cancer and genetic influences
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Cancer and genetic influences: overview & oncogenesTRANSCRIPT
Cancer and genetic Cancer and genetic influencesinfluences 1. overview & oncogenes1. overview & oncogenes
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What is cancer?What is cancer?A name used to describe a form of A name used to describe a form of neoplasianeoplasia
Uncontrolled cell proliferation leading to a mass or Uncontrolled cell proliferation leading to a mass or tumor (neoplasm)tumor (neoplasm)
Occurs due to imbalance between cellular proliferation Occurs due to imbalance between cellular proliferation and cellular deathand cellular death
Normal growthNormal growth NeoplasmNeoplasm
Mutations in genesMutations in genescontrollingcontrolling-prolif or cell cycle.-prolif or cell cycle.-cytoskeletal -cytoskeletal inv’ed with contactinv’ed with contact inhibitioninhibition-programmed cell -programmed cell deathdeath-detecting and -detecting and repairing DNA repairing DNA damagedamage
What is cancer?What is cancer?
In addition, the neoplasm must also In addition, the neoplasm must also be malignantbe malignant
NOTE: Tumors that do not invade or spread are not cancerous, but NOTE: Tumors that do not invade or spread are not cancerous, but
referred to as referred to as benignbenign
growth no longer growth no longer
controlled and can now controlled and can now
invade neighboring invade neighboring
tissues and/or spread to tissues and/or spread to
more distant sites more distant sites
(metastasis)(metastasis)
Major types of cancerMajor types of cancerCarcinoma Carcinoma
Derived from epithelial cells, which line surface of skin and Derived from epithelial cells, which line surface of skin and organs, digestive tract, airways and mammary ductsorgans, digestive tract, airways and mammary ducts
Most common cancer type (89-90% of all reported cases)Most common cancer type (89-90% of all reported cases)
SarcomaSarcoma Derived from mesenchymal tissue – muscle, bone, cartilage, fat, Derived from mesenchymal tissue – muscle, bone, cartilage, fat,
connective tissuesconnective tissues
HematopoieticHematopoietic Leukemia – derived from white blood cells or their precursorsLeukemia – derived from white blood cells or their precursors
Lymphoma – involves cells of the lymphatic systemLymphoma – involves cells of the lymphatic system
Myelomas – involves white blood cells responsible for the Myelomas – involves white blood cells responsible for the production of antibodies (B lymphocytes or B-cells) production of antibodies (B lymphocytes or B-cells)
Cancer prefixesCancer prefixes
Examples: Examples: Osteosarcoma – cancer Osteosarcoma – cancer arising in bonearising in bone
Hepatocarcinoma – Hepatocarcinoma – cancer arising in the livercancer arising in the liver
Stages of tumor progressionStages of tumor progressionmore growth – abnormal more growth – abnormal cellular appearance; may cellular appearance; may become disorganizedbecome disorganized
uncontrolled cell division leading to an excess of cells
cells become primitive in cells become primitive in capability – invasive capability – invasive
potential existspotential exists
ability to invade ability to invade &/or metastasize&/or metastasize
Characteristics of cancer cellsCharacteristics of cancer cellsCytoskeletal changesCytoskeletal changes
Cell adhesion altered – cells able to moveCell adhesion altered – cells able to move
Changes in structure of nucleusChanges in structure of nucleus
Secretion of enzymes that enable them to invade Secretion of enzymes that enable them to invade
neighboring tissuesneighboring tissues
Unlimited number of cell divisionsUnlimited number of cell divisions
Growth in the absence of “go” signalsGrowth in the absence of “go” signals
Avoidance of cell deathAvoidance of cell death
Tumors stimulate the growth of blood vessels Tumors stimulate the growth of blood vessels
(angiogenesis)(angiogenesis)
Cancer in familiesCancer in families
Many forms have higher incidence in Many forms have higher incidence in
relatives than in general populationrelatives than in general population
Nearly 50 mendelian disorders where risk of Nearly 50 mendelian disorders where risk of
cancer is very high among relativescancer is very high among relatives
For other cancers, the increased incidence is For other cancers, the increased incidence is
2-3 fold higher for 12-3 fold higher for 1oo relatives – complex relatives – complex
disorderdisorder
Cancer as a genetic diseaseCancer as a genetic disease whether sporadic or familial, cancer is whether sporadic or familial, cancer is
