Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-01-25
2002-08-06
Caputa, Anthony C. (Department: 1642)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C436S064000, C536S023100
Reexamination Certificate
active
06429302
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
This invention relates to genes differentially expressed in pancreatic disease, in particular, pancreatic cancer, dysplasis, and diabetes. More specifically, it relates to polynucleotides that are differentially regulated in pancreatic cancer and dysplasia.
BACKGROUND OF THE INVENTION
Cancer of the pancreas is the fifth leading cause of cancer death in the United States. According to the American Cancer Society, approximately 28,000 people will die of pancreatic cancer in the United States in 1998. The pancreas is a tongue-shaped glandular organ composed of both endocrine and exocrine gland portions, as well as ducts that connect the pancreas to the bile duct and small intestine. The endocrine portion of the pancreas secretes hormones, such as insulin and glucagon which are involved in blood sugar regulation, into the bloodstream. The exocrine portion of the pancreas produces pancreatic enzymes involved in the digestion of fats and proteins; these enzymes are delivered to the bile duct and into the small intestine.
Little is known about the causes of pancreatic cancer, although it is apparent that a high risk of developing pancreatic cancer, without a corresponding increase in the risk of developing other cancers, may be passed along in some families. Cigarette smoking is the most consistently observed non-genetic risk factor for tumor development, with the disease being two to three times more common in heavy smokers than in nonsmokers. However, it is uncertain whether this apparent association reflects a direct carcinogenic effect of metabolites of cigarette smoke or whether an as yet undefined exposure is responsible for the observed enhanced risk. Both chronic pancreatitis and long-standing diabetes mellitus have each been linked to an increased risk of pancreatic cancer. Mutations in K-ras genes have been found in more than 85 percent of specimens of human pancreatic cancer. The development of pancreatic cancer has also been associated with a mutation of the p16
INK4
gene located on chromosome 9p21, a gene which is also implicated in the pathogenesis of cutaneous malignant melanoma.
Overall, pancreatic cancers occur twice as frequently in the pancreatic head (about 70% of cases) as in the body (about 20%) or tail (about 10%). Pancreatic adenocarcinomas usually begin in the ducts of the pancreas, but may sometimes develop from the acinar cells. Greater than 90% of pancreatic cancers are ductal adenocarcinomas, with the remaining 5 to 10% being islet cell tumors. Cancers of the exocrine cells of the pancreas are usually adenocarcinomas (about 95%). Less common cancers of the exocrine pancreas include adenosquamous carcinomas, squamous cell carcinomas, and giant cell carcinomas.
The initial symptoms of pancreatic cancer are usually nonspecific (e.g., abdominal pain and weight loss) and are frequently disregarded. The deep anatomic location of the pancreas makes detection of small localized tumors unlikely during the routine abdominal examination. Even in patients with confirmed pancreatic cancer, an abdominal mass is palpable in only 15-25% of cases. Diagnosis of pancreatic cancer is further complicated by the occurrence of dysplastic cells, i.e., abnormal cells that are not cancerous. Thus., even a biopsy can result in an erroneous diagnosis. Biopsy diagnoses may also be complicated by other underlying pancreatic disorders such as diabetes or pancreatitis. Unfortunately, because pancreatic cancer is generally very aggressive, some 80-90% of patients have regional and distant metastases by the time they are diagnosed and only 3% of the 24,000 patients annually diagnosed with pancreatic cancer live more than 5 years after diagnosis.
Although early and accurate diagnosis can thus be extremely important in treatment success, there are presently no reliable screening tests for detecting pancreatic cancer in asymptomatic persons. Imaging procedures such as magnetic resonance imaging and computed tomography are too costly to use as routine screening tests, while more accurate tests such as endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound are inappropriate for screening asymptomatic patients due to their invasiveness. Abdominal ultrasonography is a noninvasive screening test, but there is little information on the efficacy of abdominal ultrasound as a screening test for pancreatic cancer in asymptomatic persons. In symptomatic patients with suspected disease it has a reported sensitivity of 40-98% and a specificity as high as 90-94%. Conventional ultrasonography is limited by visualization difficulties in the presence of bowel gas or obesity and by its range of resolution (2-3 cm). Even tumors less than 2 cm in diameter are frequently associated with metastatic disease, thus limiting the ability of ultrasound to detect early disease.
Most persons with pancreatic malignancy have elevated levels of certain serologic markers such as CA19-9, peanut agglutinin, pancreatic oncofetal antigen, DU-PAN-2, carcinoembryonic antigen, alpha-fetoprotein, CA-50, SPan-1, and tissue polypeptide antigen (Rhodes et al. (1990)
Bailleres Clin. Gastroenterol.
4:833; Steinberg (1990)
Am. J. Gastroenterol.
85:350; Satake et al. (1990)
Int. J. Pancreatol.
7:25; Satake (1991)
Int. J. Pancreatol.
9:93). None of these markers is, however, tumor specific or organ specific (Satake (1991), supra). Elevations of various serologic markers also occur in significant proportions of persons with benign gastrointestinal diseases or malignancies other than pancreatic cancer (Carter (1990)
Gut
31:494; Rhodes et al. (1990), supra; Satake et al. (1990), supra; Satake (1991), supra). Most of these markers have been studied exclusively in high-risk populations, such as symptomatic patients with suspected pancreatic cancer. CA19-9 has probably achieved the widest acceptance as a serodiagnostic test for pancreatic carcinoma in symptomatic patients, with an overall sensitivity of approximately 80% (68-93%) and specificity of 90% (73-100%); sensitivity was highest in patients with more advanced disease (Steinberg (1990), supra; Satake et al. (1990), supra). Among healthy subjects, CA19-9 has good specificity (94-99%) (DelVillano et al. (1983)
Clin. Chem.
29:549; Ritts et al. (1984)
Int. J. Cancer
33:339; Fabris et al. (1988)
Am. J. Gastroentrol.
83:549) but nevertheless generates a large proportion of false-positive results due to the very low prevalence of pancreatic cancer in the general population (Frebourg et al. (1988)
Cancer
62:2287; Homma et al. (1991)
Int. J. Pancreatol.
9:119). The predictive value of a positive test could be improved if a population at substantially higher risk could be identified. Diabetes mellitus in older adult patients might be useful as a marker for a population at high risk of having pancreatic cancer. Cohort studies have reported incidences of pancreatic cancer among diabetic patients ranging from 51 to 166/100,000 person-years (Everhart et al. (19950 JAMA 273:1605).
The inadequacies of conventional diagnostic methods for pancreatic cancer highlight the need for diagnostic and therapeutic methods and compositions, as well as for a better understanding of the disease to provide the basis for more rationale and more quickly responsive therapy. The fact that some patients suffer from combinations of pancreatic cancer, dysplasia, and/or diabetes further complicates diagnosis and rationale therapy design. The present invention addresses this need by providing nucleotide sequence that are differentially expressed in these diseases.
Relevant Literature
A review of diagnostic methods available for pancreatic cancer is provided in Bramhall (1998)
Int. J. Pancreatol.
23:83; Friess et al. (1997)
Digestion
58:557; and Lemoine (1997)
Digestion
58:550; as well as at the National Cancer Institute web site http://cancernet.nci.nih.gov/clinpdq/soa/Pancreatic_cancer_Physician.html.
Expression analysis using nucleic acid arrays is reviewed by Ramsay (1998)
Nat. Biotech.
16:40-44. Methods for creating microarrays of biologi
Blackburn Robert P.
Caputa Anthony C.
Chiron Corporation
Francis Carol L.
Morley Kimberlin L.
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