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Recent advances of molecular genetics have made a noticeable impact in some areas of clinical medicine. Almost comprehensive understanding of the nature of hereditary tumors is frequently heralded as the most substantial practical achievement of molecular oncology. Proper diagnostic algorithms have already been developed for the vast majority of known familial cancer syndromes. Interestingly, an unexpectedly strong "founder" effect has been documented at least for some hereditary cancers occurring in Russia, that significantly simplifies the detection of the corresponding disease-associated gene variants. The number of tests aimed to customize cancer treatment continues to grow every year. EGFR mutation test appears to be the most impressive, as it allows to predict lung cancer response or non-response to gefitinib or erlotinib with indeed unique level of accuracy. The approaches helping to determine individual efficacy and safety profiles for fluoropyrimidines, platinum compounds, irinotecan etc. are currently under development Methods aiming to detect residual amounts of disseminated cancer cells represent another popular avenue of the research. It is expected that these technologies will improve the quality of prediction of local and distant metastases, facilitate monitoring of the minimal residual disease and, in the long perspective, provide the tool for early cancer diagnosis. One has to remember that the molecular detection of disseminated tumor cells is currently used mainly in research settings and is not yet incorporated into routine clinical practice.
Mol Biol (Mosk)
PMID:[Molecular diagnosis in oncology]. 1898 27

The human MLL gene is one of the most promiscuous recombination hot spots of our genome with regard to the onset of malignant diseases. With the exception of gene internal partial-tandem duplications involving several exons located in the 5'-end of MLL, all recombination events occur in a small genomic region flanked by MLL exons 8-14, designated as the MLL breakpoint cluster region. Efforts from different laboratories, including our own, have led to the identification of more than 50 MLL fusion partners that were characterized at the molecular level. The common theme of recombination events involving the human MLL gene is the creation of "functional" fusion genes that are translated into oncoproteins. Many different labs have already demonstrated that these MLL fusion proteins have the capability to instruct hematopoietic stem/precursor cells to convert into a preleukemic state, which finally leads to the onset of leukemia in experimental model systems.Here we have focused on the identification of MLL fusion partners by using the genomic DNA of acute leukemia patients. After initial screening using for example split signal FISH experiments (as an example for technologies to identify MLL rearrangements), genomic DNA from leukemia patients is analyzed by long-distance-inverse (LDI)-PCR. LDI-PCR is based on the hydrolysis of patient DNA using distinct combinations of restriction enzymes, self-ligation of the resulting DNA fragments and a subsequent PCR reaction using a specific set of oligonucleotides. This strategy allows in principle any investigator to identify known and unknown MLL fusion partner genes. Furthermore, the genomic fusion site in MLL rearrangements represent a unique and reliable molecular marker that allows the tracing of minimal residual disease (MRD) in these patients before, during, and after therapy.
Methods Mol Biol 2009
PMID:LDI-PCR: identification of known and unknown gene fusions of the human MLL gene. 1927 76

A sensitive and specific quantitative real-time polymerase chain reaction method, involving three rounds of amplification with two allele-specific oligonucleotide primers directed against an rearrangement, was developed to quantify minimal residual disease (MRD) in B-lineage acute lymphoblastic leukemia (ALL). For a single sample containing 10 microg of good quality DNA, MRD was quantifiable down to approximately 10(-6), which is at least 1 log more sensitive than current methods. Nonspecific amplification was rarely observed. The standard deviation of laboratory estimations was 0.32 log units at moderate or high levels of MRD, but increased markedly as the level of MRD and the number of intact marker gene rearrangements in the sample fell. In 23 children with ALL studied after induction therapy, the mean MRD level was 1.6 x 10(-5) and levels ranged from 1.5 x 10(-2) to less than 10(-7). Comparisons with the conventional one-round quantitative polymerase chain reaction method on 29 samples from another 24 children who received treatment resulted in concordant results for 22 samples and discordant results for seven samples. The sensitivity and specificity of the method are due to the use of nested polymerase chain reaction, one segment-specific and two allele-specific oligonucleotide primers, and the use of a large amount of good quality DNA. This method may improve MRD-based decisions on treatment for ALL patients, and the principles should be applicable to DNA-based MRD measurements in other disorders.
J Mol Diagn 2009 May
PMID:Sensitive and specific measurement of minimal residual disease in acute lymphoblastic leukemia. 1932 89

