1. Cancer and geneticCancer and genetic
influencesinfluences
1. overview & oncogenes1. overview & oncogenes
Lec 24Lec 24
2. What is cancer?What is cancer?
A name used to describe a form ofA name used to describe a form of neoplasianeoplasia
Uncontrolled cell proliferation leading to a mass or tumorUncontrolled cell proliferation leading to a mass or tumor
(neoplasm)(neoplasm)
Occurs due to imbalance between cellular proliferation andOccurs due to imbalance between cellular proliferation and
cellular deathcellular death
Normal growthNormal growth NeoplasmNeoplasm
Mutations in genesMutations in genes
controllingcontrolling
-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 DNArepairing DNA
damagedamage
3. What is cancer?What is cancer?
In addition, the neoplasm must alsoIn addition, the neoplasm must also be malignantbe malignant
NOTE: Tumors that do not invade or spread are not cancerous, butNOTE: Tumors that do not invade or spread are not cancerous, but
referred to asreferred to as benignbenign
growth no longergrowth no longer
controlled and can nowcontrolled and can now
invade neighboringinvade neighboring
tissues and/or spread totissues and/or spread to
more distant sitesmore distant sites
(metastasis)(metastasis)
4. Major types of cancerMajor types of cancer
CarcinomaCarcinoma
Derived from epithelial cells, which line surface of skin andDerived 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 theMyelomas – involves white blood cells responsible for the
production of antibodies (B lymphocytes or B-cells)production of antibodies (B lymphocytes or B-cells)
6. Stages of tumor progressionStages of tumor progression
more growth – abnormalmore growth – abnormal
cellular appearance; maycellular appearance; may
become disorganizedbecome disorganized
uncontrolled cell
division leading to
an excess of cells
cells become primitive incells become primitive in
capability – invasivecapability – invasive
potential existspotential exists
ability to invadeability to invade
&/or metastasize&/or metastasize
7. Characteristics of cancer cellsCharacteristics of cancer cells
Cytoskeletal 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 invadeSecretion 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 vesselsTumors stimulate the growth of blood vessels
(angiogenesis)(angiogenesis)
8. Cancer in familiesCancer in families
Many forms have higher incidence in relatives thanMany forms have higher incidence in relatives than
in general populationin general population
Nearly 50 mendelian disorders where risk ofNearly 50 mendelian disorders where risk of
cancer is very high among relativescancer is very high among relatives
For other cancers, the increased incidence is 2-3For other cancers, the increased incidence is 2-3
fold higher for 1fold higher for 1
oo
relatives – complex disorderrelatives – complex disorder
9. Cancer as a genetic diseaseCancer as a genetic disease
whether sporadic or familial, cancer is fundamentally duewhether sporadic or familial, cancer is fundamentally due
to mutation in various genes controlling cell growth or cellto mutation in various genes controlling cell growth or cell
deathdeath
once initiated, the cancer evolves by accumulatingonce initiated, the cancer evolves by accumulating
additional mutations in other genesadditional 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 intoOriginal clone of neoplastic cells can evolve into
numerous sublineages with different but overlappingnumerous sublineages with different but overlapping
mutationsmutations
Tumor suppressor geneTumor suppressor gene ProtooncogeneProtooncogene
10. Classifying the genes involvedClassifying the genes involved
in cancerin cancer
OncogenesOncogenes –– mutant forms of genes (proto-mutant forms of genes (proto-
oncogenes) that positively regulate cell proliferationoncogenes) that positively regulate cell proliferation
and cell survivaland cell survival -usu dominant, gain-of-fn mutations-usu dominant, gain-of-fn mutations
Tumor suppressorsTumor suppressors – genes which function to block– genes which function to block
tumor development by negatively regulating cellulartumor development by negatively regulating cellular
growth-growth-usu need loss of both copiesusu need loss of both copies
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
11. OncogenesOncogenes
in altered (mutated) form, gene expression leads toin altered (mutated) form, gene expression leads to
abnormal stimulation of cell division and proliferationabnormal stimulation of cell division and proliferation
have a dominant effect at the cellular level – a singlehave a dominant effect at the cellular level – a single
mutant allele is enough to change cellular phenotypemutant allele is enough to change cellular phenotype
from normal to malignant (gain of function)from normal to malignant (gain of function)
Mutations: gene, regulatory region, copy #Mutations: gene, regulatory region, copy #
normalnormal mutantmutant
12. OncogenesOncogenes
in its normal form, thein its normal form, the
gene is called agene is called a
proto-oncogeneproto-oncogene
Most proto-oncogenesMost proto-oncogenes
are components ofare components of
signal transductionsignal transduction
pathways:pathways:
translate extracellulartranslate extracellular
signals into changes insignals into changes in
gene expressiongene expression
Increase blood supplyIncrease blood supply
to the tumor or inhibitto the tumor or inhibit
apoptosisapoptosis
13. RET, METRET, MET
Receptor 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 kinasechange 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 to
be constitutively activebe constitutively active
RET mut-multiple endocrineRET mut-multiple endocrine
neoplasianeoplasia
