Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-06-08
2001-01-23
Horlick, Kenneth R. (Department: 1656)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C536S025400, C536S025410, C536S025420
Reexamination Certificate
active
06177251
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a method of detecting a target nucleic acid in stool and reagents usefull therein.
2. Description of Related Art
An increasing body of evidence implicates somatic mutations as causally important in the induction of human cancers. These somatic mutations may accumulate in the genomes of previously normal cells, some of which may then demonstrate the phenotypes associated with malignant growth. Such oncogenic mutations may include a number of different types of alterations in DNA structure, including deletions, translocations and single nucleotide alterations. The latter, also known as point mutations, may frequently intervene in carcinogenesis, in that a variety of mutagenic chemicals induce such mutations. In addition, such mutations may occur spontaneously as a result of mistakes in DNA replication.
Advances in recombinant DNA technology have led to the discovery of normal cellular genes (proto-oncogenes and tumor suppressor genes) which control growth, development, and differentiation. Under certain circumstances, regulation of these genes is altered and they cause normal cells to assume neoplastic growth behavior. There are over 40 known proto-oncogenes and suppressor genes to date, which fall into various categories depending on their functional characteristics. These include, (1) growth factors and growth factor receptors, (2) messengers of intracellular signal transduction pathways, for example, between the cytoplasm and the nucleus, and (3) regulatory proteins influencing gene expression and DNA replication.
Point mutations have been directly implicated in the causation of many human tumors. Some tumors carry oncogenes of the ras gene family, which differ from their normal cellular counterpart proto-oncogenes by the presence of a point mutation at one of a limited number of sites in these genes. Similarly, point mutations in critical regions of tumor suppressor genes, such as p53, are often detected in tumor cells. These mutations represent qualitative changes in the tumor cell genome which distinguish these cells from normal cells and provide a basis for diagnosis of the genetic origin of a tumor under study. Identification of the mutations that have created active oncogenes may provide important diagnostic and prognostic clues for tumor development. For example, a number of mutations have been found to alter the 12th codon of the ras oncogenes, causing replacement of a normally present glycine by any of a number of alternative amino acid residues. Such amino acid substitutions create a potent transforming allele. Thus, the presence of a particular nucleotide substitution may be a strong determinant of the behavior of the tumor cell (e.g., its rate of growth, invasiveness, etc.). As a result, DNA probes of oncogene mutations have promise as diagnostic reagents in clinical oncology.
Among the various types of neoplasms, a number of those which are found in the gastrointestinal tract are associated with oncogenic mutations. This association is particularly significant for colorectal cancer. Colorectal cancer is the third most common malignancy in the world, with 570,000 new cases expected in 1992. In the United States alone, over 60,000 people will die from colorectal cancer in this same year. While patients with advanced disease have a very poor prognosis, colorectal tumors diagnosed at any stage prior to metastasis can usually be cured by surgical or colonoscopic excision. A method to detect surgically resectable tumors could, therefore, considerably reduce deaths from this disease (Winawer, et al.,
J. National Cancer Institute,
83:243, 1991). The only non-invasive test currently available for such a purpose involves testing stool for occult blood. Although stool blood tests may have value in certain circumstances, their utility is controversial, in part because the appearance of hemoglobin in stool is not specific for neoplasia (Ransoboff, et al.,
New England Journal of Medicine,
325:37, 1991; Miller, et al.,
Int. J. Cancer,
46:761, 1990). Although this has stimulated efforts to develop additional, non-invasive tests that could more reliably detect neoplasms of the colon and rectum, such attempts have failed. The present invention addresses this need.
SUMMARY OF THE INVENTION
The present invention arose from the unexpected finding that nucleic acid having a mutant nucleotide sequence associated with gastrointestinal neoplasia is present in detectable levels in stool specimens from patients with gastrointestinal neoplasia.
As a consequence of this discovery, the present invention represents a significant advance over such techniques as tissue biopsy by providing a non-invasive, rapid, and accurate method for detecting mutant nucleotide sequences associated with gastrointestinal neoplasia. Based on this finding, it is now possible to detect various other target nucleic acids associated with other disease states.
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Kinzler Kenneth W.
Vogelstein Bert
Banner & Witcoff , Ltd.
Horlick Kenneth R.
The Johns Hopkins University
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