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Results for “Knudson's two-hit”

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At least 19 recordsLinked to original sources

PubMed1995

Early detection of Knudson's two-hits in preneoplastic renal cells of the Eker rat model by the laser microdissection procedure.

Hereditary renal cell carcinomas invariably develop by the age of 1 year in Eker rats. At the histological level, renal cell carcinomas develop through multiple stages from early preneoplastic lesions (e.g., phenotypically altered tubules) to adenomas. We previously reported that ionizing radiation induces additional tumors (large adenomas and carcinomas) in a linear dose-response relationship and that loss of heterozygosity (LOH) at chromosome 10, where the predisposing tuberous sclerosis (Tsc2) gene is localized, was found in the renal cell carcinomas which developed from hybrid F1 rats carrying the Eker mutation, indicating that in heterozygotes two events (one inherited, one somatic) are necessary to produce at least large adenomas and carcinomas. This study was designed to examine LOH in the earliest preneoplastic lesions, using a laser microdissection procedure. We could accurately dissect single altered renal tubules out of freeze-dried sections and clearly detected LOH in 4 of 19 altered tubules (21%). This is the first demonstration of LOH in single renal tubules. Our present results support the theory of a second, somatic mutation (second hit) as rate-limiting step of renal carcinogenesis in the Eker rat model of dominantly inherited cancer and the tumor suppressor nature of the Tsc2 gene function.

Animals↗

PubMed1986

Unilateral vs. bilateral retinoblastoma. Correlations between age at diagnosis and stage of ocular disease.

Retrospective analysis of 358 cases of retinoblastoma for correlation between age and intraocular stage at the time of diagnosis revealed: in both early and advanced stages of intraocular disease, bilateral retinoblastoma presents at an earlier age than does unilateral retinoblastoma; support for the Knudson "two-hit" hypothesis of retinoblastoma genetics, the existence of a positive family history for retinoblastoma does not guarantee an earlier age at diagnosis compared to sporadic disease; and for any age at diagnosis, unilateral or bilateral disease, Group V is the most common intraocular stage found.

Age Factors↗

PubMed1990

Frequent inactivation of the retinoblastoma anti-oncogene is restricted to a subset of human tumor cells.

We have used polyclonal anti-synthetic peptide serum to study the role of retinoblastoma gene (RB) inactivation in a variety of human tumor cell lines. Our analysis indicates that inactivation of the RB protein, p105-Rb, is universal in retinoblastoma cells, vindicating the predictions of the Knudson "two-hit" hypothesis. In addition, our analysis has shown that inactivations of the RB gene are nearly as frequent in a more common human tumor, small cell lung carcinoma. One-third of bladder carcinomas surveyed also carry altered or absent p105-Rb. Other human tumors by contrast demonstrate only infrequent inactivation of the RB gene. These results suggest that inactivation of the RB gene is a critical step in the pathogenesis of a subset of human tumors.

Base Sequence↗

PubMed1985

The two-hit theory of neoplasia: implications for the pathogenesis of hyperparathyroidism.

Knudson's two-hit or two-mutational-event hypothesis for the initiation of neoplasia suggests that two somatic mutations are necessary for initiation of sporadic neoplasms, and that a genetic plus a somatic mutation are required for hereditary neoplasms. Glucose-6-phosphate dehydrogenase (G6PD) studies of parathyroid tumors of 11 heterozygotes with hyperparathyroidism (HPT), including one with hereditary HPT, have shown both A and B isoenzymes. These findings suggest multicellular development of parathyroid tumors and are compatible with tumors being manifestations of either nonneoplastic hyperplasia or a genetic first mutational event. Parathyroid carcinoma may be the result of a second mutation in cells made susceptible by previous genetic or somatic mutations. Comparison of parathyroid cancer in families with hereditary HPT with sporadic cases from the literature reveals a generally younger onset with hereditary HPT compatible with the two-hit theory. Consideration of these age-of-onset and G6PD findings suggest that hyperparathyroidism may result from either non-neoplastic or mutational-induced processes even though no histologic distinctions have been observed in the hyperplasia associated with these processes.

