Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2001-07-31
2004-08-10
Helms, Larry R. (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C436S504000, C436S064000
Reexamination Certificate
active
06773883
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to nucleic acid microarray markers for cancer, particularly for endometrial cancer. The invention also relates to methods for diagnosing cancer as well as optimizing cancer treatment strategies.
BACKGROUND OF THE INVENTION
Endometrioid endometrial adenocarcinomas are the most common gynecologic malignancy, the risk of which is increased by an abnormal endocrine environment or premalignant lesions with loss of tumor suppressor function. The 6000 deaths yearly make uterine cancer the seventh leading cause of death from malignancy in females. It is primarily a disease of postmenopausal women, although 25 percent of cases occur in women below age 50 and 5 percent below age 40 (Harrison's Principles of Internal Medicine 1998).
Although much progress has been made toward understanding the biological basis of cancer and in its diagnosis and treatment, it is still one of the leading causes of death in the United States. Inherent difficulties in the diagnosis and treatment of cancer include among other things, the existence of many different subgroups of cancer and the concomitant variation in appropriate treatment strategies to maximize the likelihood of positive patient outcome.
The prognosis of endometrial cancer depends upon stage, histologic grade, and extent of myometrial invasion. The staging of endometrial cancer requires surgery to establish the extent of disease and the depth of myometrial invasion. Peritoneal fluid should be sampled; the abdomen and pelvis explored; and pelvic and para-aortic lymphadenectomy performed depending upon the histology, grade, and depth of invasion in the uterine specimen on frozen section.
Initial evaluation of patients suspected of endometrial cancer includes a history and physical and pelvic examination followed by an endometrial biopsy or a fractional dilation and curettage. Outpatient procedures such as endometrial biopsy or aspiration curettage can be used but are definitive only when positive. Once a diagnosis is made, the options for treating endometrial cancer are assessed with respect to the needs of the patient. These options traditionally include surgical intervention, radiotherapy, chemotherapy, and adjuvant systemic therapies. Adjuvants may include but are not limited to chemotherapy, radiotherapy, and endocrine therapies with progestational agents such as hydroxyprogesterone, megastrol, and deoxyprogesterone, and the antiestrogen tamoxifen.
It is difficult to predict from standard clinical and pathologic features the clinical course of endometrial cancer. However, it is very important in the treatment of endometrial cancer to select and implement an appropriate combination of therapeutic approaches. The available methods for designing strategies for treating endometrial cancer patients are complex and time consuming. The wide range of cancer subgroups and variations in disease progression limit the predictive ability of the healthcare professional. In addition, continuing development of novel treatment strategies and therapeutics will result in the addition of more variables to the already complex decision-making process involving matching the cancer patient with a treatment regimen that is appropriate and optimized for the cancer stage, extent of myometrial invasion, tumor growth rate, and other factors central to the individual patient's prognosis. Because of the critical importance of selecting appropriate treatment regimens for endometrial cancer patients, the development of guidelines for treatment selection is of key interest to those in the medical community and their patients. Thus, there presently is a need for objective, reproducible, and sensitive methods for predicting endometrial cancer patient outcome and selecting optimal treatment regimens.
SUMMARY OF THE INVENTION
It now has been discovered that particular sets of genes are expressed differentially in normal and malignant endometrium. These sets of genes can be used to discriminate between normal and malignant endometrial tissues. Accordingly, diagnostic assays for classification of tumors, prediction of tumor outcome, selecting and monitoring treatment regimens, and monitoring tumor progression/regression can now be based on the expression of sets of genes.
According to one aspect of the invention, methods for diagnosing endometrial cancer in a subject suspected of having endometrial cancer are provided. The methods include obtaining from the subject an endometrial tissue sample and determining the expression of a set of nucleic acid molecules or expression products thereof in the endometrial tissue sample. The set of nucleic acid molecules includes at least two nucleic acid molecules selected from the group consisting of SEQ ID NOs:1-50. In preferred embodiments, the endometrial tissue sample is suspected of being cancerous.
In some embodiments the set of nucleic acid molecules includes more than 2, and up to all of the nucleic acid molecules set forth as SEQ ID NOs:1-50, and any number of nucleic acid sequences between these two numbers. For example, in certain embodiments the set includes at least 3, 4, 5, 10, 15, 20, 30, 40 or more nucleic acid molecules of the nucleic acid molecules set forth as SEQ ID NOs:1-50.
In other embodiments, the method further includes determining the expression of the set of nucleic acid molecules or expression products thereof in a non-cancerous endometrial tissue sample, and comparing the expression of the set of nucleic acid molecules or expression products thereof in the endometrial tissue sample suspected of being cancerous and the non-cancerous endometrial tissue sample.
The invention in another aspect provides solid-phase nucleic acid molecule arrays. The arrays have a cancer gene marker set that consists essentially of at least two and as many as all of the nucleic acid molecules set forth as SEQ ID NOs:1-50 fixed to a solid substrate. The set of nucleic acid markers can include any number of nucleic acid sequences between these two numbers, selected from SEQ ID NOs:1-50. For example, in certain embodiments the set includes at least 3, 4, 5, 10, 15, 20, 30, 40 or more nucleic acid molecules of the nucleic acid molecules set forth as SEQ ID NOs:1-50. In some embodiments, the solid-phase nucleic acid molecule array also includes at least one control nucleic acid molecule.
In certain embodiments, the solid substrate includes a material selected from the group consisting of glass, silica, aluminosilicates, borosilicates, metal oxides such as alumina and nickel oxide, various clays, nitrocellulose, or nylon. Preferably the substrate is glass.
In other embodiments, the nucleic acid molecules are fixed to the solid substrate by covalent bonding.
According to yet another aspect of the invention, protein microarrays are provided. The protein microarrays include antibodies or antigen-binding fragments thereof, that specifically bind at least two different polypeptides selected from the group consisting of SEQ ID NOs:51-100, fixed to a solid substrate. In some embodiments, the microarray comprises antibodies or antigen-binding fragments thereof, that bind specifically to least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 different polypeptides selected from the group consisting of SEQ ID NOs:51-100. In certain embodiments, the microarray also includes an antibody or antigen-binding fragment thereof, that binds specifically to a cancer-associated polypeptide other than those selected from the group consisting of SEQ ID NOs:51-100, preferably An endometrial cancer associated polypeptide. In some embodiments, the protein microarray also includes at least one control polypeptide molecule. In further embodiments, the antibodies are monoclonal or polyclonal antibodies. In other embodiments, the antibodies are chimeric, human, or humanized antibodies. In some embodiments, the antibodies are single chain antibodies. In still other embodiments, the ant
Helms Larry R.
The Brigham & Women's Hospital, Inc.
Wolf Greenfield & Sacks P.C.
Yu Misook
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