Download Cancer is a genetic disease gene dysfunction is implicated in

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Cancer is a genetic disease
o gene dysfunction is implicated in initiating and driving cancerous changes in all
tissues
o heritable (genetic) cancer syndrome genes are linked to sporadic cancer
development
o analysis and documentation of common mutations in cancer tissue (signature or
profile)
o genomic studies identify changes associated with cancer
o no two cancers will be the same (although many have mutations in common)
 personalized medicine---tumor’s gene signature---may provide prognosis
 candidate drugs to target specific cellular processes—tyrosine kinases
not a single disease, name used to describe the rapid and uncontrolled cellular
proliferation that produces a mass/tumor
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must be malignant
o cell growth is no longer controlled by normal boundaries of cellular function
o capable of progression by invading neighboring tissues
o capable of invasion of more distant tissue
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Three types
o Sarcoma: originates in mesenchymal tissue
o Carcinoma: originates in epithelial tissue
o Hematopoetic/lymphoid: originate in bone marrow, lymphatic system and
peripheral blood
o Within each type classified based on site, tissue type, histological appearance and
degree of malignancy (stage)
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Development of cancer: oncogenesis
o Multi-step process resulting from gene dysregulation
o process that produces genetic mutations induced by chemicals or physical
agents (initiation promotion progression localized tumor metastasis)
 initiation-irreversible genetic change in single cell
 promotion-increased proliferative ability in initiated cell (clonal growth)
 progression-acquisition of more genetic damage that allows cell(s) to
proceed to malignant phenotype
o General scheme for mechanisms of oncogenesis by proto-oncogene
activation, loss of tumor-suppressor gene expression, activation of antiapoptotic genes, or loss of pro-apoptotic gene expression
o Tumor formation is driven by accumulation of mutations (drivers) in key genes
that encode functions of cell cycle regulation, cell growth, and programmed cell
death (clonal evolution)
o Oncogene co-operativity: cells divide without regulation
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Important terms
o Hereditary cancer syndrome: first cancer causing gene mutation inherited;
therefore present in every cell in the body followed by a somatic mutation at a
second point in time (ex: Lynch Syndrome)
o Sporadic Cancer: a mutation occurs in a single cell; progression to tumor via
accumulation of other mutations and clonal evolution
o Oncogene (Onc): mutation of a proto-oncogene(normal cellular protein coding
genes) that are involved in growth or cell survival that when altered stimulate cell
division and proliferation
o Tumor-Suppressor Gene (TSG): encode proteins that protect the transition of
cells through checkpoints (gatekeepers)or proteins that protect cell division or
integrity/stability of the genome (caretakers)
o Loss of Function of caretakers: gene mutation that allows the accumulation of
deleterious mutations in proto-oncogenes and gatekeepers that can initiate or
promote cancer
o Tumor Initiation: irreversible genetic alterations that allow dysfunction in a
single cell
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Fearon- Vogelstein Adenoma- Carcinoma Model
o Classic model for mutli-stage progression of colorectal cancer
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Cancer cell phenotypes
o Immortality
 Replication of telomeres protected
 Loss of growth control via loss of tumor suppressor activity
o Decreased dependence on growth factors for proliferation
 Tumor cells can autocrine signal with GF
o Loss of anchorage dependent growth /altered cell adhesion
 Allows for metastasis through protealitic cleavage of BM
 MPPs (matrix metalloproteins)not normally expressed in adult cells
but are over-expressed in tumor cells
o Loss of cell cycle control (mitosis)
 CDKs control progression through cell cycle
 Controlled by oncogene and tumor suppressor gene products
 Invalid or abnormal checkpoints can produce genome instability and
increased mutation frequency
 Cip/Kip family members: p21/ Cip1/ waf1/Sdi1, p21/Kip1,
p57/Kip2 Proteins in this family ---broad specificity---bind and
inactivate most of the cyclin/cdk complexes that are needed for the
progression of the cell cycle
