myc amplification was not detected in 41 of 41 tumors studied. All 78 patients were alive 8-92 months after completion of treatment. CONCLUSIONS: At least 20.0% of neuroblastomas detected by mass screening have unfavorable biologic prognostic markers. These patients may benefit from early detection and immediate treatment. However, the biologic features associated with a poor prognosis are not predictive of poor outcome in individual patients, and, therefore, should not be used to justify more intensive therapies.

Aneuploidy↗
PubMed2003

Clinical significance of intensive surgery with intraoperative radiation for advanced neuroblastoma: does it really make sense?

PURPOSE: The aim of this study was to evaluate the significance of intensive surgery combined with intraoperative radiation therapy (IORT) in advanced neuroblastoma. METHODS: Clinical features and outcome were reviewed in 33 advanced neuroblastoma patients (24 with INSS stage 4, 9 with stage 3), who had surgery (total excision 29, subtotal excision 4) with IORT (10 to 15 Gy) against the primary tumor site. RESULTS: Three patients (8.8%) had relapse at the primary site, all of which arose from the unirradiated area after stem cell transplantation. Among 29 patients with total excision, disease-free survival was obtained in 15 (51.7%) for an average of 6.9 years, which included 5 survivors of 9 patients (55.9%) with amplified N-myc. In contrast, none of 4 patients with macroscopic residual survived. The Kaplan-Meier analysis showed significantly longer survival rates in the patients with total resection compared with those with macroscopic remnants. CONCLUSIONS: The intensive surgery with IORT dramatically increased the local eradication and improved the outcome even in advanced neuroblastoma with N-myc amplification. However, long-term survival was not obtained in patients with unresectable residual disease. These results may indicate the key role of surgical eradication in advanced neuroblastoma.

Adrenal Gland Neoplasms↗
PubMed1994

Rapid detection of prognostic genetic factors in neuroblastoma using fluorescence in situ hybridisation on tumour imprints and bone marrow smears. United Kingdom Children's Cancer Study Group.

A number of biological factors have been identified which correlate with prognosis in neuroblastoma. Among these are genetic aberrations, including ploidy, deletions of chromosome 1p and N-myc amplification. Conventional methods of detecting these changes, such as tissue culture for karyotyping and Southern blotting, are time-consuming and yield interpretable results in only a small proportion of cases. We have developed interphase fluorescence in situ hybridisation for use on tumour imprints and bone marrow smears, allowing rapid visualisation of the relevant genetic changes. Valuable prognostic information is therefore available in a few days: the results in our cases were later confirmed by conventional methods. In the foreseeable future it will be possible to define distinct prognostic categories on the basis both of this genetic information and other parameters, and separate therapeutic strategies may then be employed for the different patient groups.

Bone Marrow↗
PubMed2000

The characteristics of mediastinal neuroblastoma.

The prognosis of mediastinal neuroblastoma has been reported to be better than for other neuroblastomas. The reason for this is however not clear. Furthermore, a comparison between mediastinal neuroblastoma and the other neuroblastomas has been rarely reported so far. In this study, the characteristics of mediastinal neuroblastoma (84 cases) are investigated and compared with those of other neuroblastomas (440 cases). Regarding clinical factors, the age distribution and the rate of cases detected at mass screening were similar in both groups. According to Evan's staging system, the rates of early stage (I, II) were 62% in the mediastinal neuroblastoma and 38% in the other neuroblastomas (p<0.001). Regarding the biological prognostic factors, a favorable histology based on Shimada's classification was found in 100% (35/35) of the mediastinal neuroblastoma cases and in 85% (112/132) of the other neuroblastoma cases (p<0.05). With regard to N-myc amplification, all of the examined 42 cases in mediastinal neuroblastoma had a N-copy number of less than 10 copies, while 32 of the examined 263 cases (12%) in the other neuroblastomas had an amplification of N-myc of more than 10 copies (p<0.05). The 5-year survival rates were 78% in the mediastinal neuroblastoma and 59% in the other neuroblastomas, respectively. Of the cases who underwent an incomplete resection of primary tumors in localized neuroblastoma, the 5-year survival rate of the mediastinal neuroblastoma cases was significantly more favorable than that of the other neuroblastomas. The majority of mediastinal neuroblastoma cases showed an early stage and favorable prognostic factors. It is likely that the clinical and biological prognostic factors of the tumor are therefore more closely correlated with the outcome of mediastinal neuroblastoma rather than the degree of the surgical resection. Regarding the treatment for mediastinal neuroblastoma, it is most important to evaluate the biology of the tumor after surgical resection.

Child, Preschool↗
PubMed1991

Neuroblastoma, retinoblastoma, and brain tumors in children.

Considerable progress has been made recently in the biologic understanding and the clinical management of pediatric tumors of the peripheral and central nervous system. Here we review important representative studies published primarily in the past 2 years regarding neuroblastoma, retinoblastoma, and brain tumors in children. Highlights include 1) the importance of tumor DNA content, N-myc amplification, and chromosome 1 deletion in predicting outcome of patients with neuroblastoma; 2) the impact of mass screening for neuroblastoma in Japan and elsewhere; 3) improvements in the clinical management of neuroblastoma, retinoblastoma, and brain tumors; and 4) neurologic sequelae of these tumors and their treatment.

Brain Neoplasms↗
PubMed1992

Dominant and recessive molecular changes in neuroblastomas.

