Loss of heterozygosity for 10q22-10qter in malignant melanoma progression.

Karyotypic and molecular data indicate that genetic events involving the chromosome region 10q22-10qter may be related to tumorigenesis in malignant melanoma. To test this we analyzed 10 polymorphic microsatellite repeats in the region 10q22-qter, using a polymerase chain reaction-based assay for loss of heterozygosity and DNA isolated from normal and tumor tissue from 26 individuals with malignant melanoma. The samples included 19 paired normal and malignant tissues representing various stages of melanoma as well as 7 cases in which samples from at least 2 different points in time during tumor progression were available.

A new highly polymorphic DNA restriction site marker in the 5' region of the human tyrosine hydroxylase gene (TH) detecting loss of heterozygosity in human embryonal rhabdomyosarcoma.

We have isolated a new marker (cos11-5TH) that detects an MspI restriction fragment length polymorphism in the 5' region of the human tyrosine hydroxylase gene (TH) on chromosome band 11p15.5. This region of human chromosome 11 contains several important loci for disease phenotypes including Beckwith-Wiedemann syndrome (BWS), Wilms' tumor, and embryonal rhabdomyosarcoma.

Analysis of the p53 gene and its expression in human glioblastoma cells.

Chromosome 17p has been shown to be an early and frequent target for loss of heterozygosity through mitotic recombination in astrocytomas. These losses are frequently accompanied by point mutations in the p53 gene of the remaining allele, resulting in loss of wild type p53 function. However, a fraction of astrocytomas retain constitutional heterozygosity and do not have p53 mutations; some of these lose wild type p53 activity through binding to the protein product of amplified mdm2 genes.

Molecular sublocalization and characterization of the 11;22 translocation breakpoint in a malignant rhabdoid tumor.

Malignant rhabdoid tumors are extremely aggressive soft-tissue sarcomas that tend to be widely metastatic at diagnosis. These tumors were first described as variants of the kidney neoplasm Wilms' tumor, although tumors of similar clinicopathologic features have been cited in a variety of extrarenal sites. Here, we have characterized the chromosomal translocation t(11;22)(p15.

The RAP1GA1 locus for human Rap1-GTPase activating protein 1 maps to chromosome 1p36.1-->p35.

Using a panel of somatic cell hybrids we have mapped the locus for Rap1-GTPase activating protein 1 (RAP1GA1) to human chromosome 1. Fluorescence in situ hybridization experiments independently confirmed the chromosomal localization and refined it to 1p36.1-->p35.

Refinement of regional loss of heterozygosity for chromosome 11p15.5 in human breast tumors.

The familial association of breast cancer with other tumors such as rhabdomyosarcoma that show loss of heterozygosity (LOH) for chromosome 11p15 as well as limited analyses showing LOH for chromosome 11p in breast tumors suggests the presence of a pleiotropic tumor suppressor gene in this region. In order to test this idea, we analyzed DNA samples for 50 matched normal and tumor tissues from unselected breast cancer patients for LOH at loci throughout the chromosome 11p15.5 region.

Loss of heterozygosity in malignant gliomas involves at least three distinct regions on chromosome 10.

A panel of glial tumors consisting of 11 low grade gliomas, 9 anaplastic gliomas, and 29 glioblastomas were analyzed for loss of heterozygosity by examining at least one locus for each chromosome. The frequency of allele loss was highest among the glioblastomas, suggesting that genetic alterations accumulate during glial tumor development. The most common genetic alteration detected involved allele losses of chromosome 10 loci; these losses were observed in all glioblastomas and in three of the anaplastic gliomas.

Homozygous inactivation of WT1 in a Wilms' tumor associated with the WAGR syndrome.

Wilms' tumor is a childhood nephroblastoma that is postulated to arise through the inactivation of a tumor suppressor gene by a two-hit mechanism. A candidate 11p13 Wilms' tumor gene, WT1, has been cloned and shown to encode a zinc finger protein. Patients with the WAGR syndrome (Wilm's tumor, aniridia, genitourinary abnormalities, and mental retardation) have a high risk of developing Wilms' tumor and they carry constitutional deletions of one chromosome 11 allele encompassing the WT1 gene.

Mutation and expression of the p53 gene in malignant melanoma cell lines.

Three monoclonal antibodies (MAbs) against p53 protein (PAb 24o, DO-I and PAb1801) were used to define the immunophenotype of 13 melanoma cell lines. Immunoreactions could be detected in 12 out of 13 cell lines by using the indirect immunofluorescence technique. In 7 of these the majority of cells displayed cytoplasmic staining whereas positive nuclei were detected in only a few cells.

DNA hypermethylation is associated with 17p allelic loss in neural tumors.

It has long been debated whether the accumulation of allelic losses in tumors involves the selection of cells which have stochastically lost chromosomal regions or whether there is, inherent to the neoplastic state, a process which predisposes to genetic instability. Changes in DNA methylation are commonly seen in human tumors and can alter chromosome structure. We now have examined specific types of primary neural tumors which allow us to determine relationships between abnormal DNA hypermethylation and allelic loss.

