Molecular Pathology - Part 2
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| What are oncofetal antigens | Proteins that are expressed in fetal tissue during development but are not normally found in the tissues of adults. These include α-fetoprotein and carcinoembryonic antigen, frequently elevated in hepatocellular and colon cancers, respectively
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| Types of Protein Markers in Serum to detect cancer | Oncofetal proteins (CEA, AFP) and epithelial proteins (CA 19-9, CA 125 and CA 15-3) and newer Mitogenic Proteins (HER2/Neu)
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| Predominant use of Tumor markers ( are not tissue specific and can also be expressed in diseases other than cancer) | Following up of patients who are being treated for known malignancies ( their sensitivities and specificities are not sufficiently high that they can be used as cancer-screening proteins)
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| Example of a tissue specific tumour marker | PSA (Prostrate specific Antigen) - it has high sensitivity for diagnosing prostate cancer.
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| New developments in the eld of early tumor detection | (1) Mitogenic proteins, like HER2/Neu (signal transduction protein) elevated in many cancers (2) detection of genes encoding these proteins in body fluids (3) proteomic approaches for patterns of expression of multiple proteins to typify specific cancers
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| Circulating tumor cell (CTC) | Identication of a circulating tumor cell (CTC) as a biomarker is a fast-growing area of research for clinical application for diagnostic and prognostic values.
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| Circulating nucleic acid | Another area of growing research and translation to clinical application in cancer biomarkers is circulating nucleic acid, including the levels as well as mutation and methylation status.
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| Central cause of human cancers | Mafunctioning of Mutant Proteins
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| Mutant Proteins critical in signal transduction pathways in which proliferation signals from growth factors at the cell membrane are transduced to the nucleus and stimulate cell division. | Growth factors, growth factor receptors, G-proteins such as ras-p21, the mitogen-activated protein kinases, and nuclear proteins such as Myc, Fos, Jun, and p53
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| How mutations modify and create the Cancer causing malfunctioning proteins | Amino acid substitutions or deletions that cause them to be permanently activated. Mutations in regulatory domains of the genes encoding these proteins can result in protein overexpression, which can also result in continuous mitogenic signaling.
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| How can the Mafunctioning Mutant Proteins be used clinically | These proteins and antibodies to them can be used to detect the presence of cancers in patients at early stages—and even to predict their future occurrence.
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| Can mutated proteins be used to typify specific cancers | Although mutated signal transduction proteins are involved in many different human cancers, it appears that there are patterns of expression of mutated proteins that typify specifc cancers.
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| For hematolymphoid disorders what diagnostic role can be played by Molecular investigations | Diagnosis, classification, prognosis, and monitoring
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| Molecular investigations of acute leukemias and chronic myeloproliferative neoplasms help in | Molecular Diagnosis and identification of major genetic abnormalities
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| Molecular minimal residual disease monitoring important for | Patients with chronic myeloid leukemia or acute promyelocytic leukemia in the era of targeted therapeutic options.
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| Prenatal Molecular pathologic origins of childhood leukemias | Many pediatric ALL (and some AML) have origins in utero with acquisition of potentially leukemogenic translocations / genetic abnormalities, but mostly, additional, later-occurring genetic alterations in are required in order to produce overt leukemia
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| Identification of Monoclonal Lymphoid Proliferations | (1) Immunophenotypic studies - Antigen receptor gene rearrangements, B-cell (Light chain restriction) or Aberrant antigen expressopn (T cell) and (2) application of molecular clonality assays (molecular assessment of Antigen receptor gene rearrangements)
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| New research and technology developments that will impact molecular diagnosis and prognosis of hematolymphoid cancers | Next Generation Sequencing , Convergence of Molecular Diagnostics and Cytogenetics, Gene expression profiling (GEP) by microarray
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| Other Names of Next Generation Sequencing | Deep Sequencing, High Throughput sequencing, Massively Parallel Sequencing
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| NGS for other species of Nucleic Acid other than DNA | Can be used for mRNA and microRNA for large-scale analysis of the transcriptome and “miRnome,” respectively. When coupled with chromatin immunoprecipitation and bisulfite treatment, NGS can analyze protein-gene interactions and methylation patterns
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| Convergence of Molecular Diagnostics and Cytogenetics - Genome-wide analysis on a scale of resolution intermediate between the base pair level of molecular diagnostics and the gross overview afforded by conventional cytogenetics and even FISH methods | Array comparative genomic hybridization (aCGH) and the genotyping of single nucleotide polymorphisms (SNPs) via microarray
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| Gene expression profiling (GEP) by microarray | In contrast to NGS and molecular karyotyping, GEP by microarray is a technique that has by now compiled a lengthy track record as a tool for biomedical research - number of clinically important observations have been made in acute leukemias and lymphomas
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| Subclassification of NHLs(2008 WHOclassification) based on | Characteristic light microscopic tumor cell features and immunophenotypic cell marker profling (flow cytometry and immunohistochemistry), the identification of recurrent, nonrandom tumor genetic abnormalities (by chromosomal translocation events)
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| Three types of genetic lesions that cause Solid tissue (mainly epithelial cell) tumors | Deletion or inactivation of tumor suppressor genes, mutation in or overexpression of oncogenes (i.e., genes encoding proteins that are vital in control of the cell cycle), and hypermethylation of the promoter regions
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| Methods for Detection of genetic lesions in Solid tissue tumours | RT-PCR (real-time polymerase chain reaction,) FISH (fl uorescence in situ hybridization), immunohistochemistry and enzyme-linked immunosorbent assay
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| Utility of Detection of genetic lesions in Solid tissue tumours | Diagnosis of specfic types, for classification of the tumor, and for determining prognosis for a patient with a specific type of cancer.