Of all human tumors, neuroblastomas bear the most prominent genetic changes. Amplifications and deletions of chromosomal DNA can be identified by light microscopy on chromosomal spreads of neuroblastoma cells with remarkable frequency and consistency. Consequently, extensive studies have been undertaken to elucidate the molecular basis of these cytogenetic changes. A rich body of information has accumulated on the role played by dominant oncogenes and recessive tumor suppressor genes in the pathogenesis of this disease. Most notably, it was found that amplification of N-myc is responsible for the presence of double minutes and homogeneously staining regions in neuroblastoma chromosomes. It has also been discovered that N-myc amplification is a prognostic sign of malignancy. More recently, recessive genetic alterations in neuroblastoma, such as deletion of putative tumor-suppressing genes have received increasing attention, and considerable efforts are being made to identify such genetic elements. Finally, the susceptibility of neuroblastoma cells to differentiating stimuli has made them a popular in vitro system for neurobiological and pharmacological research. The need for suitable in vivo systems has spurred the development of several animal models employing tumor viruses and transgenic technologies.

Amino Acid Sequence↗
PubMed2002

In vivo interference with Skp1 function leads to genetic instability and neoplastic transformation.

Skp1 is involved in a variety of crucial cellular functions, among which the best understood is the formation together with Cul1 of Skp1-cullin-F-box protein ubiquitin ligases. To investigate the role of Skp1, we generated transgenic (Tg) mice expressing a Cul1 deletion mutant (Cul1-N252) able to sequestrate and inactivate Skp1. In vivo interference with Skp1 function through expression of the Cul1-N252 mutant into the T-cell lineage results in lymphoid organ hypoplasia and reduced proliferation. Nonetheless, after a period of latency, Cul1-N252 Tg mice succumb to T-cell lymphomas with high penetrance (>80%). Both T-cell depletion and the neoplastic phenotype of Cul1-N252 Tg mice are largely rescued in Cul1-N252, Skp1 double-Tg mice, indicating that the effects of Cul1-N252 are due to a sequestration of the endogenous Skp1. Analysis of Cul1-N252 lymphomas demonstrates striking karyotype heterogeneity associated with c-myc amplification and c-Myc overexpression. We show that the in vitro expression of the Cul1-N252 mutant causes a pleiotrophic phenotype, which includes the formation of multinucleated cells, centrosome and mitotic spindle abnormalities, and impaired chromosome segregation. Our findings support a crucial role for Skp1 in proper chromosomal segregation, which is required for the maintenance of euploidy and suppression of transformation.

Animals↗
PubMed1992

Mapping chromosomal breakpoints of Burkitt's t(8;14) translocations far upstream of c-myc.

To analyze the region upstream of c-myc, a number of novel probes were established. These were generated by chromosomal walking starting from the breakpoint of the chromosomal translocation of the B-cell line 380 and by cloning the breakpoint of the translocation of the Burkitt lymphoma cell line IARC/BL72. Using the newly isolated probes a detailed physical map of 500 kilobases of the region upstream of c-myc was established applying pulsed-field gel electrophoresis. The chromosomal breakpoint of IARC/BL72 cells was mapped to a site 55 kilobases 5' of c-myc. A region 20 kilobases in length and containing the breakpoints of 380, EW36, P3HR-1, and Daudi cells was identified 170-190 kilobases upstream of c-myc. In addition the HPV18 integration site in HeLa cells was located between 340 and 500 kilobases 5' of c-myc. The probes were used to define the c-myc amplification units in Colo320-HSR and HL60 cells as well as in four cases of small cell lung cancer. Evidence is provided that the amplicon of HL60 cells is discontinuously organized.

Base Sequence↗
PubMed1992

Large-cell medulloblastomas. A distinct variant with highly aggressive behavior.

We present four cases of infantile cerebellar neoplasms composed of cells with large vesicular nuclei with prominent nucleoli. All four cases were strongly immunoreactive for synaptophysin, and one case showed immunoreactivity for neurofilaments. Filter hybridization for N-myc and c-myc oncogenes showed a 27-fold c-myc amplification in one case. The cytogenetic analysis in this case showed Double-Minutes and isochromosome 17q. An intracerebral xenograft in nude mice obtained from one such tumor showed a similar morphology to that of the original tumor as well as strong immunoreactivity for synaptophysin and neurofilaments. All the neoplasms were characterized by highly aggressive behavior leading to early cerebrospinal fluid dissemination despite radiotherapy and chemotherapy. We conclude that large-cell medulloblastoma represents a distinct and more aggressive variant of medulloblastoma that requires more aggressive therapy.

Blotting, Southern↗
PubMedDate not supplied

Flow cytometric and molecular analysis of proliferative activity and DNA content in neuroblastoma: presence of stationary cells in S-phase.

Twenty-nine previously untreated neuroblastomas were analyzed for DNA content and percentage of cells in S-phase, both determined by flow cytometry, and N-myc oncogene copy number. Twelve of them were also tested for histone H3 transcript levels as a marker of actual proliferative activity. A significantly higher S-phase fraction was associated with advanced stages of disease, unfavorable (i.e., near-diploid and near-tetraploid) DNA content, and N-myc amplification. The occurrence of six tumors with a remarkable (greater than or equal to 10%) S-phase fraction but lacking histone H3 transcripts suggests the presence of stationary S-phase cells in neuroblastoma.

Cell Division↗
PubMed1990

The cytogenetics and molecular genetics of lung cancer. Implications for pathologists.

The interactions of cytogenetic and molecular genetic changes in the pathogenesis and progression of lung cancer are complex. To the practicing pathologist, certain of these changes may prove useful as diagnostic or prognostic markers and may help in selecting patients for particular types of therapy. Changes such as 3p14-23 deletions, c-myc amplification, and L-myc RFLPs have already been reported to predict aggressive behavior in lung cancer. Future studies will clarify the application of these changes to the clinical care and treatment of patients with carcinoma of the lung.

Cytogenetics↗