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Biomedical subjects

A G Knudson

Publications and source records attributed to A G Knudson.

At least 37 records · Page 2Linked to original sources
PubMed1993

Antioncogenes and human cancer.

The antioncogenes, or tumor suppressor genes, as negative regulators of cell division, stand in contrast to oncogenes. For most human cancers, the more frequently mutated genes are the antioncogenes, the principal exception being the leukemias and lymphomas. Persons heterozygous for germ-line mutations in antioncogenes are strongly predisposed to one or more kinds of cancer, and most dominantly inherited cancer is attributable to such heterozygosity. Seven antioncogenes have been cloned through the study of these persons, and several others have been mapped. An eighth one was mapped and cloned through the investigation of tumors and is not yet known in hereditary form. Three dominantly inherited forms of cancer are not attributable to mutations in antioncogenes. The corresponding nonhereditary forms of most cancers generally reveal abnormalities of the same antioncogenes that are found in the hereditary forms but may also show additional ones. Some cancers, especially the embryonal tumors of children, have a small number of antioncogene mutations; some others, such as most sarcomas, have more, and the common carcinomas have the most, reflecting a hierarchy of controls over growth of stem cell populations. Still more members of this gene category remain to be mapped and cloned through the study of cancer families and of tumors. The genes that have been cloned act at diverse points in the signal transduction pathway in cells, from the outer cell membranes to sites of gene transcription, in some cases as negative regulators of oncogene expression.

Breast Neoplasms↗
PubMed1993

Susceptibility to renal carcinoma in the Eker rat involves a tumor suppressor gene on chromosome 10.

Germ-line mutations of tumor suppressor genes confer strong predisposition to tumor formation. In the rat, a form of dominantly inherited renal carcinoma (RC) results in multiple chromophobe cell tumors that resemble the human disease, and heterozygous carriers (RC/+) are highly susceptible to environmental agents (radiation and chemical carcinogens), making it a desirable model to study epithelial carcinogenesis. By linkage analysis, the locus of the inherited RC mutation was mapped to rat chromosomal band 10q12, near the protamine locus (logarithm of odds score = 17.96). Renal tumors also showed a loss of heterozygosity at this locus, lending support to the recessive nature of this putative tumor suppressor gene. Our result suggested that the human homolog of the RC gene may reside on human chromosome 16, not known to be altered commonly in human RC.

Animals↗
PubMed1993

Pediatric molecular oncology. Past as prologue to the future.

The great successes in the treatment of childhood cancers have been followed in recent years with a new understanding of the molecular genetic abnormalities that underlie their origin. For some cancers these genetic changes are in oncogenes; in others, they are in antioncogenes, or tumor suppressor genes. Initiating aberrations in the former are associated characteristically with chromosomal translocations, the analysis of which should soon lead to the identification of oncogenes other than those in the myc family. Several tumor suppressor genes of importance in the childhood cancers have been cloned and others should soon follow. It is reasonable to expect that during the current decade molecular understanding of the genetic defects in the major pediatric cancers will be achieved. The knowledge gained through these studies, past and future, may provide new approaches to prevention and treatment and lead to additional progress.

Child↗
PubMed1993

Spontaneous and radiation-induced renal tumors in the Eker rat model of dominantly inherited cancer.

Hereditary renal carcinoma (RC) in the rat, originally reported by R. Eker in 1954, is an example of a Mendelian dominant predisposition to a specific cancer in an experimental animal. At the histologic level, RCs develop through multiple stages from early preneoplastic lesions (e.g., atypical tubules) to adenomas in virtually all heterozygotes by the age of 1 year. The homozygous mutant condition is lethal at approximately 10 days of fetal life. Ionizing radiation induces additional tumors in a linear dose-response relationship, suggesting that in heterozygotes two events (one inherited, one somatic) are necessary to produce tumors, and that the predisposing gene is a tumor suppressor gene. No genetic linkage has yet been found between the Eker mutation and rat DNA sequences homologous to those in human chromosome 3p, the presumed site of the putative tumor suppressor gene responsible for human RC. Nonrandom loss of rat chromosome 5 in RC-derived cell lines is sometimes associated with homozygous deletion of the interferon gene loci at rat chromosome bands 5q31-q33. Since this locus is not linked with the predisposing inherited gene in the Eker rat, it probably represents a second tumor suppressor gene involved in tumor progression.

Adenoma↗
PubMed1993

Introduction to the genetics of primary renal tumors in children.