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| Common mutation in several of Solid Tissue tumors | Overexpression of the epidermal growth factor receptor (EGFR). Discovery of this lesion allows for implementation of anti-EGFR therapy
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| When is efficacy of anti-EGFR agents diminished even with presence of over-expression of EGFR in a solid tissue tumor | (1) When there is additionally a mutation in ras gene (commonly mutated in many human cancers) - because ras-p21 is a downstream target of EGFR (2) Less commonly, oncogenic mutations can be found in downstream targets of ras-p21, such as BRAF
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| Examples on non-specific and Specific Oncogene Expression in Solid Tissue Tumors | Non-Specific - BRAF in Melanoma and Thyroid cancer
Specific - RET in Medullary Thyroid Cancer
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| Tumors that behave similar to Solid Tissue Tumors | Sarcomas
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| Genetic Abnormalities in Sarcomas | Reciprocal translocations resulting in oncogenic fusion transcripts (accounting for 15% to 20% of cases) and by specific oncogenic mutations (e.g., KIT and PDGFRA mutations in gastrointestinal stromal tumors) - Both types are specific for certain sarcomas
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| Basis for screening for Familial Cancers | Because the genetic alterations or changes that underlie many familial types of cancers are known, it is possible to screen for these in the children and close relatives of patients known to have a form of familial cancer
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| Molecular diagnostic technique that is currently widely used in the selection of pathway-based therapy and prediction of treatment resistance of many types of cancer. | Next Generation Sequencing (NGS)
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| What has facilitated the emergence of high-throughput genomic and proteomic technologies. | Completion of the human genome project that has provided scientists with a detailed map of the human genome and predicted coding regions
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| Mature platforms for high-throughput profiling of gene expression in human tissue | Serial analysis of gene expression (SAGE), DNA microarrays, and real competitive polymerase chain reaction.
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| Techniques to explore the dynamic and complex protein composition of healthy and diseased human tissue. | Proteomic technologies, including mass spectrometry and protein arrays
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| techniques used to identify diagnostic gene-expression signatures for a number of hematologic and solid malignancies that are often difficult to distinguish using traditional histologic analysis. | DNA microarray and SAGE technologies
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| Prognostic gene and protein expression profiles have been identifed in which cancers | Large number of cancers, including lymphoma, lung cancer, breast cancer, and acute myeloid leukemia
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| What needs to be done before widespread clinical implementation of High Throughput Genomic and Proteonomic technologies can be achieved | Validation in large clinical trials, standardization of techniques and controls, and inclusion of analytic standards
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| Why is Molecular testing for inherited disorders the most rapidly growing area of molecular pathology, | Owing to the plethora of disease genes discovered through the Human Genome Project and subsequent studies.
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| How to detect the mutations for single-gene disorders, whether dominant or recessive | By variety of molecular diagnostic techniques, either specific to the mutation in question, if it is known, or by comprehensive gene sequencing or mutation scanning approaches if the mutation is not known.
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| Targets for large-scale population screening programs. | Certain disorders, such as cystic fibrosis with sufficiently high mutation carrier frequencies
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| Appropriate targets of presymptomatic testing, provided sufficient attention is paid to the associated genetic counseling and ethical concerns. | Late-onset dominant disorders, such as Huntington disease and familial cancers
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| What technique can replace or supplement single-gene testing. | NGS sequencing promises to revolutionize the field, with whole-exome or whole-genome sequencing tending to replace or supplement
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| What Ethical issues are raised by Molecular testing for inherited disorders | Genetic privacy, informed consent, pregnancy termination, potential stigmatization, and theoretical risk for insurance discrimination.
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| What forms the basis of commercially available kits for DNA analysis in Parentage and forensic testing | Standardized marker systems with known allelic polymorphisms are used in testing panels. Alleles with short tandem repeats form the basis of commercially available kits.
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| Forensic testing requires Documentation of which all steps is required during forensic testing to withstand legal challenges | All Collection, extraction, and testing steps
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| What can be obtained from any sample that contains cellular material | Deoxyribonucleic acid (DNA) can be obtained from any sample that contains cellular material. The stability of DNA allows it to withstand harsh environmental conditions and long postmortem intervals.
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| What care must be taken to maintain the integrity of DNA evidence | By avoiding contact or exposure of the evidence to any conditions that may contaminate and/or further degrade the original stain/evidence.
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| Why can Mitochondrial DNA can be extracted from bone and teeth after hundreds and even thousands of years | Because it is small and present at hundreds to thousands of copies per cell. Mitochondrial DNA is maternally inherited and can be useful for identifying remains.
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| Uses of DNA is in identification of remains | Link a suspect to a crime, Exculpate falsely accused suspects, Recognize serial crimes, Distinguish copycat crimes, Aid in accident reconstruction
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| How can pathology laboratories resolve specimen mix-ups such as when samples are inadvertently switched or pathologic material floats onto a histologic or cytologic slide. | By using DNA testing
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| Standards and quality assurance guidelines for identity testing laboratories have been developed by | American Association of Blood Banks (for parentage testing), the U.S. Department of Justice Federal Bureau of Investigation’s Working Groups, the Forensic Science Standards Board, and the International Society for Forensic Standards (for forensic testing)
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| What technologies have provided unprededented ability to personalize output of biomarkers implicated in select disease states. | High throughput array technologies such as genomics and proteomics
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| Pharmacogenomics - What it detects | Through utilization of novel technologies, can detect unique polymorphisms to serve as diagnostic and/or prognostic biomarkers, which relate to an individual or group response to particular therapies.
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| Pharmacogenomics -Benefits | Elucidation of unique or personal responses can tailor therapy to the individual, thereby maximizing drug choice, dose, and effect.
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| Why can Interpretation of pharmacogenomic responses be discretionary | Because many genotypic and phenotypic variables are often involved
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