Carcinogenesis Ppt Powerpoint Presentation slides herni Medical Slideshow Carcinogenesis involves accumulation of several somatic lesions, leading to

Carcinogenesis

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MOLECULAR BASIS OF CANCER Dr Herni Talib Department of Pathology Faculty of Medicine & Health Sciences UPM, Serdang.

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CARCINOGENESIS Def: The process by which normal cells are transformed into cancer cells.

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Carcinogenesis vs acute inflammation

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Cancer pathogenesis

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Cancer Cancer is genetic disease Genetic injury in somatic cells acquired by environmental agents/inherited in germ-line Gene that are targets of genetic damage growth-promoting proto-oncogenes growth-inhibiting tumor suppressor genes genes that regulate programmed cell death (apoptosis) genes involved in DNA repair

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Carcinogenesis Carcinogenesis is a multistep process at both the phenotypic and the genetic levels resulting from the accumulation of multiple mutations phenotypic attributes to tumor progression excessive growth, local invasiveness, and the ability to form distant metastases At the genetic level, tumor progression and associated heterogeneity result from multiple mutations that accumulate independently in different cells, generating subclones with varying abilities to grow, invade, metastasize, and resist (or respond to) therapy

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Oncogene & cancer Proto-oncogenes are normal cellular genes affect cellular growth, proliferation & differentiation Converted into oncogene by: Transduction into retrovirus (v-onc) changes in situ that affect their expression &/ function (c-onc) Oncogenes are genes whose products are associated with neoplastic transformation Most human tumors cause by v-onc

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Oncogenes Protein products of oncogene: Growth factors eg: c-cis? PDGF Growth factor receptors eg: v-erb B? thyrosine kinase receptor c-erb B1, B2? EGF-receptor 3. Signal-transducing proteins 2 categories: GTP-binding protein ras & G protein Non-receptor associate thyrosine kinase c-abl (tranlocation & fusion to bcr gene? unregulated TK activity) 4. Nuclear regulatory proteins myc, jun, fos & myb? nuclear proteins

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Activation of oncogene Proto-onc converted to oncogene by 3 mechs: Point mutations Translocations Gene amplifications

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Mechanisms of activation Point mutations A single nucleotide base change in the DNA. consist of the loss of a nucleotide, the insertion of an additional nucleotide, or the substitution of one nucleotide for another. eg: activation of ras proto-oncogene 15% tumor carry H-ras/K-ras onc. Possible mech - exposure to cancer-causing chemical

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Translocations Activate proto-onc by 2 mech: Placement of genes next to strong promoter/enhancer element eg: Burkitt lymphoma, t(8;14) translocation places c-myc of chrom 8 in close prox with IgH-expressing gene in chrom 14. Fusion of gene with new genetic sequences eg: CML, t(9;22) translocation relocates the c-abl gene from chrom 9 to the bcr locus on chrom 22. c-bcr-abl hybrid gene codes for a chimeric protein that exhibit tyrosine kinase activity

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Gene amplification Increase activity result from reduplication of proto-onc eg: N-myc amplification (3 to 300 copies) in neuroblastoma (related with adv stage & poor prognosis) c-erb B2 (HER2) amplification in 30-40% of breast ca (related with prognosis)

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Cancer suppressor gene (CSG) Cancer can arise by inactivation of gene that normally suppress cell proliferation (anti-oncogene). eg: Rb gene (on chrom 13q14) is CSG involve in pathogenesis of Retinoblastoma Mechanism of action- not clear Mutation of these genes disrupt the orderly regulation of cell cycle.

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Suppressor genes NF-1 Mutated in neurofibromatosis type 1 Act in concert with ras oncogene Normal NF-1? inactivate ras protein Mutated NF-1? unchecked ras-activation p53 Most common genetic alteration in human cancers Ca breast, colon & lung Person inherited mutant p53 gene are @ risk developing variety of tumors Prevent cells damaged by mutagenic agents from proceeding to divide (allow DNA repair & if beyond repair, proceed to apoptosis) Mutant p53 fail to arrest damaged cell from dividing? accumulating mutations? neoplastic transformation. Others: APC, WT-1, DCC, NF-2, VHL

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Genes that regulate apoptosis Prototypic gene: bcl-2 Prevent programmed cell death (apoptosis) Over expression of bcl-2? extend cell survival Genetically damaged cells? continue additional mutation in oncogenes & CSG. eg: B cell lymphoma (follicular type) Other genes: p53, c-myc

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MULTISTEP CARCINOGENESIS No single genetic alteration sufficient to induce cancers. Multiple controls lost by 3 categories of gene (oncogenes, CSG, ARG)? cancer cells proliferation.

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Adenocarcinoma of colon Benign adenoma (increasing & additive mutation affecting ras, APC, p53 & DCC genes) ? Genetic change in master ‘mutator gene’ in chrom 2p (normal form favors repair of DNA)

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Morphologic and molecular changes in the adenoma-carcinoma sequence Postulate: loss of one normal copy of the tumor suppressor gene APC occurs early, (born with one mutant allele) making them extremely prone to develop colon cancer inactivation of APC may occur later in life. This is the "first hit" according to Knudson's hypothesis The loss of the intact copy of APC follows ("second hit"). Other mutations include: KRAS emergence of carcinoma losses at 18q21 involving SMAD2 and SMAD4 ? inactivation of the tumor suppressor gene p53 additional mutations occur the accumulation of mutations, rather than their occurrence in a specific order, is most critical.

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Endometrial carcinoma

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