Molecular markers for minimal residual disease in B-lineage acute lymphoblastic leukemia were identified by determining, at the time of diagnosis, the repertoire of rearrangements of the immunoglobulin heavy chain (IGH) gene using segment-specific variable (V), diversity (D), and junctional (J) primers in two different studies that involved a total study population of 75 children and 18 adults. This strategy, termed repertoire analysis, was compared with the conventional strategy of identifying markers using family-specific V, D, and J primers for a variety of antigen receptor genes. Repertoire analysis detected significantly more markers for the major leukemic clone than did the conventional strategy, and one or more IgH rearrangements that were suitable for monitoring the major clone were detected in 96% of children and 94% of adults. Repertoire analysis also detected significantly more IGH markers for minor clones. Some minor clones were quite large and a proportion of them would not be able to be detected by a minimal residual disease test directed to the marker for the major clone. IGH repertoire analysis at diagnosis has potential advantages for the identification of molecular markers for the quantification of minimal residual disease in acute lymphoblastic leukemia cases. An IGH marker enables very sensitive quantification of the major leukemic clone, and the detection of minor clones may enable early identification of additional patients who are prone to relapse.
J Mol Diagn 2009 May
PMID:Determining the repertoire of IGH gene rearrangements to develop molecular markers for minimal residual disease in B-lineage acute lymphoblastic leukemia. 1932 94

A complete diagnostic procedure was developed that allows single molecules of mRNA AML1-ETO to be detected in samples of whole blood and bone marrow of the leukemia t(8;21)(q22;q22) patients. The procedure includes: a method for preservation of biological samples ensuring the RNA integrity; an improved method for isolation of RNA from the unfractionated whole blood and bone marrow; an optimized reverse transcription; and the use of nanocolonies for detection and enumeration of RNA target molecules. The developed procedure is the first one that provides for determination of the absolute titer of an RNA target without reference to a control (housekeeping) gene, and significantly increases sensitivity, precision and reliability of detection of the minimal residual disease at a leukemia associated with known chromosomal translocation.
Mol Biol (Mosk)
PMID:[Use of nanocolonies for detection of minimal residual disease in patients with leukemia t(8;21)]. 1933 41

Fluorescent in situ hybridization has become an essential tool for diagnosing and monitoring hematological disease. Testing for minimal residual disease requires precise and accurate normal cut-offs. There is no consensus in the field on the correct method of establishing a normal reference range. We discuss and compare several proposed statistical methods to calculate normal reference ranges, including Gaussian statistics, the beta inverse function, and a binomial treatment of the data. We demonstrate that a binomial treatment of the data is an accurate and simple method to calculate a normal reference range.
J Mol Diagn 2009 Jul
PMID:Statistical treatment of fluorescence in situ hybridization validation data to generate normal reference ranges using Excel functions. 1952 36

The molecular profiling of myeloproliferative neoplasms (MPNs) has introduced a paradigm shift in the process of diagnosis, prognostication, monitoring and treatment of these diseases. The discovery of the BCR-ABL fusion oncogene is an example of a remarkable bench-to-bedside story. It has provided a comprehensive explanation of the pathogenesis of chronic myelogenous leukemia, and has resulted in the development of excellent treatment strategies. It has led to the use of advanced diagnostic techniques, such as fluorescence in situ hybridization and PCRs that allow for more effective means to monitor disease treatment, including the detection of minimal residual disease, early relapse and drug resistance. Unlike chronic myelogenous leukemia, the exact molecular pathways for the BCR-ABL-negative MPNs have not been completely elucidated. The discoveries of the JAK2 and the MPL mutations have set the ball rolling in trying to achieve this target. The JAK2 mutational screen has provided us with a relatively simple screening assay to establish clonality in the setting of MPNs. In patients with clonal eosinophilic disorders and mast cell disease, the use of molecular diagnostics to identify novel mutations and gene rearrangements, has resulted in superior diagnostic and therapeutic strategies.
Expert Rev Mol Diagn 2009 Jul
PMID:Molecular diagnosis of myeloproliferative neoplasms. 1958 Apr 32