Glucosephosphate Dehydrogenase↗

PubMed1995

Molecular genetic basis of renal carcinogenesis in the Eker rat model of tuberous sclerosis (Tsc2).

We have recently identified on rat chromosome 10q a germline mutation in the tuberous sclerosis gene (Tsc2), the gene predisposing to renal carcinoma (RC) in the Eker rat. The homozygous mutant condition is lethal at around the 13th day of fetal life. In heterozygotes, RCs invariably develop in the first year of life. Histologically, RCs develop through multiple stages from early preneoplastic lesions (i.e., phenotypically altered tubules) to adenomas. The wild-type allele mutation has been found even in the earliest preneoplastic lesions, fitting Knudson's two-hit hypothesis and supporting the hypothesis that Tsc2 is a tumor suppressor gene. In this study, homozygous deletion of the Ink4 homologue on rat chromosome 5q was observed in 14 of 24 (58%) RC-derived cell lines. This may represent involvement of a second tumor suppressor gene, contributing to tumor progression. Considering previous results of studies of homozygous deletion of the Ifn alpha gene in five of 24 cases (21%) and the Ifn beta gene in one of 24 cases (4%), the order of the genes may be Ink4-Ifn alpha-Ifn beta. Microsatellite instability was not observed in 26 Eker rat tumors.

Amino Acid Sequence↗

PubMed1995

Allelic loss at the tuberous sclerosis 2 locus in spontaneous tumors in the Eker rat.

Somatic events leading to the inactivation of tumor suppressor genes often involve chromosomal alterations that can be detected as loss of heterozygosity (LOH). In the Eker rat, spontaneous tumors of the kidney, uterus, and spleen develop as a result of a germline mutation of the tuberous sclerosis 2 (Tsc2) gene. We examined the pattern and frequency of LOH at the predisposing locus in 77 primary tumors and cell lines to gain an understanding of the role of Tsc2 allelic loss in the pathogenesis of Eker-derived tumors. Although most renal and uterine tumors (primary and cell lines) displayed LOH, splenic hemangiosarcomas did not. Although the presence of normal tissue may account for some of this difference, the possibility exists that an alternative mechanism, such as subtle mutation or gene dosage effects, may be involved during splenic tumorigenesis. Northern analysis confirmed that LOH resulted in loss of the wild-type transcripts for the Tsc2 gene. Thus, the inactivation of both alleles plays an important role in renal and uterine tumor development, in keeping with Knudson's two-hit hypothesis. In addition, renal tumors that retained the wild-type allele also did not express the normal transcript, suggesting that the remaining Tsc2 alleles had acquired subtle mutations resulting in loss of gene function.

Alleles↗

PubMed2026

Integrating germline and tumor sequencing to improve hereditary cancer diagnosis and care.

A subset of cancers arises due to inherited germline pathogenic variants in specific genes, known as hereditary cancers. These genes typically include tumor suppressors, DNA repair and replication fidelity genes, and occasionally oncogenes. In most hereditary cancer syndromes, Knudson's two-hit hypothesis applies, where a second somatic event inactivates the remaining allele of a tumor suppressor or DNA repair gene, leading to tumorigenesis. Advancements in genome-wide sequencing have significantly enhanced our understanding of the mutational processes involved in hereditary cancers. In particular, the assessment of microsatellite instability (MSI), tumor mutational burden (TMB), and mutational signatures has emerged as a powerful tool for the identification of hereditary tumors. Tumors with high or ultra-high TMB often reflect underlying DNA repair deficiencies, while specific mutational signatures can pinpoint the defective pathway. These tumor mutational features are especially informative in syndromes involving mismatch repair (MMR), homologous recombination (HR), base excision repair (BER), nucleotide excision repair (NER), and polymerase proofreading. Moreover, tumor sequencing aids in the interpretation of germline variants, identifies somatic mosaicism, and helps differentiate hereditary from sporadic cancers. Additionally, tumor molecular features associated with DNA repair deficiencies offer insights into personalized therapies, such as the use of PARP inhibitors for BRCA1/2-deficient tumors and immune checkpoint inhibitors for MMR- and polymerase proofreading-deficient cancers. Tumor profiling also uncovers actionable mutations in oncogenes like RET and VHL, which can be targeted with specific therapies. This review explores the integration of tumor molecular features with germline genetic data to refine diagnosis, risk assessment, and therapeutic strategies in hereditary cancer.

