Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2001-05-11
2002-05-14
McKelvey, Terry (Department: 1636)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
Reexamination Certificate
active
06387633
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a method for identifying genetic instability and screening for genes involved in genetic alterations by using genes that are capable of inducing genetic instability. More specifically, the present invention provides a method for generating genetically unstable cell lines by using the human metastasin 1.
BACKGROUND OF THE INVENTION
Neoplastic cells typically possess numerous lesions, which may include sequence alterations such as point mutations, small deletions, insertions and/or gross structural abnormalities in one or more chromosomes such as large-scale deletions, rearrangements, or gene amplifications (Hart and Saini, 1992
Lancet,
333:1453-61; Seshadri et al., 1989
Int. J. Cancer,
43:270-72. Based upon this general observation, it has been suggested that cancer cells are genetically unstable and that acquisition of genomic instability may represent an early step in the process of carcinogenesis and a general feature of many human tumors (Liotta et al., 1991
Cell,
64:327-36. The ensuing genetic instability drives tumor progression by generating mutations in oncogenes and tumor-suppressor genes, which leads to the clonal outgrowth of a tumor (Ponta et al., 1994
BBA,
1198:1-10; Berstein and Liotta, 1994
Current Opt. In Oncology;
6:106-13; Brattein et al., 1994
Current Opt. In Oncology;
6:477-81; Fidler and Ellis, 1994
Cell,
79:315-28). These mutant genes provide cancer cells with a selective growth advantage by promoting resistance to immune-based destruction, allowing disobeyance of cell cycle checkpoints that would normally induce apoptosis, facilitating growth factor/hormone-independent cell survival, supporting anchorage-independent survival metastasis, reducing dependence on oxygen and nutrients, and conferring resistance to cytotoxic anticancer drugs and radiation. Therefore, elucidation of the genes that cause genetic instability in cancer cells, as well as identification of the genes that are most susceptible to the alterations, represents a promising approach for development of new strategies for combating cancer and for its diagnosis at early stages of development.
A. Genomic Instability
Genomic instability in its broadest sense is a feature of virtually all neoplastic cells. In addition to the mutations and/or gene amplification that appear to be a prerequisite for the acquisition of a neoplastic phenotype, human cancers exhibit other markers of genomic instability, and in particular, a high degree of aneuploidy. Many studies have shown that aneuploidy is an almost invariant feature of cancer cells, and it has been argued by some that the emergence of aneuploid cells is necessary step during tumorigenesis. The functional link between genomic instability and cancer is strengthened by the existence of several “genetic instability” disorders of humans that are associated with a moderate to severe increase in the incidence of cancers. These disorders include ataxia telangiectasia (Gonzalez-del Angel, A. et al., 2000
Am. J. Med. Genet.,
90:252-4), Bloom's syndrome (Karow, J. K. et al., 2000
Proc. Natl. Acad. Sci. USA,
97:6504-8), Faconi anemia (Leteutre, F. et al., 1999
Brit. J. Hematol.,
105: 883-93), xeroderma pigmentosum, and Nijmegen breakage syndrome (Mathur, R. et al., 2000
Indian Pediatr.
37: 615-25), of all which are very rare and are inherited in a recessive manner. Analysis of the cells from such cancer prone individuals is clearly a potentially fruitful approach for delineating the genetic basis for instability in the genome. It is assumed that by identifying the underlying cause of genetic instability in these disorders, one can derive valuable information not only about the basis of particular genetic diseases, but also about the underlying causes of genomic instability in sporadic cancers in the general population.
Currently, methods and strategies for identifying the pathology of related genes include genetic analysis of hereditary diseases, cytological methods including analysis of chromosomal aberrations and segregation analysis, and molecular biology methods including comparative genomic hybridization, microsatellite analysis, differential screening, differential display, methods of gene fishing, transgenics, knockout animals and gene function analysis.
Genomic instability plays a leading role in tumor progression and formation of metastatic cancer. This process involves activation of oncogenes, rearrangement of chromosomes, karyotipic, genetic and epigenetic instability and amplification of genes (Hart and Saini, 1992
Lancet,
339:1453-61; Seshadri et al., 1989
Int. J. Cancer,
43:270-72). The metastatic process depends not only on transformation, but also on a chain of interactions between tumor cells with the host's cells and tissues (Ponta et al., 1994
BBA,
1198: 1-10; Berstein and Liotta, 1994
Current Opt. In Oncolgy,
6:106-13; Brattein et al., 1994
Current Opt. In Oncolgy,
6:77-81; Fidler and Ellis, 1994
Cell,
79:315-28). A series of experiments revealed that neoplastic transformation resulted in changes in expression of genes coding Ca
++
binding proteins from the S100 gene family (Ebralidze et al., 1989
Gen. Dev.,
3:1086-93; Schafer and Heizmann, 1996
TIBS,
21:134-40). Expression of genes encoding metastasin (S100A4) (Ebralidze et al., 1989
Gen. Dev.,
3:1086-93), calcycline (S100A6) (Tomasetto et al., 1995
Genomics,
28:367-76), psoreasine (S100A7) and S100C (Moog-Lutz et al., 1995
Int. J. Cancer,
63:297-03) was enhanced, whereas expression of gene S100A2 was weakened (Lee et al., 1992
Proc. Nat. Acad. Sci. USA,
89:2504-08). It is hypothesized that these proteins participate in the tumor progression and metastasis through regulation of cell cycle and differentiation (Schafer and Heizman, 1996
TIBS,
21:134-40). The human protein metastasin-1, (hereinafter, “mts-1”), which is also referred to as its rodent homologue known also under the names of S100A4, calvasculin, cap1, p9ka, 42A, 18A2 and pEL98 as well the rodent homolog of the human protein has attracted attention from cancer researchers. The expression of mts-1 is observed in various aggressive cell strains (Baraclough et al., 1987
J. Mol. Biol.,
29:293-98; De Vouge and Mukerjee, 1992
Oncogene,
7:109-19). Moreover, it has been demonstrated that transfection of malignant rodent cell strains with the gene metastasin may enhance metastasis. (Grigorian et al., 1993
Gene,
135:229-38 and Davies et al., 1993
Oncogene,
8:999-1008). For example, when mouse embryonic fibroblasts were transfected with the scr gene, the rat homologue of mts-1, the protein pEL98 was co-localized on cytoskeleton elements identical with actin filaments and interacted with the heavy chain of non-muscular myosin.
Chromosome instability is a characteristic cytogenetic feature of a number of genetically determined disorders collectively referred to as the chromosome breakage syndrome or DNA repair disorders. These disorders are characterized by their increased susceptibility and frequency to chromosomal breakage and chromosome interchanges occurring either spontaneously or following exposure to various DNA damaging agents. These genetic disorders share a number of features. They are all autosomal recessive, demonstrate an increased tendency for chromosomal aberrations and development of malignancies. The principal diseases in this group, which have diverse etiologies and clinical manifestations, include Fanconi anemia (FA), ataxia telangiectasia (AT), Nijmegen breakage syndrome (NBS), Bloom syndrome (BS) (Karow, J. K. et al,
Proc Natl Acad. Sci. USA
2000; 97: 6504-8), xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). The underlying defect in each of these syndromes is the inability to repair a particular type of DNA damage. A number of phenotypes are caused by more than one gene. The initial diagnosis of these syndromes is made by the characteristic clinical features specific to each disease, but the definitive diagnosis is achieved by laboratory investigations such as
Gibbons Del Deo Dolan Griffinger & Vecchione
McKelvey Terry
Supratek Pharma Inc.
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