Genetics of cancer predisposition and progression.

The development of human cancer is a multistep process that entails a progressively more malignant phenotype through the evolution of cellular subsets with increasing numbers of genetic alterations. Here we review the molecular genetics of human cancer predisposition and progression and describe paradigmatic cancer types and cancer syndromes. We also briefly consider the future impact of molecular biology on cancer diagnosis and treatment.

Loss of heterozygosity for loci on chromosome 10 is associated with morphologically malignant meningioma progression.

Meningioma is a common tumor of the central nervous system which displays morphological heterogeneity. In order to determine whether this phenotypic variability is associated with distinct or overlapping genetic lesions, we compared genotypes at several loci defined by allele length polymorphism in tumor and normal tissues from patients with meningioma. In particular, we concentrated on loci on chromosomes 22 and 10 because these genomic regions have previously been shown to be altered in the former in sporadic and familial meningiomas and in the latter as a late stage event in progression of another common brain tumor, astrocytoma.

A genetic linkage map with 29 loci spanning human chromosome 13q.

A genetic linkage map for the long arm of human chromosome 13 contains 29 loci derived from 38 probe and enzyme combinations and two protein polymorphisms. Thirteen loci form a continuous linkage map of 106 cM in males and 230 cM in females; each was placed on the map with support of at least 1000:1 against alternative orders. On a sex-combined basis, the mean distance between markers is less than 13 cM.

Turcot's syndrome of glioma and polyposis occurs in the absence of germ line mutations of exons 5 to 9 of the p53 gene.

The term "Turcot's syndrome" has been used to describe approximatively 55 patients with an association of colonic polyposis and primary neuroepithelial tumors of the central nervous system. The p53 tumor suppressor gene is a possible candidate underlying the syndrome because (a) mutations in the p53 gene are ubiquitous in human cancer, including colon carcinoma and gliomas, and (b) somatic or germ line mutations of the p53 tumor suppressor gene cause the Li-Fraumeni syndrome, which is characterized by the association of breast and soft tissue tumors. We determined the DNA sequence of the conserved regions of the p53 gene (exons 5 to 9) in the tumor tissues and lymphocytes of two patients with glioma-polyposis and found that mutations did occur as independent tumor-specific alterations but did not involve the germ line of these patients, suggesting that p53 may play a role in progression but not initiation of the disease.

Retinoblastoma and p53 gene product expression in breast carcinoma: immunohistochemical analysis and clinicopathologic correlation.

We examined 100 breast cancers for retinoblastoma (Rb) and p53 protein expression by immunohistochemistry using the PMG3.245 and PAb 1801 antibodies. We assessed percentages of reactive cells and their intensity, as well as staining patterns.

Gliomas in families.

This is a descriptive study of 19 families with glial tumors. Twelve were identified prospectively from 178 consecutive, unrelated adults and children with newly diagnosed gliomas seen at a regional cancer center between 01 Jan 89 and 31 Mar 91 (6.7%).

Accumulation of genetic defects during astrocytoma progression.

Background: The development of human cancer generally is thought to entail a series of events that cause a progressively more malignant phenotype. This hypothesis predicts that tumor cells of the ultimate stage will carry each of the events; cells of the penultimate stage will carry each of the events minus the last one; and so on. Therefore, a dissection of the pathway from a normal cell to a fully malignant tumor may be viewed as the unraveling of a nested set of aberrations.

Loss of heterozygosity for chromosomes 1 or 14 defines subsets of advanced neuroblastomas.

Neuroblastomas have been characterized genetically by N-myc amplification and by deletions or loss of heterozygosity (LOH) for the short arm of chromosome 1. However, recent studies have suggested deletion or allelic loss involving at least three other chromosome arms, 11q, 14q, and 17p. Therefore, we undertook an analysis of allelic loss for these respective chromosomal arms to determine the frequency and pattern of LOH as well as the correlation of these findings with other biological and clinical variables.

Human chromosome 11 contains two different growth suppressor genes for embryonal rhabdomyosarcoma.

The identification of acquired homozygosity in human cancers implies locations of tumor suppressor genes without providing functional evidence. The localization of a defect in embryonal rhabdomyosarcomas to chromosomal region 11p15 provides one such example. In this report, we show that transfer of a normal human chromosome 11 into an embryonal rhabdomyosarcoma cell line elicited a dramatic loss of the proliferative capacity of the transferrants.

Muscle-specific gene expression in rhabdomyosarcomas and stages of human fetal skeletal muscle development.

Rhabdomyosarcomas (RMS) bear a morphological resemblance to developing striated muscle. It has been reported that two histologically distinct subtypes of RMS, embryonal and alveolar, behave differently in many clinical aspects, such as age distribution, primary site, and prognosis. We have investigated the expression of various genes, which are preferentially expressed in normal muscle tissue or cell culture (actins, myosins, and creatine kinases, and myogenic regulatory genes MyoD, myogenin, MRF4, and Myf5), in embryonal and alveolar subtypes and compared the results to the stages of developing human fetal limb muscle.