Humans↗

PubMed1989

A model for embryonal rhabdomyosarcoma tumorigenesis that involves genome imprinting.

Embryonal rhabdomyosarcomas (malignant pediatric tumors of striated muscle origin) have been shown to arise from cells that are clonally isodisomic for loci on chromosome 11p. We determined the parental origin of alleles in this genomic region in familial and sporadic cases of this disease and found that isodisomic chromosome 11p alleles in each tumor were of paternal origin. We have developed a modification of Knudson's two-hit model from these data that is capable of explaining the preferential allele retention and of resolving the apparent contradiction between such specific and early events in several embryonal tumors and discrepancies in the inheritance of predisposition in some of these diseases.

Alleles↗

PubMed1987

Structural evidence for the authenticity of the human retinoblastoma gene.

The retinoblastoma (Rb) gene is the prototype for a class of recessive human cancer genes in which loss of activity of both normal alleles is thought to be associated with tumorigenesis. Sixteen of 40 retinoblastomas examined with a complementary DNA probe shown to be the Rb gene had identifiable structural changes of the Rb gene including in some cases homozygous internal deletions with corresponding truncated transcripts. An osteosarcoma also had a homozygous internal deletion with a truncated transcript. In addition, possible hot spots for deletion were identified within the Rb genomic locus. Among those tumors with no identifiable structural changes there was either absence of an Rb transcript or abnormal expression of the Rb transcript. Comparison of the structural changes in the tumor cells and fibroblasts of certain patients provided support for Knudson's two-hit hypothesis for the development of retinoblastoma at the molecular level. The ability to detect germline structural deletions in fibroblasts from some patients with bilateral retinoblastoma also indicates that the isolated gene is useful for diagnostic purposes.

Alleles↗

PubMed1994

A developmental context for multiple genetic alterations in Wilms' tumor.

Wilms' tumor has served as an example of Knudson's two-hit hypothesis of recessive tumor genes, but the genetics has proven to be surprisingly complex. WT1, a tumor suppressor gene on 11p13, is mutated in only a small fraction of Wilms' tumors, and a second chromosomal region, 11p15, harbors a second Wilms' tumor gene also involved in other cancers. In addition, loss of genomic imprinting, or parental origin-specific gene expression of at least two genes, appears to be an early step in Wilms' tumorigenesis and common cancers. Finally, genes on other chromosomes also play a role. I propose a model of Wilms' tumorigenesis in which multiple genetic alterations act within a specific developmental context, accounting for the epidemiological and pathological heterogeneity of Wilms' tumor, as well as the tissue specificity of the tumor types arising from alterations in these genes.

Beckwith-Wiedemann Syndrome↗

PubMed1992

Genome imprinting and cancer genetics.

Parent-of-origin-dependent modification of the genome (genome imprinting) is thought to be involved in the formation of several types of human cancer. Simple modifications of Knudson's two-hit model give rise to two types of predictions with respect to the genetic behavior of such diseases. In the first, rare alleles of modifier genes will give rise to the retention of the same parent's tumor suppressor alleles in sporadic cases. In the second, other variants of the modifier genes will result in failure to establish linkage between tumor suppressor genes and disease predisposition in familial cases. Both of these predictions are fulfilled by experiment. Additional modifications of existing models are predicted to result in more complex patterns of inheritance. The demonstration of such patterns in human pedigrees will require an extremely sophisticated level of genetic analysis.

Genome, Human↗

PubMed2026

Novel insights into retinoblastoma: From oncogenic circuitry to precision diagnosis and eye-preserving therapies.