Wilms tumor can be explained only partially by the "two hit" model that was originally developed for retinoblastoma. Heterogeneity of two kinds operates. The first is that four other primary tumors are regularly observed in children, and the second is that Wilms tumor itself appears to represent more than one genetic entity. All five of these primary renal tumors arise from primary or secondary mesenchyme, renal blastema, or renal epithelium. Mesoblastic nephroma, and possibly clear cell sarcoma, may have some genetic affinity with Wilms tumor, but rhabdoid tumor of the kidney and renal carcinoma do not. At least three different genes seem to be important in the origin of Wilms tumor. One, WT1, whose mutations may be associated with aniridia, may follow the "two hit" model in that there are cases in which both copies of the gene are defective or lost, as expected for a tumor suppressor gene. A second gene, which is associated with Beckwith-Wiedemann Syndrome (BWS) and which has not been cloned, appears to be imprinted in females, and may have an oncogene function. It is evidently activated by gain of a paternal allele or by loss of the inactive, but possibly trans-sensing, maternal allele. Activation of the insulin-like growth factor II gene may be a final common pathway for mutation in both WT1 and BWS. A third gene is unlinked to either of the other two, but its location and function are unknown. It shares with WT1 specificity for Wilms tumor, which is not true of the BWS gene.

Child↗
PubMed1993

Assignment of 22 loci in the rat by somatic hybrid and linkage analysis.

Twenty structural genes and two unique anonymous DNA fragments have been mapped in the rat (Rattus norvegicus) with a panel of mouse x rat hybrids and linkage analysis. Ten of the 20 autosomes are represented by at least one of these markers. A new syntenic relationship among rat Chromosome (Chr) 16, mouse Chr 14, and human Chr 10q was established. Results of this study further support the extensive conservation of synteny between the rat and mouse and, to a lesser degree, between rat and human.

Animals↗
PubMed1993

New markers, D16FC1 and Tp12, differentiate between rat chromosomes 16 and 17.

Problems in differentiating rat chromosomes 16 and 17 cytogenetically can be resolved with unique probes mapped to these chromosomes. Using somatic cell hybridization and nonisotopic in situ hybridization, probes D16FC1 and Tp12 were localized to 16p16-->p15 and 17q12.1-->q12.2, respectively. The locations of these probes can serve as reference points to facilitate mapping of future probes to rat chromosomes 16 and 17.

Animals↗
PubMed1993

The retinoblastoma-related gene, RB2, maps to human chromosome 16q12 and rat chromosome 19.

A retinoblastoma-related human gene, referred to as RB2, has been cloned based on sequence homology of the E1A-binding domain of the retinoblastoma gene. Structural homology with the retinoblastoma gene suggests a possible function of RB2 as a tumor suppressor gene. In this study, we have mapped this gene to human chromosome 16q12.2 and rat chromosome 19, using fluorescence in situ hybridization and somatic hybrid cell analysis, respectively. Based on known syntenic relationships among human, rat and mouse, the data suggest that the mouse homolog resides on chromosome 8. Deletions of chromosome 16q have been found in several human neoplasias (including breast, ovarian, hepatic, and prostatic cancers) which is in support of an involvement of RB2 in human cancer as a tumor suppressor gene.

Animals↗
PubMed1992

Stem cell regulation, tissue ontogeny, and oncogenic events.

The number of necessary oncogenic events is a function of tissue ontogeny. A minimum of two events appears to suffice for certain embryonal tumors, leukemias, and lymphomas for which the target tissues normally show stem cell proliferation. Other tumors, including those featured in the Li-Fraumeni syndrome, arise in target tissues whose stem cells are conditionally stimulated to proliferate, as in response to hormones, and involve more events. The most complex cancers include most carcinomas, which arise in renewal tissues whose stem cells do not normally proliferate. The number of necessary oncogenic events appears to increase with the number of controls on proliferation.

Cell Division↗
PubMed1991

Hereditary renal cell carcinoma in the rat associated with nonrandom loss of chromosomes 5 and 6.

