Mammalian tumor susceptibility genes and their uses

Details Mammalian tumor susceptibility genes and their uses Mammalian tumor susceptibility genes and their uses

1998-09-01

2001-06-19

Brusca, John S. (Department: 1631)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

C530S350000, C530S387700, C536S023500

Reexamination Certificate

active

06248523

ABSTRACT:

INTRODUCTION
1. Technical Field
The field of the subject invention is mammalian genes associated with susceptibility to tumors.
2. Background
There has been considerable interest in the development of a method for identifying mammalian cell genes whose concurrent homozygous inactivation de novo leads to a defined phenotype, where multiple alleles of a gene have been inactivated and where it is easy to confirm that the inactivation results in a phenotype distinguishable from the wild-type. One use of this method is the identification of genes involved in tumor susceptibility.
Tumor susceptibility genes may be oncogenes, which are typically upregulated in tumor cells, or tumor suppressor genes, which are down-regulated or absent in tumor cells. Malignancies may arise when a tumor suppressor is lost and/or an oncogene is inappropriately activated. When such mutations occur in somatic cells, they result in the growth of sporadic tumors. Familial predisposition to cancer may occur when there is a mutation, such as loss of an allele encoding a tumor suppressor gene, present in the germline DNA of an individual. In the best characterized familial cancer syndromes, the primary mutation is a loss of function consistent with viability, but resulting in neoplastic change consequent to the acquisition of a second somatic mutation at the same locus.
Extensive studies of the early-onset breast cancer families have led to the recent identification of two candidate breast cancer suppressor genes, BRCA1 and BRCA2. Although frequent mutations of BRCA1 or BRCA2 have been demonstrated in familial early onset breast cancer, this type of cancer represents only about 5-10% of all breast malignancies, and the possible role(s) of BRCA1 and BRCA2 in the remaining 90-95% of sporadic breast cancers has not been determined.
Deletion and loss of heterozygosity (LOH) of markers in human chromosome band 11p15 have been shown in a variety of human cancers, including lung cancer, testicular cancer and male germ cell tumor, stomach cancer, Wilms' tumor, ovarian cancer, bladder cancer, myeloid leukemia, malignant astrocytomas and other primitive neuroectodermal tumors, and infantile tumors of adrenal and liver. About 30% of sporadic breast carcinomas show a LOH in this region. Since LOH is believed to indicate inactivation of a tumor suppressor gene at the location where LOH occurs, the frequent LOH found at 11p15 in a variety of human cancers suggests the presence of either a cluster of tumor suppressor genes or a single pleiotropic gene in this region.
The clinical importance of these cancers makes the identification of this putative tumor suppressor gene of great interest for diagnosis, therapy, and drug screening.
Relevant Literature
Lemke et al. (1993)
Glia
7:263-271 describes loss of function mutations engineered through the expression of antisense RNA from previously cloned genes and through the insertional inactivation of the P
o
gene, by homologous recombination in embryonic stem cells, and the generation of P
o
-deficient mice. Kamano et al. (1990)
Leukemia Res.
10:831-839; van der Krol et al. (1988)
Biotechniques
6:958; Katsuki et al. (1988)
Science
241:593-595; Owens et al. (1991)
Development
112:639-649; and Owens et al. (1991)
Neuron
7:565-575 describe changes in cell phenotype associated with the expression of antisense RNAs in different cell types. Giese et al. (1992)
Cell
71:565-576 describes the inactivation of both copies of a gene in a transgenic mouse.
Studies of LOH in Wilms' tumors identified a tumor suppressor locus at 11p15, for example see Dowdy et al. (1991)
Science
254:293-295. Two familial breast cancer genes have been previously described, BRCA1 in Miki et al. (1994)
Science
266:66-71, and BRCA2 in Wooster et al. (1995)
Nature
378:789-792.
The interaction of stathmin with a coiled coil domain is described in Sobel (1991)
Trends Biochem. Sci.
16:301-305.
SUMMARY OF THE INVENTION
Mammalian tumor susceptibility genes and methods for their identification are provided, including the complete nucleotide sequences of human TSG101 and mouse tsg101 cDNA. Deletions in TSG101 are associated with the occurrence of human cancers, for example breast carcinomas. The cancers may be familial, having as a component of risk an inherited genetic predisposition, or may be sporadic. The TSG101 nucleic acid compositions find use in identifying homologous or related proteins and the DNA sequences encoding such proteins, in producing compositions that modulate the expression or function of the protein; and in studying associated physiological pathways. In addition, modulation of the gene activity in vivo is used for prophylactic and therapeutic purposes, such as treatment of cancer, identification of cell type based on expression, and the like. The DNA is further used as a diagnostic for a genetic predisposition to cancer, and to identify specific cancers having mutations in this gene.