fundamentally due to mutation in various genes fundamentally due to mutation in various genes controlling cell growth or cell deathcontrolling cell growth or cell death
once initiated, the cancer evolves by once initiated, the cancer evolves by accumulating additional mutations in other genesaccumulating additional mutations in other genes
leads to an ever-worsening cascade of mutationsleads to an ever-worsening cascade of mutations
Original clone of neoplastic cells can evolve into Original clone of neoplastic cells can evolve into numerous sublineages with different but numerous sublineages with different but overlapping mutationsoverlapping mutations
Tumor suppressor geneTumor suppressor gene Protooncogene Protooncogene
Classifying the genes involved Classifying the genes involved in cancerin cancer
OncogenesOncogenes – – mutant forms of genes mutant forms of genes
(proto-oncogenes) that positively regulate cell (proto-oncogenes) that positively regulate cell
proliferation and cell survival proliferation and cell survival -usu dominant, gain--usu dominant, gain-
of-fn mutationsof-fn mutations
Tumor suppressorsTumor suppressors – genes which function to – genes which function to
block tumor development by negatively block tumor development by negatively
regulating cellular growth-regulating cellular growth-usu need loss of both usu need loss of both
copiescopies
Cellular maintenance genesCellular maintenance genes – responsible for the – responsible for the
detection and repair of genetic damage in cellsdetection and repair of genetic damage in cells
OncogenesOncogenes
in altered (mutated) form, gene expression in altered (mutated) form, gene expression leads to abnormal stimulation of cell division leads to abnormal stimulation of cell division and proliferationand proliferation
have a dominant effect at the cellular level – a have a dominant effect at the cellular level – a single mutant allele is enough to change single mutant allele is enough to change cellular phenotype from normal to malignant cellular phenotype from normal to malignant (gain of function)(gain of function)
Mutations: gene, regulatory region, copy #Mutations: gene, regulatory region, copy #
normalnormal mutantmutant
OncogenesOncogenesin its normal form, in its normal form, the gene is called a the gene is called a proto-oncogeneproto-oncogene
Most proto-oncogenes Most proto-oncogenes are components of are components of signal transduction signal transduction pathways: pathways: translate extracellular translate extracellular signals into changes signals into changes in gene expressionin gene expression
Increase blood supply Increase blood supply to the tumor or inhibit to the tumor or inhibit apoptosisapoptosis
RET, METRET, METReceptor tyrosine kinasesReceptor tyrosine kinases-transduce an extracellular-transduce an extracellular signal inwardsignal inward-bind a ligand, conformational -bind a ligand, conformational change that results in kinase change that results in kinase activity, leading to phosphor-activity, leading to phosphor-lation of cellular proteinslation of cellular proteins-pt mut’s cause receptors to-pt mut’s cause receptors tobe constitutively activebe constitutively activeRET mut-multiple endocrine RET mut-multiple endocrine neoplasianeoplasiaMET mut-hereditary papillary MET mut-hereditary papillary renal carcinomarenal carcinoma
Ras, AblRas, Abl
MycMyc
RAS family of proto-oncogenesRAS family of proto-oncogenesOne of the first activated oncogenes discovered One of the first activated oncogenes discovered by the DNA transformation assayby the DNA transformation assay
Encodes a small guanosine triphosphate (GTP) –Encodes a small guanosine triphosphate (GTP) –binding protein (G-protein)binding protein (G-protein)
3 members of this family; H-RAS, K-RAS, N-RAS3 members of this family; H-RAS, K-RAS, N-RAS
Serves as an “on/off” switch to activate or Serves as an “on/off” switch to activate or inhibit downstream molecules when bound to inhibit downstream molecules when bound to GTPGTP
The protein’s effect is ended by self-directed The protein’s effect is ended by self-directed cleavage of GTPcleavage of GTP
RAS family of proto-oncogenesRAS family of proto-oncogenes
Ras associates with the plasma membraneRas associates with the plasma membrane
Ras relays signals from the cell surface Ras relays signals from the cell surface receptors to the nucleus, functioning as a receptors to the nucleus, functioning as a switchswitch
‘‘Active’ when GTP is boundActive’ when GTP is bound