o P53 when DNA damage detected—halts cell cycle for
DNA repair (serious problem if this is mutated)
 INK4 Family members: p16/INK4a, p15/INK4b, p18/INK4c,
p19/INK4d restricted binding to cdk4/6---primary function to
regulate phosphorylation of Rb critical cell cycle checkpoint
o Reduced sensitivity to apoptosis
o Critical effectors: caspases
o Death receptor mediated apoptosis examples:
 P38 promotes Bim/Bax>> caspase 9, inhibits Bcl-2
 Fas/FasL (death inducing signaling complex= DISC)>> caspase 8
o Cancer overcomes these through overexpression of Bcl-2 and mutated Fas
receptor
o increased genetic instability
 chromosomal aneuploidy—gain or loss of one or more chromosomes
 chromosomal polyploidy---accumulation of extra set(s) of chromosomes
 Translocation and re-arrangements can provide growth advantages
 Examples:
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Burkitt’s lymphoma –t(8,14) translocation where c-myc protooncogene expressed from IgH promoter/enhancer due to
chromosome re-positioning resulting in transcriptional fusion
protein
 Philadelphia chromosome (CML)-- t(9;22) translocation where
c-Abl+Bcr kinase +GAP are spliced to form constitutively active
chimeric kinase that drives cell proliferation
Gene amplification: multiple rounds of DNA replication at a single site
o Angiogenesis (neo-vascularization with cancer cell proliferation)
 “angiogenic switch” up-regulation of angiogenesis and down-regulation
of of anti-angiogenic factors significant transformation that leads to more
lethal tumors
 VEGF—(vascular endothelial growth factor) first identified as a factor
secreted from tumor cells caused normal blood vessels to become
hyperpermeable
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Cancer genes
o Oncogenes: derived from cellular genes (proto-oncogenes/c-onc) that become
dysregulated as a result of mutation contribute to cell proliferation or decrease
sensitivity to cell death
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7 classes of prot-oncogenes (Mutant forms alter intracellular cascades
conferring selective growth advantage that allow tumors to develop)
 GF
 GF receptors
 GF and receptors autocrine signal up-regulating unregulated
proliferation
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G proteins
 Activated by mutation and go on to activate further oncogenes
 RAS functions in cell proliferation, cell survival, and remodeling
of the actin cytoskeleton
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Ser-Tyr kinases
 RAF recruited by ras and then activates one of mitogen-induced
protein kinases (MAPKs)
 action invokes activation of transcription factors in nucleus
containing “Elk-1” response elements
 can also activate protein kinase C that signals other kinases to
activate –c-jun
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Non-receptor Tyr Kinase
 SRC
o SH1 has kinase activity
o SH2 and SH3 involved in protein-protein interactions
intracellular signaling function---mutations may generate
constitutive signaling within cell
 Bcr-Abl (Philadelphia chromosome)
o chimeric fusion derived from t(9;22) in chronic
myelogenous leukemia (CML)—Ph chromosome
o c-Abl (chromosome 9) is a tyrosine kinase
o Bcr (chromosome 22) is a GTPase activating (GAP)
protein---fusion protein causes unregulated cell growth by
initiating ras signaling---reduces growth factor dependence,
alters cell adhesion properties, enhances cell viability
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Nuclear proteins
 Transcription factors
o c-myc transcription factor Burkitt’s Lymphoma
 The c-myc gene is a central oncogenic switch for
oncogenes and the tumor suppressor APC.
o c-jun transcription factor (AP-1) osetosarcoma
o c-fos transcription factor (AP-1) sarcoma
o cellular functions include: cell proliferation and metastasis
AP-1 nuclear target for growth factor induced signaling
also regulates genes like the MMPs and gene products that
aid in cell migration through connective tissue
 Telomerases
o Telomerase activity has been observed to be active in
cancer cells; allowing tumor cells to proliferate indefinitely
 mutation in telomerase gene
 up-regulated via other pathways or oncogene
products
 uncharacteristic end to end fusions of
chromosomes---disrupt mitosis
 important step in progression of cancer
Cytoplasmic proteins engaged in cell survival
o bcl-2 oncogene disrupts apoptotsis increased expression
seen in variety tumor cells --associated with poor prognosis
o Tumor Suppressor Genes
 For tumor suppressor product to generate a tumor both copies must be
lost/ mutated---recessive effect!
