Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2000-12-29
2004-02-03
Myers, Carla J. (Department: 1634)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007200, C435S007210, C435S007230, C530S388800, C530S389700
Reexamination Certificate
active
06686165
ABSTRACT:
TECHNICAL FIELD
This invention relates to the field of cancer diagnosis and the application of diagnostic techniques in pathology and hematology. Specifically, the invention relates to techniques that indicate the presence of chromosomal aberrations by detecting tumor-specific gene products that are exclusively expressed by tumor cells containing the chromosomes.
BACKGROUND OF THE INVENTION
Chromosomal abnormalities or aberrations are a leading cause of genetic disorders or diseases, including congenital disorders and acquired diseases, such as malignancies. Malignant cells have a common clonal origin as they are believed to originate from a single autonomously growing cell that withdrew from environmental growth regulating signals.
The term ‘cancer’ comprises a heterogeneous group of neoplasms, in which each type has its own characteristic when considering its malignant potential and its response to therapy. Currently, the effectiveness of cancer treatment is empirically determined. Depending on the moment in time in the development of cancer, the origin and spread of the cancer, and on the physiological condition of the patient, the most proper and most effective treatment is selected. At present, selections from surgical treatment, radiation therapy and chemotherapy (or combinations of the former therapies) can be made. Yet, it is realized that each therapy bears side-effects that compromise the benefits of treatment enormously. It goes without saying that accurate diagnosis of the various cancer types is pre-eminent in helping select the most effective therapy.
The basis of cancer stems from chromosomal aberrations such as translocations, inversions, insertions, deletions and other mutations within or among chromosomes. Often, one chromosome or two different chromosomes are involved in the development of malignancies. In this way, genes, or fragments of genes are removed from the normal physiological context of the non-aberrant chromosome and fuse with or find a location in a recipient chromosome, (be it the same or a second chromosome) adjacent to non-related genes or fragments of genes (often oncogenes or proto-oncogenes), where the new genetic combination can be the foundation of a malignancy.
Rearrangements, such as translocations happen often in a somewhat established pattern, where genes, or fragments thereof, are removed from the non-aberrant chromosome at a breakpoint or breakpoint cluster region, and are inserted in the recipient chromosome at a fusion region, thereby creating rearranged, deleted, translocated or fused genes that are specific for that specific cancer. Moreover, rearrangements or translocations can be reciprocal, in that two chromosomes exchange parts which leads to cells containing two, reciprocally rearranged chromosomes which both contain new fused genes.
When the fused gene is translated, it generates a gene-product, mRNA, that is unique for the tumor. The chimeric mRNA comprises parts or fragments of two mRNA's that correspond to and were originally transcribed by the originally separated genes. This tumor-specific mRNA is uniquely characterized by a fusion point, where the RNA fragments meet. In some cases, these fusion points can be detected by hybridizing nucleic acid probes. However, considering the large variation within the individual rearrangements seen in these translocations and depending on the localization of the breakpoint within the non-aberrant gene wherein (even when the translocations occur within the same two genes) different tumor-specific genes can be generated, it is deemed likely that within each separate case of these types of cancer, new fusion points arise. Detection of cancer by specific detection of the fusion-point of the tumor-specific gene-product (mRNA) has therefore never been widely applicable.
When the fused gene is fused in frame, the fused mRNA is translated into a fusion protein that is unique for the tumor. The protein comprises parts of two proteins that correspond to and were originally transcribed by and translated from the originally separated genes. Tumor-specific proteins are uniquely characterized by a fusion point, where the two proteins meet. Fusion points are antigenically exposed, comprising distinct epitopes which sometimes can be immunologically detected. However, considering the large variation within the individual rearrangements seen in these translocations and depending on the localization of the breakpoint within the non-aberrant gene wherein (even when the translocations occur within the same two genes) different tumor-specific genes can be generated, it is deemed likely that within each separate case of these types of cancer, new fusion points arise. Detection of cancer by specific detection of the fusion-point epitope of the tumor specific protein has therefore never been widely applicable. The tumor-specific gene products (fusion products) of the fused or rearranged genes may contribute to the further development of the cancer.
An area where chromosomal aberrations are relatively well studied (as compared with other cancer types) is the field of leukemia. Comparable to most malignant tumors, leukemias differ in the degree of differentiation of tumor cells. According to clinical presentation, leukemias are divided in to acute and chronic forms, depending on the rapidity with which they evolve and, if untreated, cause death.
Depending on the cell lineage(s) involved in the leukemic process, acute leukemias are classified as acute lymphoblastic leukemias (ALL) and acute non-lymphoblastic leukemias (ANLL), with ALL the most predominant type (>80%) occurring in childhood. Chronic leukemias are malignancies in which the uncontrolled proliferating leukemic cells are capable of maturation. Two subtypes of chronic leukemia are distinguished, chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML). Within these four groups, a considerable heterogeneity in biology and prognosis is seen, which currently is stratified along morphological features. This stratification bears, as yet, little value as to an understanding and prediction of the prognosis of a leukemic patient and to rational therapy design.
However, recent molecular genetic studies of leukemic patients have shown that a wide variety of chromosomal aberrations can be found with the various forms of leukemia. One group consists of immunoglobulin (IG) or T-cell receptor (TCR) gene rearrangements, comprising antigen-receptor gene rearrangements that go beyond the normal, physiological processes that are required to generate the diversity of the antigen receptor molecules which typify the lymphoid cell population. In one large group of IG and TCR rearrangements known to be associated with leukemia, tumor specific antigen receptor molecules are expressed. Another group of aberrations comprise deletions of a whole gene or parts of a gene from a genome. As a result of the deletion, promotor regions normally belonging to the now deleted gene can exert control over another gene, resulting in aberrant transcription the gene. An example is the deletion of the coding regions of the SIL gene in T-cells, resulting in the transcription of the normally not expressed TAL-1 gene in T-cells, resulting in ectopic expression of TAL-1 fusion protein. Yet another group comprises translocations of gene fragments between chromosomes, resulting in fusion genes that may well transcribe unique fusion proteins that contribute to the development of the malignancy. Well known examples are the translocations resulting in BCR-ABL fusion genes found in >95% of cases of CML and in 30% of cases of adult ALL and TEL-AML1 which is found in 25-30% of cases of childhood ALL. However, many more fusion genes, such as E2A-PBX1, ETO-AML1 and PML-RARa are known.
Chromosomal aberrations can be detected by a wide array of techniques, various of which entail modern biomolecular technology. Traditional techniques such as cytogenetic analysis by conventional chromosomal banding techniques are, although highly precise, very labor intensive, require skilled person
Berendes Paulus Benjamin
van Denderen Adriana Cornelia
van der Velden Vincent Henricus Johannes
van Dongen Jacobus Johannes Maria
Erasmus Universiteit Rotterdam
Myers Carla J.
TraskBritt
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