Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-05-13
2002-07-23
Caputa, Anthony C. (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S004000, C435S007100, C435S007210, C435S007230, C435S007920, C435S007950, C436S063000, C436S064000
Reexamination Certificate
active
06423491
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the fields of oncology, genetics and molecular biology. More particular the invention relates to the identification of the gene responsible for familial juvenile polyposis. Defects in this gene are associated with a predisposition to gastrointestinal cancers.
2. Description of Related Art
Colorectal cancer is the second leading cause of cancer death in the United States. and was responsible for 57,407 deaths in 1994 (Landis et al., 1998). Approximately 5-10% of the nearly 131,600 new colorectal cancer cases each year will involve a clear heritable predisposition, of which the majority of cases involve hereditary non-polyposis colorectal cancer (HNPCC). About 1% of new colorectal cancers are related to inherited polyposis syndromes, which include familial adenomatous polyposis (FAP) and familial juvenile polyposis (FJP) (Rustgi, 1994).
Identification of the genes responsible for HNPCC and FAP have greatly increased our understanding of the molecular mechanisms contributing to the development of both familial and sporadic colorectal cancer. The intense studs of sporadic colorectal carcinogenesis over the last decade has shown that these tumors develop through the multi-step accumulation of different genetic mutations within colonic epithelial cells (Vogelstein et al., 1988). Genes known to be involved in this progression include APC and MCC on 5q21, KRAS2 on 12p12, p53 at 17p13, and several mismatch repair genes as seen in HNPCC (reviewed in Howe and Guillem, 1997).
Deletions on 18q21 also are quite common, occurring in approximately 75% of colorectal cancers (Vogelstein et al, 1988). Initial studies suggested that the tumor suppressor gene DCC (deleted in colorectal cancer)was the predisposing gene from this region (Fearon et al., 1990), but this has not been clearly established by further investigation.
Familial juvenile polyposis (JP) is an autosomal dominant condition characterized by multiple juvenile polyps of the gastrointestinal (GI) tract. Kindreds have been described in which there is involvement of the colon only juvenile polyposis
coli
, MIM 174900) (Veale et al., 1966; Grotsky et al, 1982; Rozen and Baratz 1982), the upper GI tract (Watanabe et al., 1979), and both upper and lower GI tracts (generalized polyposis) (Sachatello et al., 1970; Stemper et al., 1975; Jarvinen and Franssila 1984), although whether these are distinct clinical entities is not clear. Affected family members often present with blood per rectum or anemia in the 2d decade of life (Jass et al., 1988).
Microscopically, the polyps contain cystically dilated glands, abundant stroma. and an inflammatory infiltrate (Morson 1962). There have been many reports of patients with juvenile polyposis developing gastrointestinal malignancy, including colon cancer (Stemper et al, 1975; Liu et al., 1978; Goodman et al. 1979; Rozen and Baratz 1982;
Jarvinen and Franssila 1984; Ramaswamy et al, 1984; Baptist and Sabatini 1985; Jones et al, 1987; Bentley et al, 1989; Scott-Conner et al, 1995), stomach cancer (Stemper et al, 1975; Yoshida et al, 1988; Scott-Conner et al. 1995), and pancreatic cancer (Stemper et al., 1975; Walpole and Cullity 1989). Affected family members' risk of developing GI malignancy has been estimated to be from 9% (Jarvinen and Franssila 1984) to as high as 50% (Jass 1990). Development of adenocarcinoma has been hypothesized to begin with an adenomatous focus within a juvenile polyp, which later becomes dysplastic, and finally undergoes malignant transformation (Goodman et al., 1979; Jarvinen and Franssila 1984).
