Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving virus or bacteriophage
Reexamination Certificate
2002-01-25
2004-06-22
Mosher, Mary E. (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving virus or bacteriophage
C435S006120
Reexamination Certificate
active
06753137
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the discovery that Epstein Barr virus may be found in the cell free fluid of a patient's blood and when such virus is found and the patient suffers from gastritis, that patient has a predisposition to progress from gastritis to gastric cancer.
BACKGROUND OF THE INVENTION
It is known that tumour-derived DNA can be released by cancer cells of a variety of tumours (Anker et al., Cancer Metastasis Rev. 18: 65-73 (1999)). Examples include oncogene mutations from pancreatic carcinoma (Anker et al., Gastroenterology. 112: 4-1120 (1997)), microsatellite alterations in lung cancer (Chen et al., Nature Medicine. 2: 3-1035 (1996)) and epigenetic changes from liver cancer (Wong et al., Cancer Res. 59: 3 (1999)). In addition, virus DNA has been found in the circulation of a number of cancers known to be associated with virus infection. Examples include Epstein-Barr virus (EBV) DNA from nasopharyngeal cancer (Mutirangura et al., Clin Cancer Res. 4: 665-9 (1998); Lo et al., Cancer Res. 59: 1188-91 (1999)) and certain lymphomas (Lei et al., Br J Haematol. 111: 239-46 (2000); Gallagher et al., Int J Cancer. 84: 442-8 (1999); Drouet et al., J Med Virol. 57: 383-9 (1999)), and human papillomavirus DNA from head and neck cancer (Capone et al., Clin Cancer Res. 6: 4171-5 (2000)).
Recently, much interest has been focused on the presence of tumor-derived DNA in the plasma and serum of cancer patients (Chen, X. Q. et al., Nat. Med., 2: 1033-1035 (1996); Nawroz, H. et al.,
Nat. Med
., 2: 1035-1037 (1996)). For virally-associated cancers, cell-free tumor-associated viral DNA has been detected in the plasma and serum of patients (Mutirangura, A. et al.,
Cancer Res
., 4: 665-669 (1998); Lo, Y. M. D. et al.,
Clin. Cancer Res
., 59: 1188-1191 (1999); Capone, R. B.
Clin. Cancer Res
., 6: 4171-4175 (2000)). One important virus which has been associated with many types of malignancy is the Epstein-Barr virus (EBV) (Cohen, J. I.
N. Engl. J Med
., 343: 481-492 (2000)). Epstein-Barr virus (EBV) is a human herpesvirus that infects the majority of the human population. EBV is commonly transmitted by saliva and established latent infection in B lymphocytes where it persists for the lifetime of the host. In this regard, circulating EBV DNA has been detected in the plasma and serum of patients with nasopharyngeal carcinoma (NPC) (Mutirangura, A. et al.,
Cancer Res
., 4: 665-669 (1998); Lo, Y. M. D. et al.,
Clin. Cancer Res
., 59: 1188-1191 (1999)) and certain lymphoid malignancies (Lei, K. I. et al.,
Br. J Haematol
., 111: 239-246 (2000); Drouet, E. et al.,
J. Med. Virol
., 57:383-389 (1999); Gallagher, A. et al.,
Int. J. Cancer
, 84:442-448 (1999)).
EBV infection has also been reported to be associated with a proportion of gastric carcinomas (Shibata, D. et al.,
Am. J. Pathol
., 140:769-774 (1992)). In Hong Kong, approximately 10% of gastric carcinoma cases have been found to be associated with EBV infection (Yuen, S. T. et al.,
Am. J. Surg. Pathol
., 18:1158-1163 (1994)).
The present invention provides methods for detecting EBV DNA in the sera of patients with gastric carcinoma and correlating the amount of EBV DNA so detected into clinical diagnosis or prognosis.
BRIEF SUMMARY OF THE INVENTION
In a first aspect, the present invention features methods for diagnosing, detecting, monitoring and determining the prognosis of gastric cancer in a patient. The methods feature detecting or determining the amount of Epstein Barr Virus DNA (EBV DNA) present in the serum or plasma of gastric cancer patients. Accordingly, the present invention have broad applicability in clinical medicine.
The methods according to the present invention are also applicable for diagnosing, detecting, monitoring and determining the prognosis of non-head and neck and lymphoid malignancies, such as breast cancer. These neoplasms have been associated with EBV infection as has gastric cancer.