 Two types: caretakers and gatekeepers
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Example
 Rb is first tumor suppressor gene identified---loss of RB protein
produces cancer. Protein active in cell nucleus; when
unphosphorylated binds to E2F transcription factor--- thus
preventing transcription of E2F associated gene targets. When RB
protein function disrupted ---deregulated cell cycle and
uncontrolled cell division---E2F can keep activating its target
genes. Dysregulated function requires loss of both Rb alleles
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Loss of Heterozygosity Tumor Suppressor Gene Inactivation
 "Loss of heterozygosity” (LOH) describes inactivation of the
2ndcopy of a tumor suppressor gene
Mutations that inactivate tumor suppressor genes= “loss-of-function”
mutations:
 point mutations or small indels that disrupt the protein function(s)
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Another example
 p53 tumor suppressor gene: activated in many cell functions
DNA damage, hypoxia, ribonucleotide depletion, cell adhesion and
cell stress created by activation cellular oncogenes
 Loss of function via three paths:
o mutant p53 gene---seen in approx. 53% sporadic tumors
and Li-Fraumeni Syndrome
o viral transforming antigens—SV40 Large T antigen form
inactive p53 complex
o cytoplasmic sequestration—can’t enter nucleus to activate
target genes
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APC mutations occur early in colon carcinogenesis---initiating
event leads to activation of c-myc (an oncogene) since wildtype
APC suppresses c-myc APC also assist in maintaining crypt
migration of cells in intestine and apoptosis
PTEN induces cell cycle cessation and apoptosis---negative
regulator of Akt activation suppresses blood vessel growth
(opposing VEGF)
Heritable cancer syndromes
o Li-Faumeni: germline p53 gene
o Breast and ovarian cancer: BRCA, BRCA 2, RAD51C RAD51D
o Lynch Syndrome (HNCCT): MSH2 and MLH1 mutation
o Xeroderma Pigmentosum: XPC mutation
o Franconi’s Anemia: FRACB genes
o Bloom’s Syndrome: BLM mutation (recQ kinase)
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miRNAs and cancer
o miRNAs can be tumor suppressors or modulate other genes with oncogenic
o or tumor suppressor roles
o miRNAs can increase expression to initiate cell processes contributing to cancer
or they can decrease expression that leads to mis-regulation and cancer
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Chemical Carcinogenesis (DNA adducts)
o Planar chemical---integrated into DNA forming an adduct can introduce
mutations when DNA replicates during mitosis
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Summary
o Cancer is a molecular genetic disease
o Derived from a single cell by clonal expansion and co-operativity
o Mutations in proto-oncogenes (c-myc, etc.) dominant
o Mutations in tumor suppressor genes (Rb, etc.) recessive
o Chemicals (benzene) and physical agents (radiation) can induce errors in DNA
repair leading to cancer
o Many cellular processes are disrupted as genome mutations accumulate and alter
“normal” cell functioning
o miRNA can alter cell functions that can cause cancer
o Cancer can be predisposed/inherited in families: “two hit” hypothesis (Cancer
Syndromes)
o Chromosomal translocation: create fusion proteins or create transcriptional
hybrids that alter cell function proteins that dysregulate cell function
o Cancer cells can evade many critical cell activities: apoptosis, mitotic
checkpoints, growth arrest, transcriptional controls, hormonal controls, etc.
o Cancer is a multiple stage process: initiation, progression, metastatic
transformation
o Cancer therapies are being “custom” designed to block critical cancer cell
activities (kinase Inhibitors)
o Genetic signatures (profiles) of cancer tissue are used to estimate prognosis and
recurrence rates