‘‘Inactive when the hydrolyzed GDP is boundInactive when the hydrolyzed GDP is bound
RAS mutation in human RAS mutation in human cancerscancers
H-RAS mutated in 10% of all bladder cancer
K-RAS mutations in about 50% of colorectal cancers, 70-90% of pancreatic cancers and 30% of lung adenocarcinomas as well as in ovarian, breast skin liver and
kidney
N-RAS mutations have been detected in 20-30% of acute nonlymphocytic leukemias
RAS oncogene activation by RAS oncogene activation by nucleotide substitutionnucleotide substitution
Conversion to oncogene usually due to a point Conversion to oncogene usually due to a point mutation in the gene where:mutation in the gene where:
the ras protein is able to signal continuously, even the ras protein is able to signal continuously, even in in absenceabsence of GTP of GTP
the ras protein is the ras protein is unable to hydrolyze GTPunable to hydrolyze GTP to turn “off” the signalto turn “off” the signal
Leads to the continuous activation of multiple Leads to the continuous activation of multiple downstream signaling pathways inducing cell downstream signaling pathways inducing cell proliferationproliferation
Mutations in the 3 RAS genes are found in 10-Mutations in the 3 RAS genes are found in 10-15% of all human cancers 15% of all human cancers
Oncogenes are also activated Oncogenes are also activated by chromosome translocationsby chromosome translocations
Breakpoint can occur within Breakpoint can occur within introns of two genes: introns of two genes: chimeric protein with novel chimeric protein with novel properties – properties – Chronic Chronic Myelogenous Leukemia-Myelogenous Leukemia-Uncontrolled proliferation of Uncontrolled proliferation of white blood cellswhite blood cells
Arises in a bone marrow Arises in a bone marrow stem cell that is a precursor stem cell that is a precursor
to the granulocytes and to the granulocytes and megakaryocytesmegakaryocytes
These cells contain a chr These cells contain a chr 9;22 translocation – 9;22 translocation –
“Philadelphia Chromosome”“Philadelphia Chromosome”
Protooncogene ABL, a tyrosine kinase, is moved from its normal position on 9 to 22.Result: increased activity
Chronic Myelogenous Chronic Myelogenous Leukemia (CML)Leukemia (CML) Proto-oncogene ABL Proto-oncogene ABL
(tyrosine kinase) moves (tyrosine kinase) moves from 9q to the from 9q to the “breakpoint cluster region “breakpoint cluster region (BCR) on 22q(BCR) on 22q
Chimeric protein has Chimeric protein has increased tyrosine kinase increased tyrosine kinase activity but altered activity but altered structure and functionstructure and function
Requires secondary Requires secondary mutation to move into mutation to move into crisis phasecrisis phase
Effective drug therapy Effective drug therapy developed to target novel developed to target novel proteinprotein
Oncogenes are also activated Oncogenes are also activated by chromosome translocationsby chromosome translocations
Breakpoint can occur within Breakpoint can occur within introns of two genes: introns of two genes: chimeric protein with novel chimeric protein with novel properties – properties – Chronic Chronic Myelogenous LeukemiaMyelogenous Leukemia
Alternately, translocation Alternately, translocation may place proto-oncogene may place proto-oncogene downstream of a strong downstream of a strong constitutive promoter from constitutive promoter from another gene – proto-another gene – proto-oncogene is now expressed oncogene is now expressed at inappropriate time/place at inappropriate time/place – – Burkitt LymphomaBurkitt Lymphoma
Burkitt LymphomaBurkitt LymphomaB-cell tumorB-cell tumor
MYC proto-oncogene MYC proto-oncogene (transcription factor) (transcription factor) translocated from 8q24 translocated from 8q24 to 14q32, distal of the to 14q32, distal of the Ig heavy chain locusIg heavy chain locus
Ig enhancers or Ig enhancers or activating sequences activating sequences act on MYC – allowing act on MYC – allowing for unregulated for unregulated expression and expression and uncontrolled cell growthuncontrolled cell growth
http://tooldoc.wncc.edu/Infections/lymphoma.JPG• Solid tumor of B-lymphocytes
• Predominantly affecting young children
in Africa,
• one of the fastest growing malignancies
in humans.
• manifested most often as a large jaw
lesion expands rapidly over a period of
a few weeks to invade the orbit.
• Visceral involvement, usually an
abdominal mass
• Treatment of the jaw and eye areas is by
radiotherapy,while visceral involvement
requires systemic chemotherapy.
In all cases, translocation of MYC is the cause