Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1991-06-13
1994-03-22
Patterson, Jr., Charles L.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435975, C12A 168
Patent
active
052963519
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a diagnostic method which may be used in leukaemia and lymphoma for detection of malignancy and determination of its lineage. Lymphocytes, the cells responsible for immunity, are of two types: molecule which attaches to a particular foreign antigen; and enables the cell to attach to a particular foreign antigen.
Each B-lymphocyte contains a unique immunoglobulin gene which differs moderately in structure from the immunoglobulin gene of all other B-lymphocytes and markedly in structure from the immunoglobulin genes of all other body cells, including T-lymphocytes. Similarly, each T-lymphocyte contains a unique T-receptor gene which differs moderately in structure from the T-receptor gene of all other T-lymphocytes and markedly in structure from the T-receptor gene of all body cells, including B-lymphocytes.
Lymphoid leukaemias and lymphomas are a form of cancer of the lymphocyte tissue. Each leukaemia or lymphoma arises from a single B- or T-lymphocyte which multiples, spreads and eventually results in death unless treated. As all the tumor cells are descended from a single cell, they are all genetically the same and all will contain the same unique gene, a unique immunoglobulin gene if the tumour arose in a B-lymphocyte, or a unique T-receptor gene if the tumour arose in a T-lymphocyte.
Conversely, if a tissue is suspected as being involved by leukaemia or lymphoma, the detection of a unique immunoglobulin gene is presumptive evidence of a tumour of B-lymphocytes whereas detection of a unique T-receptor gene is presumptive evidence of a tumour of T-lymphocytes.
The object of the present invention is to determine whether or not leukaemia or lymphoma is present in a tissue sample by determining whether or not a monoclonal B- or T-lymphocyte population is present in the sample. In general terms, the invention does this by focussing on a discrete segment of the immunoglobulin or T-receptor molecule and determining whether all or most of these segments in the tissue sample are rearranged and have precisely the same length, implying that they are derived from the same unique molecule.
Present methods for detection of monoclonality are based on restriction enzyme digestion, followed by Southern blotting and gene probing. This approach is complex, expensive and time consuming, so that information is usually provided too late to be of substantial practical value.
By contrast, the method of the present invention provides a rapid and sensitive diagnostic test. In addition, it is also very versatile as material which can be used as the tissue sample includes blood, tumour tissue in node or bone marrow, formalin-fixed embedded histological material, aspirated cytological material or cells on slides.
According to the present invention, there is provided a method for lymphoid leukaemia and/or lymphoma in a tissue sample, which comprises the determination of the homogeneity or heterogeneity of the length of immunoglobulin and/or T-receptor gene segments in said tissue sample to indicate the presence or absence of monoclonality of the B- and/or T-lymphocyte population in said sample.
According to one embodiment of the present invention there is provided a method for the detection of monoclonality and presumptive malignancy in a tissue sample, and/or for the determination of the B-lymphocyte or T-lymphocyte origin of a tumour, which comprises the steps of: tissue sample by means of the polymerase chain reaction using specific primers or mixtures of primers for said immunoglobulin and/or T-receptor gene segments; and heterogeneity of the length of the amplified segments.
In one particular embodiment, the primers used are consensus primers for the immunoglobulin and/or T-receptor gene segments.
The present invention also extends to a kit for performance of the method of the invention as broadly outlined above, comprising a set of specific primers or mixture(is of primers for immunoglobulin and/or T-receptor gene segments for amplification of immunoglobulin and/or T-receptor gene segments in a tissue
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Brisco Michael J.
Morley Alexander A.
Morley Alexander A.
Patterson Jr. Charles L.
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