Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
2000-12-18
2002-09-10
Bansal, Geetha P. (Department: 1642)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S070100, C435S320100, C435S325000, C536S023100, C536S023500
Reexamination Certificate
active
06448041
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a mammalian cDNA which encodes a colon cancer marker and to the use of the cDNA and the encoded protein in the diagnosis and treatment of colon disorders, particularly colon cancer and polyps.
BACKGROUND OF THE INVENTION
Phylogenetic relationships among organisms have been demonstrated many times, and studies from a diversity of prokaryotic and eukaryotic organisms suggest a more or less gradual evolution of molecules, biochemical and physiological mechanisms, and metabolic pathways. Despite different evolutionary pressures, the proteins of nematode, fly, rat, and man have common chemical and structural features and generally perform the same cellular function. Comparisons of the nucleic acid and protein sequences from organisms where structure and/or function are known accelerate the investigation of human sequences and allow the development of model systems for testing diagnostic and therapeutic agents for human conditions, diseases, and disorders.
Colorectal cancer is the fourth most common cancer and the second most common cause of cancer death in the United States with approximately 130,000 new cases and 55,000 deaths per year. Colon and rectal cancers share many environmental risk factors and both are found in individuals with specific genetic syndromes (Potter (1999) J Natl Cancer Institute 91:916-932). Colon cancer is the only cancer that occurs with approximately equal frequency in men and women, and the five-year survival rate following diagnosis of colon cancer is around 55% in the United States (Ries et al. (1990) National Institutes of Health, DHHS Publ. No. (NI)90-2789).
Colon cancer is causally related to both genes and the environment. Several molecular pathways have been linked to the development of colon cancer, and the expression of key genes in any of these pathways may be affected by inherited or acquired mutation or by hypermethylation. There is a particular need to identify genes for which changes in expression may provide an early indicator of colon cancer or a predisposition for the development of colon cancer.
For example, it is well known that abnormal patterns of DNA methylation occur consistently in human tumors and include, simultaneously, widespread genomic hypomethylation and localized areas of increased methylation. In colon cancer in particular, it has been found that these changes occur early in tumor progression such as in premalignant polyps that precede colon cancer. Indeed, DNA methyltransferase, the enzyme that performs DNA methylation, is significantly increased in histologically normal mucosa from patients with colon cancer or in the benign polyps that precede cancer. This increase continues during the progression of colonic neoplasms (El-Deiry et al. (1991) Proc Natl Acad Sci USA 88:3470-3474). Increased DNA methylation occurs in G+C rich areas of genomic DNA termed “CpG islands” that are important for maintenance of an “open” transcriptional conformation around genes, and hypermethylation of these regions results in a “closed” conformation that silences gene transcription. It has been suggested that the silencing or downregulation of differentiation genes by such abnormal methylation of CpG islands may prevent differentiation in immortalized cells (Antequera et al. (1990) Cell 62:503-514).
Familial adenomatous polyposis (FAP) is a rare autosomal dominant syndrome that precedes colon cancer and is caused by an inherited mutation in the adenomatous polyposis coli (APC) gene. FAP is characterized by the early development of multiple colorectal adenomas that progress to cancer at a mean age of 44 years. The APC gene is a part of the APC-&bgr;-catenin-Tcf (T-cell factor) pathway. Impairment of this pathway results in the loss of orderly replication, adhesion, and migration of colonic epithelial cells that results in the growth of polyps. A series of other genetic changes follow activation of the APC-&bgr;-catenin-Tcf pathway and accompanies the transition from normal colonic mucosa to metastatic carcinoma. These changes include mutation of the K-Ras proto-oncogene, changes in methylation patterns, and mutation or loss of the tumor suppressor genes p53 and Smad4/DPC4. While the inheritance of a mutated APC gene is a rare event, the loss or mutation of APC and the consequent effects on the APC-&bgr;-catenin-Tcf pathway is believed to be central to the majority of colon cancers in the general population.
Hereditary nonpolyposis colorectal cancer (HNPCC) is another inherited autosomal dominant syndrome with a less well defined phenotype than FAP. HNPCC, which accounts for about 2% of colorectal cancer cases, is distinguished by the tendency to early onset of cancer and the development of other cancers, particularly those involving the endometrium, urinary tract, stomach, and biliary system. HNPCC results from the mutation of one or more genes in the DNA mis-match repair (MMR) pathway. Mutations in two human MMR genes, MSH2 and MLH1, are found in a large majority of HNPCC families identified to date. The DNA MMR pathway identifies and repairs errors that result from the activity of DNA polymerase during replication. Furthermore, loss of MMR activity contributes to cancer progression through accumulation of other gene mutations and deletions, such as loss of the BAX gene which controls apoptosis, and the TGF&bgr; receptor II gene which controls cell growth. Because of the potential for irreparable damage to DNA in an individual with a DNA MMR defect, progression to carcinoma is more rapid than usual.
Although ulcerative colitis is a minor contributor to colon cancer, affected individuals have about a 20-fold increase in risk for developing cancer. Progression is associated with mutations in the p53 gene which may occur early, appearing even in histologically normal tissue. The progression of the disease from ulcerative colitis to dysplasia/carcinoma without an intermediate polyp state suggests a high degree of mutagenic activity resulting from the exposure of proliferating cells in the colonic mucosa to the colonic contents.
Almost all colon cancers arise from cells in which the estrogen receptor (ER) gene has been silenced. The silencing of ER gene transcription is age related and linked to hypermethylation of the ER gene (Issa et al. (1994) Nature Genetics 7:536-540). Introduction and expression of an exogenous ER coding sequence into cultured colon carcinoma cells results in marked suppression of growth. Inhibition of cancer cell invasion depends on the function of the hormone binding domain and the N-terminal zinc finger region of the ER (Platet et al. (2000) Mol Endocrinol 14:999-1009). Activation of the ER by hormone binding induces transcription of specific target genes and may be linked to the reduction in cancer invasiveness. In the absence of hormone, protein-protein interactions with the zinc finger region may also contribute to the inhibition of cancer cell migration. The connection between loss of the ER protein in colonic epithelial cells and the consequent development of cancer has not been established.
The FYVE-finger proteinsplay roles in cellular processes such as receptor signaling, vesicular trafficking, and actin-regulated membrane rearrangements (Stenmark and Aasland (1999) J Cell Science 112:4175-4183). The FYVE domain is a type of zinc finger that typically contains eight conserved cysteines which bind two Zn
2+
cations, has conserved glycine and arginine residues, and a basic motif with the consensus sequence R(R/K)HHCR. The FYVE domain binds to phosphoinositides found in specific membranes. The presence of other domains in FYVE-finger proteins may mediate protein—protein interactions with other molecules at the membrane and may be involved in the recruitment of signaling molecules such as small GTPases to membranes at particular cellular locations. In mice with a null muation in the FYVE finger protein Hrs, embryos showed defects in ventral folding morphogenesis and died in utero (Komada and Soriano (1999) Genes Dev 13:1475-1485). The embryos developed with t
Baughn Mariah R.
Krasnow Randi E.
Warren Bridget A.
Wolven Amy K.
Bansal Geetha P.
Davis Natalie
Incyte Genomics Inc.
Incyte Genomics, Inc.
LandOfFree
Colon cancer marker does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Colon cancer marker, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Colon cancer marker will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2863448