The methods according to the present invention are also applicable for diagnosing, detecting, monitoring and determining the prognosis of gastritis. EBV DNA can be detected in the plasma and serum of patients having non-neoplastic gastric diseases, such as gastritis. In turn, gastritis has been linked to gastric cancer. The invention further comprises patients that can be or have been diagnosed with gastric cancer and the cancer cells are free of EBV nucleic acid or contain EBV.
The methods according to the present invention generally comprise the steps of (1) obtaining a blood sample from a patient, (2) extracting DNA from the blood sample, (3) measuring the amount of circulating EBV DNA present in the blood sample, and (4) comparing the amount of circulating EBV DNA present in the blood sample to a control.
Preferably, the blood sample is a non-cellular fluid sample. By non-cellular we mean that the sample is either blood sera where the cells are extracted by clotting and separation of the cells from the remaining fluid or by inhibiting clotting and centrifuging the fluid fraction (plasma). The EBV DNA is measured from the fluid fraction. When EBV is found in the fluid of a non-cellular sample, it is understood that the infection is active and infected cells releasing EBV.
In a second aspect, the present invention features diagnostic kits comprising suitable reagents for detecting EBV DNA in the serum or plasma of patients. The kits according to the present invention may further comprise one or more of a device for obtaining a blood sample from a patient, a means to separate the EBV DNA from the blood sample and a means to quantify the amount of EBV DNA present in the blood sample. Such kits are useful for diagnosing, detecting, monitoring and determining the prognosis for gastric cancers and gastritis
REFERENCES:
Lo et al (Clinical Cancer Research 7: 1856-9, Jul. 2001).*
Anker et al., “Detection of Circulating Tumour DNA in the Blood (Plasma/Serum) of Cancer Patients,”Cancer Metastasis Rev. 18:65-73 (1999).
Anker et al.,“K-ras Mutations are Found in DNA Extracted from the Plasma of Patients with Colorectal Cancer,”Gastroenterology. 112:1114-1120 (1997).
Chen et al.,“Microsatellite Alterations in Plasma DNA of Small Cell Lung Cancer Patients,”Nature Medicine. 2:1033-1035 (1996).
Wong et al., “Detection of Aberrantp16 Methylation in the Plasma and Serum of Liver Cancer Patients,”Cancer Res. 59:71-3 (1999).
Mutirangura et al., “Epstein-Barr Viral DNA in Serum of Patients with Nasopharyngeal Carcinoma,”Clin Cancer Res. 4:665-9 (1998).
Lei et al., “Quantitative Analysis of Circulating Cell-Free Epstein-Barr Virus (EBV) DNA Levels in Patients with EBV-Associated Lymphoid Malignancies,”Br J Haematol. 111:239-46 (2000).
Nawroz et al., Microsatellite Alterations in Serum DNA of Head and Neck Cancer Patients,Nat. Med., 2:1035-1037 (1996).
Lo et al., “Quantitative Analysis of Cell-free Epstein-Barr Virus DNA in Plasma of Patients with Nasopharyngeal Carcinoma,”Clin. Cancer Res., 59:1188-1191 (1999).
Capone, “Detection and Quantitation of Human Papillomavirus (HPV) DNA in the Sera of Patients with HPV-Associated Head and Neck Squamous Cell Carcinoma,”Clin. Cancer Res., 6:4171-4175 (2000).
Cohen, “Epstein-Barr Virus Infection,”N.Engl. J. Med., 343:481-492 (2000).
Drout et al., “High Epstein-Barr Virus Serum Load and Elevated Titers of Anti-ZEBRA Antibodies in Patients with EBV-Harboring Tumor Cells of Hodgkin's Disease,”J. Med. Virol., 57:383-389 (1999).
Shibata et al., “Rapid Communication,”Am. J. Pathol., 140:769-774 (1992).
Yuen et al., “In SituDetection of Epstein-Barr Virus in Gastric and Colorectal Adenocarcinomas,”Am. J. Surg. Pathol., 18:1158-1163 (1994).
Lo et al., “Quantitative and Temporal Correlation between Circulation Cell-Free Epstein-Barr Virus DNA and Tumor Recurrence in Nasopharyngeal Carcinoma,”Cancer Res., 59:5452-5455 (1999).
Gallagher et al., “Detection of Epstein-Barr Virus (EBV) Genomes in the Serum of Patients with EBV-Associated Hodgkin's Disease,”Int. J. Cancer, 84:442-448 (1999).
Lo et al., “Molecular Prognostication of Nasopharyngeal Carcinoma by Quantitative Analys
Chan Wing Yee
Lo Yuk Ming Dennis
Ng Kwok Wai
Mosher Mary E.
The Chinese University of Hong Kong
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