Biomedical subjects
Publications and source records attributed to H Brauch.
Renal oncocytomas were tested for loss of alleles at loci on the short arm of chromosome 3, a genetic change characteristic of human renal cell carcinoma. Five renal oncocytomas did not show loss of alleles at loci on 3p supporting the view that renal oncocytoma is a distinct form of renal neoplasia.
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In small cell lung carcinoma, one of the short arms of chromosome 3 is typically lost. To investigate chromosome 3 in extrapulmonary small cell carcinoma, we used DNA probes that detect restriction-fragment-length polymorphisms at loci on 3p. These probes were used to study DNA extracted from tumors and normal tissues and/or tumor cell lines from five patients with extrapulmonary small cell cancer. Tumor DNA from four of the five patients with extrapulmonary small cell cancer retained heterozygosity at loci on 3p. Cytogenetic studies of the tumor cell lines established from these four patients showed retention of both short arms of chromosome 3. We conclude that the loss of genetic material from 3p observed in small cell lung cancer is not typical in extrapulmonary small cell cancer.
Previous reports showed that the loss of DNA sequences on the short arm of chromosome 3 (3p) is consistently found in sporadic renal cell carcinomas. To evaluate the significance of this genetic change, we looked for the loss of 3p alleles in hereditary renal cell carcinomas and other tumors from patients with von Hippel-Lindau disease. Specific loss of alleles from chromosome 3p was detected with polymorphic DNA markers in 11 renal cell carcinomas, one pheochromocytoma, two spinal hemangioblastomas and one cerebellar hemangioblastoma from von Hippel-Lindau patients. Multiple renal cell carcinomas in individuals with von Hippel-Lindau disease showed loss of the same chromosome 3p alleles, which demonstrated that the same chromosome was deleted in each tumor. Analysis of haplotypes indicated that the loss of chromosome 3p alleles was from the chromosome bearing the balancing, wild-type allele of the VHL gene. These results are consistent with the concept that the VHL gene is a recessive oncogene. Renal cell carcinoma, pheochromocytoma, and spinal and cerebellar hemangioblastomas develop in predisposed family members when somatic mutational events lead to loss of chromosome 3p sequences bearing the wild-type allele of the VHL gene.
The ERBA beta gene codes for a DNA-binding thyroid hormone receptor (THR) and maps to chromosome 3p21-p25, overlapping a 3p deletion characterizing small-cell lung carcinoma (SCLC). A DNA clone detecting an RFLP at the ERBA beta locus has been used to probe a large number of lung tumors. Virtually all SCLC had lost heterozygosity, showing that the 3p deletion in SCLC includes this gene. A substantial but smaller proportion of non-small-cell carcinomas had lost heterozygosity at ERBA beta. Among all non-small-cell tumors some had lost heterozygosity at the proximal locus DNF15S2 (band 3p21) but not at ERBA beta, whereas none were found where the reverse was true. Therefore, the locus which plays a role in non-small-cell tumorigenesis probably lies closer to DNF15S2 than to ERBA beta and is almost certainly not the latter.
The c-raf-1 oncogene is located at chromosome 3p25, near a region known to be specifically deleted in patients with renal cell carcinoma and small cell lung carcinoma (SCLC). From cytogenetic analyses of SCLC cell lines, we have estimated that one c-raf-1 allele was deleted in approximately 80% of the cases. However, c-raf-1 was generally thought to be distal to the most common deletion in SCLC, 3p14-23. Using restriction site polymorphisms (RFLPs) located within the c-raf-1 locus, we have examined DNA from 84 human lung carcinomas. In an analysis of 11 paired (normal versus tumor) SCLC DNA samples, all five informative cases showed loss of heterozygosity at this locus in the corresponding tumor sample. Analysis of 73 unpaired lung carcinoma DNAs showed that out of 31 non-SCLC samples, 19% were heterozygous for the BglI polymorphism and 25% showed heterozygosity with TaqI. However, all of the 42 SCLC samples were homozygous for both of these RFLPs. This striking loss of heterozygosity at the c-raf-1 locus in SCLC indicates that one allele of c-raf-1 is deleted in SCLC. The kinase activity of the c-raf protein appears to be constitutively activated in these cells. Whether this apparent activation results from genetic or epigenetic events is under investigation.
Previous studies have suggested that the loss of DNA sequences on the short arm of chromosome 3 (3p) is associated with small-cell lung carcinoma. We therefore looked for loss of 3p alleles in tumor tissue from 42 patients with either small-cell or non-small-cell lung carcinoma. All 13 patients with small-cell lung carcinoma who were heterozygous for one or more alleles at 3p in normal tissue had the loss of at least one codominant allele in the tumor tissue. Cell lines of small-cell lung carcinoma from an additional eight patients were homozygous for 3p alleles; this result was significantly different from the predicted frequency of homozygosity. The tumor tissue studied included cell lines of small-cell lung carcinoma obtained from biopsy specimens, an autopsy sample, and an excised lymph node containing tumor cells. Loss of alleles at 3p was observed in tumor samples obtained before and after chemotherapy. Four of 15 evaluable patients with non-small-cell carcinoma of the lung had loss of 3p alleles. We conclude that loss of alleles at 3p is a change found consistently in small-cell lung carcinoma and occasionally in non-small-cell lung carcinoma.
A glycoprotein from human erythrocyte membranes has been found to inhibit lysis of target cells by the attack-phase components C5-C9 from human complement. The inhibiting molecule was purified and identified as glycophorin A. Thus, glycophorin A may have a regulatory function in the lytic complement attack on isologous cells.
Loss of genes at specific chromosomal loci is a characteristic of retinoblastoma, Wilms' tumour, transitional cell carcinoma of the bladder, embryonal tumours and small cell carcinoma of the lung. The significance of nonrandom gene loss in these neoplasms is that gene loss on one chromosome may uncover null mutations at corresponding loci of the homologous chromosome. Loss of specific gene products from somatic cells may be critical in the origin or evolution of certain human tumours. Clues to identification of new loci of gene loss in common adult solid tumours may be found in literature that describes chromosomal abnormalities in rare heritable cancers. Karyotypes of tumours in two families with hereditary renal carcinoma showed translocations involving the short arm of chromosome 3 (refs 10 and 11). We have examined tumours from 18 patients with non-hereditary renal cell carcinomas and found loss of alleles at loci on the short arm of chromosome 3 in all eleven of the patients who could be evaluated.
Small cell lung cancers express neuroendocrine (NE) cell features, while most non-SCLC tumors lack these features. We studied the cytogenetic and genetic alterations in cell lines derived from three unusual subtypes of lung cancer: including carcinoids, non-small cell lung cancers expressing NE properties (NSCLC-NE) and extrapulmonary small cell cancers (ExPuSC) and compared them with those of SCLC and NSCLC lines. Our studies included: cytogenetic studies, restriction fragment length polymorphism (RFLP) analyses with 8 probes spanning commonly deleted loci on chromosomes 3p, 13q and 17p, retinoblastoma gene product (RB) expression, and mutations in the ras and p53 genes. We also summarize previously published data on in vitro chemosensitivity patterns and MDRl gene expression. Our studies demonstrate that all three of the NE cell subtypes have their own distinctive genotypes and phenotypes, each having some similarities and dissimilarities with SCLC and NSCLC.