A spontaneous form of renal cell carcinoma occurs in rats that arises as the result of the inheritance of a mutation in a single autosomal gene. Cytogenetic analysis was performed on seven cell lines and four primary tumor cell preparations derived from this hereditary form of renal cell carcinoma. Banded karyotypes prepared from these seven lines exhibited loss and/or partial deletion of both chromosomes 5 and 6. Translocations involving chromosome 4, resulting in a net loss of genetic material located near the centromere (4q11), were observed in three of the cell lines. Monosomy, translocation, and breakage of chromosome 5 involving band 5q31 and monosomy and partial deletion of chromosome 6 involving band 6q22-q24 were independently observed in primary tumor cells from three of four tumors examined. Monosomy of chromosome 4 was observed in cells from a single tumor. The smallest region of deletion of chromosome 6 common to all the cell lines and tumor cells was 6q24, suggesting the presence of a tumor suppressor gene at this locus. These results indicate that loss of genes located on chromosomes 4, 5, and 6, possibly tumor suppressor gene(s), may be important for tumor development and/or progression in rat renal cell carcinoma and is consistent with the hypothesis that a gene locus on one of these chromosomes may be the site of the original predisposing mutation.

Animals↗
PubMed1991

Altered expression of transforming growth factor-alpha in hereditary rat renal cell carcinoma.

A hereditary form of renal cell carcinoma exists in rats that results from a single gene mutation and is histologically similar to that described in humans. Cell lines derived from these rat tumors were shown to express abundant transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF)-receptor RNA transcripts, but no EGF mRNA. In contrast, normal kidney expressed EGF and EGF-receptor transcripts, but TGF-alpha transcripts were barely detectable. Other kidney epithelial cell lines examined (NRK 52E, MDCK, and LLCPK) were negative for expression of both TGF-alpha and EGF transcripts, but expressed EGF receptors. In addition, the renal cell carcinoma-derived lines secreted TGF-alpha into the media. Immunohistochemistry of normal kidney with a TGF-alpha specific antibody revealed a characteristic pattern of staining of collecting ducts and, to a lesser degree, proximal tubules. In the neoplastic kidney tissue, both the cystic and solid portions of the tumors displayed intense immunoreactivity, indicating that altered expression of this growth factor by the transformed cells occurred in situ. These results suggest that altered TGF-alpha expression is an important aspect of the neoplastic phenotype in rodent as well as human renal cell carcinoma, and support the use of this hereditary rodent tumor model for studying the pathogenesis of this disease.

Animals↗
PubMed1991

Overview: genes that predispose to cancer.

Heredity and environment both operate in the origin of cancer. Dominantly heritable cancer is caused by 'cancer' genes that impart high relative risks but account for only a small part of the incidence of cancer; they are usually recessive in oncogenesis, mutation or loss of the second allele being necessary. Non-hereditary forms of cancer may involve the same genes. Other genes interact with environment in carcinogenesis; these may impart relatively small relative risks, but because their frequencies may be high, the attributable risks can be great, as probably is the case with lung cancer. The process of carcinogenesis is thought to involve 2 or more somatic genetic events in most cases. The genes whose germline mutations cause dominantly inherited cancer can also be mutated somatically to cause non-hereditary cancer. Other genes may influence the numbers of target cells, or the proliferation of once-hit stem cells, without being critical events on the path to cancer. However, such genes could greatly influence the incidence of a cancer. Other genes, such as that for Bloom's syndrome, may affect the rates at which first and second events occur. Finally, other genes may influence the occurrence of events critical for progression and metastasis, such as vascularization of a small tumor.

Cell Transformation, Neoplastic↗
PubMed1989

Epidemiology of genetically determined cancer.

Dominantly heritable susceptibility is known for virtually every cancer. Susceptibility is typically restricted to one or a few tumours. For some tumours there appear to be at least two different predisposing conditions. Some mutant gene carriers survive to old age without developing the expected tumour(s). Some cases are new germline mutations. None of the conditions is very common, because of natural selection against gene carriers. Two questions arise: What is inherited? What is the relationship between the hereditary and non-hereditary forms of the same tumour? Retinoblastoma is a prototypic tumour. Penetrance in humans is nearly complete by the age of five years in the heritable form, which usually affects both eyes. Rare cases in which there is a constitutional deletion of chromosomal band 13q14 permitted localization of the responsible gene. Tumour formation is clearly a rare event at the cellular level, suggesting the necessity of a second, somatic, event. The difference in ages at diagnosis between unilateral and bilateral cases also suggests that two somatic events occur in non-hereditary cases. One explanation is that the gene is recessive and the second event involves loss of the remaining normal allele by mutation, non-disjunction, deletion or somatic recombination. The normal allele may be regarded as anti-oncogenic.

Disease Susceptibility↗