Retinoblastoma (RB) represents the most common primary intraocular malignancy in childhood and stands as a paradigm for translating molecular oncology into precision clinical management. This review synthesizes the comprehensive evolution in the understanding and treatment of RB. First, we deconstruct the intricate oncogenic circuitry that extends far beyond Knudson's classic "two-hit" RB1 inactivation model, describing non-classical MYCN-driven pathogenesis, multi-layered epigenetic reprogramming (including chromatin, RNA and histone changes), and distinct histological subtypes with defined clinical correlates, such as the favorable-prognosis cavitary RB. Single-cell genomics has elucidated the cellular origin from cone precursor cells and intratumoral heterogeneity. Risk stratification has been refined through well-defined classification systems, from the therapy-guiding International Intraocular Retinoblastoma Classification (IIRC) to the comprehensive American Joint Committee on Cancer Tumor-Node-metastasis (AJCC TNM) staging. Furthermore, the diagnostic paradigm has advanced from conventional anatomical imaging to liquid biopsies, enabling non-invasive molecular staging and monitoring via tumor-derived cell-free DNA analysis. Concurrently, the therapeutic landscape has undergone a radical shift, moving from enucleation and external-beam radiotherapy to an era dominated by local sight-preserving strategies. We provide a critical synthesis of the evidence for intravenous chemotherapy and the transformative role of super-selective intra-arterial chemotherapy (IAC), and describe essential randomized controlled trials, technical innovations, and optimized drug regimens. Finally, we explore emerging targeted molecular therapies and future directions. By integrating cutting-edge molecular insights with robust, high-level clinical evidence, this review offers the framework for achieving patient and eye survival as well as vision preservation in children with Retinoblastoma.

Intra-arterial chemotherapy↗

PubMed1983

Genetic models of carcinogenesis.

The major genetic models of carcinogenesis are critically reviewed to determine their validity and relevance for clinical and experimental oncologists. Of major concern are the "two-hit" theory of Knudson and the host resistance system of Matsunaga. These models may be used to explain the pathobiologic peculiarities of human neoplasms, particularly those occurring in early life. It is proposed that certain benign and regressive tumors encountered in early life are expressions of the activity of the host resistance system.

Adult↗

PubMedDate not supplied

Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome.

Tumour suppressor genes, whose usual function seems to be controlling normal cell proliferation, have been implicated in many inherited and sporadic forms of malignancies Much evidence supports the concept of tumour formation by loss-of-function mutations in suppressor genes, as predicted by the two-hit model of Knudson and DeMars. The suppressor gene, p53, is affected in such a manner by numerous mutations, which occur in a variety of human tumours. These mutations usually represent the loss of one allele and the substitution of a single base in the other. We have now analysed the p53 gene in a family affected by Li-Fraumeni syndrome, a rare autosomal dominant syndrome characterized by the occurrence of diverse mesenchymal and epithelial neoplasms at multiple sites. In some instances the neoplasms seem to be related to exposure to carcinogens, including ionizing radiation. The Li-Fraumeni family that we studied had noncancerous skin fibroblasts (NSF) with an unusual radiation-resistant phenotype. DNA derived from the NSF cells of four family members, spanning two generations, had the same point mutation in codon 245 (GGC----GAC) of the p53 gene. This mutation leads to substitution of aspartic acid for glycine in one of the regions identified as a frequent target of point mutations in p53. The NSF cell lines with the mutation also retained the normal p53 allele. This inherited p53 mutation may predispose the members of this family to increased susceptibility to cancer.

Base Sequence↗

PubMed1986

Epidemiological investigations on neuroblastomas in Denmark 1943-1980.

