Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1996-03-28
2001-11-06
Myers, Carla J. (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C536S023100, C536S023500, C536S024310, C536S024330
Reexamination Certificate
active
06312890
ABSTRACT:
FIELD OF THE INVENTION
The invention is in the field of tumor suppressor genes. More specifically, the invention relates to the Von Hippel-Lindau (VHL) disease gene and its corresponding cDNA and to methods for detecting carriers of the VHL disease gene using probes derived from the DNA sequences of the present invention.
BACKGROUND OF THE INVENTION
Von Hippel-Lindau (VHL) disease is a familial cancer syndrome. This disease is an autosomal dominant disorder and patients who are heterozygous for mutations in the VHL disease gene are predisposed to a variety of cancers, the most frequent being hemangioblastomas of the central nervous system and retina, renal cell carcinoma (RCC) and pheochromocytoma. The multisystem character of the illness, combined with the fact multiple tumors may form in each target organ, produces considerable morbidity and mortality as evidenced by the reduction in life expectancy of affected individuals to 49 years (McKusick, V. A., Mendelian Inheritance in Man (1983) Johns Hopkins University Press, Baltimore and London, p 534-535). Although the prevalence of VHL disease is only 1 in 36,000, because of its late onset most individuals have children before they realize they have inherited VHL disease. For many years, the only method of presymptomatic or prenatal diagnosis of the disease has been periodic examination of the eye, brain, and abdomen in all asymptomatic members of VHL families. Unfortunately, examination of all target organs is required to ensure detection of disease that may be limited to a single organ. In addition to the obvious inconvenience and the cost of these examinations, they have the additional drawback that they may not yield definitive diagnostic information. Therefore, in order to develop a method which allows the unequivocal diagnosis of VHL disease in individuals at risk, researchers have focused intensive efforts on identifying and isolating the VHL disease gene.
Results of this research have shown that the VHL disease gene is a member of the family of tumor suppressor genes (Tory, K. et al. J. Natl. Canc. Inst. (1989) 81:1097-1101; Maher, E. R. et al. J. Med. Genet. (1990) 27:311-314) and that it behaves in accordance with Knudson's theory of human carcinogenesis (Knudson, A., Proc. Natl. Acad Sci. USA (1971) 68:816-823). In addition, the identification of DNA markers tightly linked to the VHL disease gene has allowed localization of the VHL disease gene to human chromosome 3p25-p26. (Hosoe, S. et al. Genomics (1990) 8:634-640; Maher, E. R. et al. Genomics (1990) 8:957-960; Glenn, G. M. et al. Hum. Genet. (1990) 87: 207-210, Latif, F. et al. Am J. Hum. Genet. (1992) 51 (suppl.) A63; Tory, K. et al. Genomics (1992) 13:275-286; Richards, F. M. et al. J. Med. Genet. (1993) 30:104-107); Seizinger, B. R. et al. Nature (1988) 332:268-269; Seizinger, B. R. et al. Proc. Natl. Acad. Sci. USA (1991) 88:2864-2868 and Vance J. M. et al. Am J. Hum. Genet. (1993) 51:203-209)). Recently, Glenn et al. (Glenn, G. M. et al. JAMA (1992) 1226-1231) have used DNA markers flanking the VHL disease gene as probes to detect linkage to the VHL disease gene via restriction fragment polymorphism analysis of DNA isolated from individuals who are members of families at risk for VHL disease. Although this DNA polymorphism method results in enhanced accuracy of identification of carriers of VHL disease gene, the method is inherently flawed in that DNA polymorphism analysis does not detect the VHL disease gene itself. More recently, a gene located in the VHL region has been cloned (Latif, F. et al. Cancer Res. (1993) 53:861-867). However, this gene was found to detect no mutation in VHL patients and thus, there are currently no available methods which can identify carriers of the VHL disease gene with 100% accuracy. However, the recent identification and isolation of the VHL disease gene (Latif et al.,
Science
, (1993) 260:1317-1320) and its corresponding cDNA should allow the development of diagnostic methods which provide unequivocal detection of carriers of the VHL disease gene.
SUMMARY OF THE INVENTION
The present invention relates to the von Hippel-Lindau (VHL) disease gene and its corresponding cDNA.
The invention further relates to methods for detecting carriers of the VHL gene. The first method comprises analyzing DNA of a subject for mutations of the VHL disease gene associated with VHL disease or other diseases, including, but not limited to, sporadic renal cancer, lung cancer, uterine cancer, breast cancer, testicular cancer, ovarian cancer, adrenal tumors, brain tumors, lung tumors or other cancers.
The second method comprises analyzing RNA of a subject for mutations or alterations in the VHL-specific mRNA associated with VHL disease or other diseases, including, but not limited to, sporadic renal cancer, lung cancer, uterine cancer, breast cancer, testicular cancer and ovarian cancer.
The third method comprises analyzing protein of a subject for alterations in VHL protein expression associated with VHL disease or other diseases, including, but not limited to, sporadic renal cancer, lung cancer, uterine cancer, breast cancer, testicular cancer and ovarian cancer.
The invention also encompasses recombinant VHL proteins derived from the VHL cDNA and antibodies directed against said VHL proteins or peptides derived therefrom.
The invention further relates to a method for treating a carrier of the VHL gene in which an expression vector containing a nucleic acid sequence representing the wild-type VHL gene is administered to the carrier.
The invention also provides a diagnostic kit for detecting carriers of the VHL gene. The kit comprises purified and isolated nucleic acid sequences useful as PCR primers in analyzing DNA or RNA for mutations of the VHL gene associated with VHL disease and diseases related thereto, including, but not limited to, sporadic renal cancer, lung cancer, uterine cancer, breast cancer, testicular cancer and ovarian cancer.
REFERENCES:
Sekido et al. Oncogene. 9:1599-1604, 1994.
Latif Farida
Lerman Michael I.
Linehan W. Marston
Zbar Berton
Morgan & Finnegan , LLP
Myers Carla J.
The United States of America as represented by the Department of
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