REFERENCES:
Baim, et al., “A Chimeric Mammalian Transactivator Based On The lac Repressor That IS Regulated By Temperature And Isopropyl &bgr;-D-Thiogalactopyranoside,”PNAS USA(1991) vol. 88:5072-5076.
Baubonis and Sauer, “Genomic Targeting With Purified Cre Recombinase,”Nucleic Acid Research(1993) vol. 21:2025-2029.
Craig, “The Mechanism of Conservative Site-Specific Recombination,”Annu. Rev. Genet.(1988) vol. 22:77-105.
Dowdy, et al.,Science(1991) vol. 254:293-295.
Ferti-Passantonopoulou, et al., “Preferential Involvement of 11q23-24 and 11p15 in Breast Cancer,”Cancer Genet Cytogenet(1991) vol. 51:183-188.
Gabra, et al., “Chromosome 11 Allele Imbalance and Clinicopathological Correlates in Ovarian Tumours,”British Journal of Cancer(1995) vol. 72:367-375.
Giese, et al., “Mouse P. Gene Disruption Leads to Hypomyelination, Abnormal Expression of Recognition Molecules, and Degeneration of Myelin and Axons,”Cell(1992) vol. 71:565-576.
Gossen, et al., “Transcriptional Activation by Tetracyclines in Mammalian Cells,”Science(1995) vol. 268:1766-1769.
Kallioniemi, et al., “Identification of Gains and Losses of DNA Sequence in Primary Bladder Cancer by Comparative Genomic Hybridization,”Genes, Chromosomes&Cancer(1995) vol. 12:213-219.
Kamano, et al., “Effects of the Antisense v-myb Expression on K562 Human Leukemia Cell Proliferation and Differentiation,”Leukemia Research(1990) vol. 14:831-839.
Katsuki, et al., “Conversion of Normal Behavior to Shiverer by Myelin Basic Protein Antisense cDNA in Transgenic Mice,”Reports(1988) vol.241:593-595.
Lemke, “The Molecular Genetics of Myelination: An Update,”GLIA(1993) vol. 7:263-271.
Maucer, et al., “Stathmin Interaction With a Putative Kinase and Coiled-Coil-Forming Protein Domains,”Proc. Natl. Acad. Sci. USA(1995) vol. 92:3100-3104.
Miki, et al.,Science(1994) vol. 266:66-71.
Mullokandov, et al., “Genomic Alterations in Cervical Carcinoma: Losses of Chromosome Heteroygosity and Human Papiloma Virus Tumor Status,”Cancer Research(1996) vol. 56:197-205.
Owens and Boyd, “Expressing Antisense Po RNA in Schwan Cells Perturbs Myelination,”Development(1991) vol. 112:639-649.
Owens and Bunge, “Schwann Cells Infected With a Recombinant Retrovirus Expressing Myelin-Associated Glycoprotein Antisense RNA Do Not Form Myelin,”Neuron(1991) vol. 7:565-575.
Sobel,Trends. Biochem. Sci.(1991) vol. 16:301-305.
Stokes, et al., “The Partial 3' Conserved Segment Duplications in the Inegrons In6 from pSa and In7 form pDG0100 Have a Common Origin,”Plasmid(1993) vol. 30:39-50.
Voorter, et al., “Loss of Chromosome 11 and 11 P/Q Imbalances in Bladder Cancer Detected by Fluorescense in situ Hybridization,”Int. J. Cancer(1996) vol. 65:301-307.
Wooster, et al.,Nature(1995) vol.378:789-792.
Genbank Accession, No. H53754, Alignment Against Human TSG 101 Sequence.
Genbank Accession, No. 230135, Alignment Against Human TSG 101 Sequence.

Affiliated with

Also associated with

Rating

Mammalian tumor susceptibility genes and their uses does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Mammalian tumor susceptibility genes and their uses, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Mammalian tumor susceptibility genes and their uses will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2500590