JP is a hamartomatous polyposis syndrome, as are Peutz-Jegher's Syndrome (PJS) and Cowden's disease (CD). Although the polyps in PJS are true hamartomata, some may undergo adenomatous change, and these family members are at increased risk for gastrointestinal malignancy. The PJS gene was mapped to chromosome 19p by comparative genomic hybridization and linkage (Hemminki et al., 1997; Mehenni et al., 1997), and germline mutations were identified in the serine threonine kinase gene LKBI (Hemminki et al., 1998). In CD, affected family members may develop multiple hamartomata of the skin, breast, thyroid, oral mucosa, or GI tract, and they are at risk for breast and thyroid malignancies. The gene for CD was localized to chromosome 10q22-23 by linkage (Nelen et al, 1996), and germline mutations in the PTEN gene have been found in affected family members (Liaw et al., 1997). A third entity, termed the “hereditary mixed-polyposis syndrome” (HMPS), differs from these syndromes in that affected family members have atypical juvenile polyps, colonic adenomas, and colorectal carcinomas. A gene for HMPS has been mapped to chromosome 6q by linkage (Thomas et al., 1996), and it remains uncertain whether HMPS is a distinct clinical syndrome or a variant of FJP (Whitelaw et al., 1997).
To date linkage studies in JP families have been limited, with one report excluding APC and MCC as the genes for FJP (Leggett et al., 1993). Other genetic studies, originally stimulated by the finding of an interstitial deletion at 10q22-24 in an infant with multiple colonic juvenile polyps and several congenital abnormalities (Jacoby et at., 1997b), have focused on the region of the PTEN gene. Evaluation for loss of heterozygosity in this region within juvenile polyps revealed somatic deletions within the lamina propria in 39 (83%) of 47 polyps derived from 13 unrelated patients with familial JP and 3 patients with sporadic juvenile polyps. These findings have been interpreted as evidence for a tumor-suppressor gene on 10q for FJP (termed “JPI”) (Jacoby et al., 1997a), but a recent study of 14 FJP families found neither mutations in PTEN nor evidence of linkage to markers on 10q22-24 (Marsh et al, 1997). Analysis of an additional 11 cases of FJP also did not uncover mutations in the PTEN gene (Riggins et al., 1997). Lynch et al., (1977) reported one family thought to have both juvenile polyposis syndrome and CD as having a nonsense mutation in PTEN, and Olschwang et al., (1998) described three patients with juvenile polyposis as having PTEN mutations. Whether these four individuals should truly be considered as having juvenile polyposis rather than CD is not clear from these reports.
It is evident from the discussion presented above that FJP is a significant disease which has yet to be definitively linked to aberrations in a particular gene. The identification of such a gene will allow the determination the molecular basis of gastrointestinal polyposis predisposing to colorectal cancer, as well as presymptomatic diagnosis of family members at risk. Such a gene also may be involved in the genesis of sporadic colorectal cancers, and therefore its discovery could ultimately impact on the treatment of this large group of patients.
SUMMARY OF THE INVENTION
A particular objective of the present invention is to identify the JP gene in a large kindred with generalized juvenile polyposis and gastrointestinal cancer and to use the gene in various diagnostic and therapeutic applications.
Thus in a preferred embodiment, the present invention provides a method of diagnosing juvenile polyposis comprising the steps of obtaining a sample from a subject; and determining the loss or alteration of a functional SM4D4 gene in cells of the sample. In certain defined embodiments the sample may be selected from the group consisting of blood, buccal smear and amniocentesis sample. In still further embodiments, the sample may be a tissue or fluid sample. In preferred embodiments, the determining may comprise assaying for a nucleic acid from the sample. In still further embodiments, the determining may further comprise subjecting the sample to conditions suitable to amplify the nucleic acid.
In alternative preferred embodiments, the determining comprises contacting the sample with an antibody that binds immunologically to a SMAD4. In particularly preferred embodiments, the method further comprises subjecting proteins of the sample to ELISA.
Aaltonen Lauri A.
Howe James R.
Caputa Anthony C.
Fulbright & Jaworski LLP
Harris Alana M.
University of Iowa Research Foundation
LandOfFree
Method of diagnosing juvenile polyposis (JP) does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method of diagnosing juvenile polyposis (JP), we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method of diagnosing juvenile polyposis (JP) will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2824451