Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-07-14
2001-05-22
Fredman, Jeffrey (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C536S023100, C536S024310, C536S024330
Reexamination Certificate
active
06235474
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for detecting and/or screening for the presence of diseases such as cancer, and for assessing the risk of contracting a disease. The present invention also relates to methods for detecting and/or screening for the presence of DNA microsatellite instability.
BACKGROUND OF THE INVENTION
The single greatest impediment to cancer diagnosis is the general requirement that the tumor itself must be detected directly. Efforts to identify genetic abnormalities in normal tissues of patients with cancer or at risk of cancer have been disappointing. For example, BRCA1 mutations are present in only about 1% of breast cancers. A small fraction of patients with colorectal cancer have predisposing mutations in the APC gene (>1%), causing adenomatous polyposis coli. An even smaller fraction show mutations in genes responsible for replication error repair (>2% of colon cancer patients, or much less than 1% of the population), show mutations in genes responsible for nucleotide mismatch error repair causing hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome).
Genetic studies of colorectal cancer present a paradox, in that 15-40% of sporadically occurring tumors show DNA microsatellite instability, depending on the number of microsatellite markers that are used to detect it, even though the overwhelming majority of such tumors do not show mutations in known error repair genes. Furthermore, microsatellite instability in many common tumors, including those of the stomach, colon, and lung, is associated with a younger age, positive family history, and/or less accessible and detectable location, suggesting that a relatively large subgroup of cancer patients in the general population are at increased risk of cancer, even though they do not fall within a well-defined syndrome.
Microsatellite instability, in particular, requires for identification that a patient already have a tumor, because the assay compares microsatellite marker length between the monoclonal tumor cell population and normal tissue derived from the same patient. Most importantly, family history still remains the most reliable diagnostic procedure for identifying patients at risk of cancer. A molecular diagnostic approach that might identify patients with cancer or at risk of cancer, using only normal tissue, would offer a decisive advantage for intervention and treatment.
Thus, there remains a need for a diagnostic method for detecting and/or screening for the presence of diseases and/or the risk of contracting a disease. In particular, there remains a need for a method for detecting and/or screening for the presence of cancer, which does not require a tumor sample. There also remains a need for a method of detecting and/or screening for the presence of cancer and/or the risk of contracting cancer which can be applied to a wide section of the population. There also remains a need for a method of detecting and/or screening for the presence of replication error repair defects which does not require a tumor sample. There also remains a need for a method for quantifying the degree of loss of imprinting. There also remains a need for a method for screening infants for the risk of sudden infant death syndrome (SIDS). There also remains a need for kits for carrying out these methods.
SUMMARY OF THE INVENTION
The present invention provides a method and a kit for the purpose of diagnosing a disease by measuring abnormalities in imprinting of a gene or population of genes. The disease that can be diagnosed by the present invention is selected from any disease that is mediated by, or is associated with, a particular gene or combination of genes that are subject to imprinting. According the present invention, the imprinting can be abnormally on or can be abnormally off or partially abnormally on or off. In those cases where the particular gene that is being examined is normally imprinted, but in the disease state is abnormally not imprinted, the present invention is designed to detect the “loss of imprinting” (hereinafter “LOI”) thereby indicating that the disease may be present.
The diseases that can be diagnosed according to the present invention includes, but is not limited to, cancers, SIDS, birth defects, mental retardation, diabetes & gestational diabetes. Cancers that can be diagnosed according to the present invention include, but are not limited to, colorectal cancer, esophageal cancer, stomach cancer, leukemia/lymphoma, lung cancer, prostate cancer, uterine cancer, breast cancer, skin cancer, endocrine cancer, urinary cancer, pancreatic cancer, other gastrointestinal cancer, ovarian cancer, cervical cancer, head cancer, neck cancer, and adenomas.
The present invention also provides a method and a kit for determining if a patient is predispositioned to a particular disease. In this case, normal tissue can be tested to determine whether there is abnormal imprinting for a particular gene or combination of genes. If the imprinting is abnormal, e.g., either abnormally on or abnormally off, then the patient may have a predisposition for a particular disease. Appropriate screening of other factors can then be done a periodic intervals to be able to detect the disease early.
Because the present invention is particularly useful for determining if a patient is predispositioned for a particular disease, such as cancer, the present invention is particularly useful for screening populations of individuals to determine if individuals are predispositioned for a particular disease. By having the capability of efficiently screening a large population of individuals for a particular disease, e.g., colon cancer, individuals that have the cancer in the early stages or individuals that are predispositioned for the cancer can be identified early and appropriate treatment can be initiated.
According to the present invention, the testing of an individual to determine if imprinting of a gene is normal or abnormal can be done on a wide variety of tissues. For example, in a test for colorectal cancer, one does not have to test tissue from the colon, but can test tissue from other parts of the body, including, but not limited to, blood cells, skin, hair, etc. Therefore, the present invention provides a method of testing any tissue in the body for a disease that is specific for a particular tissue in the body.
Analysis of imprinting of genes of biological tissues and cells to be used for transplantation can be performed according to the present invention to avoid the possibility of increasing a disease risk in the transplant recipient. Examples of tissues or cells that can be analyzed according to the present invention includes, but is not limited to, skin grafts, ligaments, eyes, kidney, liver, heart valves, lung, bone-marrow (Leukemia), neural tissue-embryonic neural tissue (used for variety of purposes such as increase dopamine production in Parkinson's patients, increase acetylcholine production in Alzheimer's patients, for enhancement of plasticity (norepinephrine), increase production of hypothalamic hypophysiotropic factors, development of neocortical cells, motor neurons, sensory neurons, blood-white cells and others of myelocyte lineage, muscle-myoblasts, seeding of “blast cells,” and genetically engineered cells for administration to patients.
According to one embodiment of the present invention, there is a strong correlation between the presence or absence of LOI in a subject's somatic cells and the presence of disease and/or the risk of contracting a disease. There is a strong correlation between the presence of LOI in a subject's somatic cells and the presence of replication repair error defects. There is also a strong correlation between the degree of LOI present in a subject's somatic cells and the presence of cancer and/or the risk of contracting cancer. In addition, there is a strong correlation between the degree of LOI present in a subject's somatic cells and the degree of replication repair error defects present in a subject's
Chakrabarti Arun Kr.
Fredman Jeffrey
Kilpatrick & Stockton LLP
The Johns Hopkins University
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