MET mut-hereditary papillaryMET mut-hereditary papillary
renal carcinomarenal carcinoma
Ras, AblRas, Abl
MycMyc
14. RAS family of proto-oncogenesRAS family of proto-oncogenes
One of the first activated oncogenes discovered by theOne of the first activated oncogenes discovered by the
DNA transformation assayDNA 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 inhibitServes as an “on/off” switch to activate or inhibit
downstream molecules when bound to GTPdownstream molecules when bound to GTP
The protein’s effect is ended by self-directed cleavageThe protein’s effect is ended by self-directed cleavage
of GTPof GTP
15. 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 receptors toRas relays signals from the cell surface receptors to
the nucleus, functioning as athe 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
16. RAS mutation in humanRAS 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
17. RAS oncogene activation byRAS oncogene activation by
nucleotide substitutionnucleotide substitution
Conversion to oncogene usually due to a pointConversion 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 inthe ras protein is able to signal continuously, even in
absenceabsence of GTPof GTP
the ras protein isthe ras protein is unable to hydrolyze GTPunable to hydrolyze GTP toto
turn “off” the signalturn “off” the signal
Leads to the continuous activation of multipleLeads to the continuous activation of multiple
downstream signaling pathways inducing celldownstream signaling pathways inducing cell
proliferationproliferation
Mutations in the 3 RAS genes are found in 10-15% ofMutations in the 3 RAS genes are found in 10-15% of
all human cancersall human cancers
18. Oncogenes are also activatedOncogenes are also activated
by chromosome translocationsby chromosome translocations
Breakpoint can occur withinBreakpoint can occur within
introns of two genes: chimericintrons of two genes: chimeric
protein with novel properties –protein with novel properties –
Chronic MyelogenousChronic Myelogenous
Leukemia-Leukemia-UncontrolledUncontrolled
proliferation of white bloodproliferation of white blood
cellscells
Arises in a bone marrow stemArises in a bone marrow stem
cell that is a precursor to thecell that is a precursor to the
granulocytes andgranulocytes and
megakaryocytesmegakaryocytes
These cells contain a chr 9;22These cells contain a chr 9;22
translocation – “Philadelphiatranslocation – “Philadelphia
Chromosome”Chromosome”
Protooncogene ABL, a tyrosine
kinase, is moved from its normal
position on 9 to 22.
Result: increased activity
19. Chronic MyelogenousChronic Myelogenous
Leukemia (CML)Leukemia (CML) Proto-oncogene ABLProto-oncogene ABL
(tyrosine kinase) moves(tyrosine kinase) moves
from 9q to thefrom 9q to the
“breakpoint cluster region“breakpoint cluster region
(BCR) on 22q(BCR) on 22q
Chimeric protein hasChimeric protein has
increased tyrosine kinaseincreased tyrosine kinase
activity but alteredactivity but altered
structure and functionstructure and function
Requires secondaryRequires secondary
mutation to move intomutation to move into
crisis phasecrisis phase
Effective drug therapyEffective drug therapy
developed to target noveldeveloped to target novel
proteinprotein
20. Oncogenes are also activatedOncogenes are also activated
by chromosome translocationsby chromosome translocations
Breakpoint can occur withinBreakpoint can occur within
introns of two genes: chimericintrons of two genes: chimeric
protein with novel properties –protein with novel properties –
Chronic MyelogenousChronic Myelogenous
LeukemiaLeukemia
Alternately, translocation mayAlternately, translocation may
place proto-oncogeneplace proto-oncogene
downstream of a strongdownstream of a strong
constitutive promoter fromconstitutive promoter from
another gene – proto-another gene – proto-
oncogene is now expressed atoncogene is now expressed at
inappropriate time/place –inappropriate time/place –
Burkitt LymphomaBurkitt Lymphoma
21. Burkitt LymphomaBurkitt Lymphoma
B-cell tumorB-cell tumor
MYC proto-oncogeneMYC proto-oncogene
(transcription factor)(transcription factor)
translocated from 8q24translocated from 8q24
to 14q32, distal of the Igto 14q32, distal of the Ig
heavy chain locusheavy chain locus
Ig enhancers orIg enhancers or
activating sequences actactivating sequences act
on MYC – allowing foron MYC – allowing for
unregulated expressionunregulated expression
and uncontrolled celland uncontrolled cell
growthgrowth
22. 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
Notas do Editor
Cancer is abnormal cellular
Oncogenes in it’s normal form the gene is called proto-oncogene. Most proto-oncogene are components of signal transduction pathways. ,translate extracellular signals into changes in gene expression by increasing the blood supply to the tumor or inhibit apoptosis.
One of the the first activated oncogenes discovered by DNA Transformation process , encodes a small guanosine triphosphate binding protein 3 members of the family the H-RAS , K-RAS And N-RAS , Serves as on / off switch to activate or inhibit molecules when bound to GTP , the effect of protein effect is ended by self directed cleavage of GTP.
RAS associated with plasma membrane
RAS activation is done by another mechanism which is done via neclueotide substitution Note the conversion of oncogene to proto-oncogene is
Proto-Oncogenes are converted to oncogenes by means of : 1-Point mutation. 2- chromosome translocation ( breakpoint can occur within 2 introns of 2 genes producing chimeric protein with novel properties ) .
B lymphocytes are one of the fastest growing malignancies (B cell solid tumor ) Slid tumors are type of cancer intiated in the tissues The outer surfaces is dealt with radiotherapy whilst the vesrical is dealt with chemotherapy