Imaging of cancer by radioimmunoscintigraphy (RIS) following administration of radiolabeled monoclonal antibodies (mAbs) or fragments has been under development for two decades. Efficacy is a function of many variables: antigen expression on tumor cells relative to normal tissues and body fluids, affinity, specificity, pharmacokinetics and immunogenicity of the mAb and properties of the radionuclide and imaging techniques. CEA-Scan (a 99mTclabeled Fab' fragment of a mouse mAb directed against CEA) has several advantageous properties, and has been approved for use in colorectal cancer SPECT imaging in North America and Europe, and is also under investigation in Japan. It has been shown to complement CT in detecting recurrent or metastatic disease, even in the liver where 111In mAbs frequently fail. In breast cancer, it provides clearer identification of malignant disease in patients with indiscriminate mammography. Recently, it has also been used intra-operatively in radio-immunoguided surgery in both colorectal and breast cancer patients. These new applications are currently under active investigation and clinical trials are planned. Clinically useful information is obtained in a relatively high percentage of patients, which can alter treatment decisions. In most cases the benefits are in reducing unnecessary surgery or biopsies in inoperable patients, but major benefits (especially in colorectal cancer) would be obtained if new therapies effective against the RIS-detected minimal residual disease were forthcoming.
Curr Opin Mol Ther 1999 Dec
PMID:Technology evaluation: CEA-Scan, Immunomedics Inc. 1962 71

A multitude of molecular techniques for monitoring minimal residual disease in lymphoproliferative disorders have been described to date. Real-Time Quantitative PCR targeting Immunoglobulin Heavy chain patient-specific sequences is increasingly being used for molecular detection of residual neoplastic B-cells using allele-specific oligos. The establishment of individually tailored PCR assays with the extensive use of patient-specific fluorescent-labeled oligos may be cumbersome and expensive. The present study was aimed at evaluating the usefulness of recently described hairpin-shaped allele-specific primers, originally intended for typing single-nucleotide polymorphisms, for the assessment of minimal residual disease using SYBR Green intercalating dye. Three cloned and 2 sequenced clonogenic Ig heavy chain rearranged gene loci, obtained from 5 cases of canine spontaneous B-cell lymphoma, were used as an experimental model. Both standard linear and hairpin-shaped forward and reverse clone-specific primers were evaluated in terms of specificity, sensitivity and PCR efficiency. Hairpin-shaped primers were demonstrated to have achieved accurate results more consistently than the respective linear primers allowing the specific and sensitive quantification of minimal residual disease of lymphoproliferative disorders with fewer validation procedures and more flexibility on the assay design.
Mol Cell Probes 2010 Feb
PMID:Real-time quantitative PCR using hairpin-shaped clone-specific primers for minimal residual disease assessment in an animal model of human non-Hodgkin lymphoma. 1965 Dec 5

The somatic mutation JAK2 V617F is associated with BCR-ABL1-negative myeloproliferative neoplasms. Detection of this mutation aids diagnosis of these neoplasms, and quantification of JAK2 V617F may provide a method to monitor response to therapy. For these reasons, we designed a clinical assay that uses allele-specific PCR and real-time detection with hydrolysis probes for the quantification of JAK2 V617F, wild-type JAK2, and GAPDH transcripts. Mutant and wild-type JAK2 were quantified by using external plasmid standards that contain the relevant JAK2 V617F or JAK2 sequence, respectively. We tested 55 peripheral blood specimens from patients with suspected myeloproliferative neoplasms and 55 peripheral blood specimens from patients not known to have myeloproliferative neoplasms. Low-level, nonspecific amplification was detected in reactions containing a high copy number of plasmid standards and in specimens from patients not known to have myeloproliferative neoplasms, necessitating the use of a laboratory-established mutant to wild-type cutoff. The limit of detection established by using cell line dilutions is 0.1%, and this method identified three JAK2 V617F-positive patients who were not detected by a less sensitive method. The assay characteristics and our initial evaluation indicate this method can be used for the detection and quantification of JAK2 V617F, which should be useful for diagnosis of myeloproliferative neoplasms and potentially for monitoring minimal residual disease in future trials of therapies targeted to myeloproliferative neoplasms.
J Mol Diagn 2010 Jan
PMID:Design and evaluation of a real-time PCR assay for quantification of JAK2 V617F and wild-type JAK2 transcript levels in the clinical laboratory. 1995 96


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