During the period 1943-1980 a significant increase in the incidence of neuroblastoma was seen in Denmark. The incidence increased from a level corresponding to that in Finland to a level corresponding to that in the USA, and the increase appears to be continuing. The increase relates to children aged under 5 years, and is most pronounced in infants under 1 year. The incidence in the first year of life has, however, not yet reached the level of the USA. The increase in incidence is most likely a result of improved diagnosis, changes in the social composition of the population, and an increase in environmental carcinogens of importance in the induction of neuroblastomas. The incidence is lower in children of self-employed parents, and higher in infants of mothers aged under 20 or over 34 years. Aside from lower socio-economic circumstances for mothers under 20 years, no specific risk factors were revealed in this study. The observations of a family in which the mother has ganglioneuroma and both daughters have developed neuroblastoma, of a child who suffered from both neuroblastoma and neurofibromatosis von Recklinghausen, and of a significantly higher frequency of infants with signs of multicentric tumours in the offspring of mothers aged under 20 and over 34 years of age, is consistent with the two-hit theory of Knudson et al. (1972).

Adolescent↗

PubMed1989

Loss of allelic heterozygosity at a second locus on chromosome 11 in sporadic Wilms' tumor cells.

Children with associated Wilms' tumor, aniridia, genitourinary malformations, and mental retardation (WAGR syndrome) frequently have a cytogenetically visible germ line deletion of chromosomal band 11p13. In accordance with the Knudson hypothesis of two-hit carcinogenesis, the absence of this chromosomal band suggests that loss of both alleles of a gene at 11p13 causes Wilms' tumor. Consistent with this model, chromosomes from sporadically occurring Wilms' tumor cells frequently show loss of allelic heterozygosity at polymorphic 11p15 loci, and therefore it has been assumed that allelic loss extends proximally to include 11p13. We report here that in samples from five sporadic Wilms' tumors, allelic loss occurred distal to the WAGR locus on 11p13. In cells from one tumor, mitotic recombination occurred distal to the gamma-globin gene on 11p15.5. Thus, allelic loss in sporadic Wilms' tumor cells may involve a second locus on 11p.

Alleles↗

PubMed2024

Pan-cancer analysis of biallelic inactivation in tumor suppressor genes identifies KEAP1 zygosity as a predictive biomarker in lung cancer.

The canonical model of tumor suppressor gene (TSG)-mediated oncogenesis posits that loss of both alleles is necessary for inactivation. Here, through allele-specific analysis of sequencing data from 48,179 cancer patients, we define the prevalence, selective pressure for, and functional consequences of biallelic inactivation across TSGs. TSGs largely assort into distinct classes associated with either pan-cancer (Class 1) or lineage-specific (Class 2) patterns of selection for biallelic loss, although some TSGs are predominantly monoallelically inactivated (Class 3/4). We demonstrate that selection for biallelic inactivation can be utilized to identify driver genes in non-canonical contexts, including among variants of unknown significance (VUSs) of several TSGs such as KEAP1. Genomic, functional, and clinical data collectively indicate that KEAP1 VUSs phenocopy established KEAP1 oncogenic alleles and that zygosity, rather than variant classification, is predictive of therapeutic response. TSG zygosity is therefore a fundamental determinant of disease etiology and therapeutic sensitivity.

Kelch-Like ECH-Associated Protein 1↗

PubMed1988

Do human renal cell carcinomas arise by a double-loss mechanism?

Combined consideration of a constitutional t(3;8) that was regularly associated with renal cell carcinoma (RCC) within a large family and cytogenetic and restriction fragment length polymorphism studies on sporadic RCC has led to the tentative conclusion that RCC may arise by a similar double-loss mechanism as retinoblastoma and Wilms' tumor. This hypothesis predicts single-hit kinetics for the age distribution of hereditary RCC and two-hit kinetics for sporadic tumors, in analogy with Knudson's original prediction for retinoblastoma and Wilms' tumor. We have compared the age distribution of 51 hereditary and 56 sporadic cases of RCC sampled from the literature. The age-incidence curve of the hereditary RCC is compatible with a single event, whereas the sporadic tumors arise as predicted from a two-hit curve. We therefore suggest that RCC arises by the loss of a recessive cancer gene, probably localized to the short arm of chromosome 3 (in band 3p14.2).

Adult↗