Cancer Genetics 2 Flashcards
Karyotypes of most cancers?
- typically abnormal karyotypes
- altered chrom. number (aneuploidy)
- chrom translocations & deletions
Two mechanisms that cause cancer?
1) Non-Genotoxic Mechanism (Non-Mutagenic Carcinogens)
2) Genotoxic Mechanism
Exogenous Mutagens (Pro-mutagens and Mutagens):
Non-Genotoxic Mechanism
Non-Mutagenic Carcinogens
- carcinogens that don’t alter DNA
- most are tumor promoters
- molecules that lead to inflammation/tissue damage, this can increase proliferation
- benefits neighboring mutated cells
Genotoxic Mechanism?
Exogenous vs Endogenous Mutagens
- Pro-mutagens & Mutagens that alter DNA
exogenous: tobacco smoke; UV light
endogenous: failure in normal cell processes; ex DNA repair, replication, metabolism, maintenance
What genes contribute to cancer?
- 291 genes
- most common are chromosomal translations creating chimeric genes
What are the two types of cancer?
1) tumor suppressor genes
2) oncogenes
tumor suppressor genes
- recessive; require two mutated genes to develop cancer
- LOSS OF FUNCTIOn
- these genes usually active and repress cell cycle; when deactivated loose breaks of cell cycle, proliferate uncontrollable
oncogenes
- dominant; gain of function
- 1 mutant allele can lead to cancer
- these genes start as healthy functioning protoncogenes; when unhealthy state changed to oncogenes
- over activation/ hyperactivation
main difference between tumor suppressor genes and oncogenes?
-cancer from oncogenes due to hyper activation; cancer from tumor suppressor genes due to inactivation (turning off)
tumor supressor genes (TSG) & inheritence?
- follow pattern of autosomal dominant inheritence
- if have affected parent; have 50% chance of offspring receiving one mutated gene that predisposes them to cancer
- still require a 2nd somatic mutation to acquire cancer; due to TSG being recessive
why tumor suppressor genes considered single gene Mendelian disorders?
-because one mutant copy can be inherited, typically family members are also exposed to same env so ended up looking like strict inheritence
What are tumor suppressor genes typical role in healthy cells?
1) TSG act as brakes to stop cell proliferation
2) restrain inappropriate cell growth & division
3) stimulate cell death
4) involved inDNArepair (prevents accumulation of mutations)
What happens to tumor suppressor genes in cancer?
- tumor suppressor genes are shut off
Characteristics of autosomal dominant inheritence?
1) Multiple generations affected
2) Males & females affected equally
3) Male to male transmission
4) offspring affected parent has 50°/o chance being affected,50% being unaffected
Retinoblastoma
- malignant tumor of retina that occurs in children
- due to malfunctioning in tumor suppressor gene Rb
- can see in retina due to light refraction from camera
Two forms of retinoblastoma?
1) hereditary (40%)
2) non hereditary (sporadic) (60%)
hereditary retinoblastoma?
- autosomal dominant, 90% penetrance
- bilateral; 3 tumors per person
- diagnosed ~15 months
- already have 1 mutated rb gene, takes less time to get random somatic mutation & damage healthy rb gene
non-hereditary retinoblastoma
- no familial association
- unilateral; 1 tumor
- diagnosed ~30 months
- takes longer to develop 2 spontaneous somatic mutations so diagnosed later
how many mutations required for rb tumor production? frequency of these mutations?
- is recessive at cell level, requires 2 mutated genes
- somatic mutations occur at low spontaneous frequency
what chromosome is rb gene on?
- chromosome 13
Hereditary vs sporadic retinoblastoma on pedigree?
- hereditary (mendelian) see in most generations, autosomal dominant transmission
- sporadic skips generations then randomly appears
what is rb role in the cell?
- gatekeeper from G1–>S
- unphosphorylated/inactive, binds E2F1 trxn factor & prevents cell cycle progression
- phosphorylated/active, unbinds E2F1 trxn factor & cell cycle progresses
- tumor suppressor gene
What phosphorylates rb?
- cyclin D/ CDK4 (mitogen sensor)
- cyclin E/CDK2
What happens when lack 2 copies of Rb on chromosome 13?
-no cell cycle arrest; unregulated growth
cancer hallmarks retinoblastoma has?
1) self-sufficiency in growth signals
2) insensitivity to antigrowth signals
since rb is absent, doesn’t respond/require either
Why is retinoblastoma just in the eyes?
- in development cone precursors express cancer related proteins that enable proliferation/suppress apoptosis
- if loose rb, cone cells now loose the breaks and easy to develop retinoblastoma
Familial Adenomatous Polyposis (FAP)
- autosomal dominant genetic syndrome
- develop thousands of benign polyps in colon
- polyps progress to malignant adenocarcinomas
- is affected by APC gene
WNT signaling pathway
-have 19 WNT signals/ligands that bind to WNT transmembrane receptors extracellulary
-in colon controls proliferation
since colon is subject to high cell turnover & proliferation
B-Catenin
- bifunctional protein
1) cytoskeleton function: anchors E-cadherin to cell membrane so it can act with E-cadherin of neighbor cell to form tight junctions
2) Trxn function: normally destroyed & no trxn occurs; when active allows trxn to occur
No WNT ligand/signal and B-catenin?
-when no ligand present, the destruction complex (including APC) bind and destroy B-catenin and no cell proliferation occur
When have WNT ligand/signal and B-catenin?
-when ligand present, destruction complex is not functional & B-catenin is able to go into nucleus, bind TCF, and activate trxn
APC protein and WNT pathway?
-APC is required for the destruction complex, if is mutated/destroyed then destruction complex cannot function and B-catenin is unregulated and able to continuously activate cell proliferation
What does B-catenin associate with in the nucleus and what is its role?
- associates with TCF which is a repressor trxn factor
- w/o B-catenin prevents trxn, once B-catenin translocates into nucleus and binds, activates trxn
What are two ways that B-catenin can activate proliferation?
1) APC destroyed so no destruction complex, B-catenin always active & free to imitate trxn
2) WNT signal constantly released/ bound causing permanent destruction of APC complex
What type of gene is APC?
- a tumor suppressor gene, when have it; blocks trxn
- when loose this gene we cause cell proliferation
Loss of APC has what cancer hallmarks?
1) self sufficiency in growth signals
2) insensitive to anti growth signals
since you loose APC it no longer responds to signals!
Lynch Syndrome (LS) or Hereditary nonpolyposis colon cancer (HNPCC)?
- have a normal looking karyotype because is due to mutations in DNA mismatch repair not genetic material fuck ups
- autosomal dominant, has high risk of colorectal & endometrium cancer
- early polyps but don’t increase numbers like in FAP
- high frequency of inheritence
Mechanism of LS/HNPCC?
- mutation in MLH1 endonuclease, can ID DNA damage but can’t open DNA for exonuclease to come in and fix mismatch
- accumulate mismatches, as cell replicates mismatches will propagate and turns into point mutation
LS/HNPCC cancer hallmarks?
1) loss of genomic stability
Li-Fraumeni (cancer family)
- syndrome, caused by germline transmission of mutations in p53
- autosomal dominant familial cancer
- affected family members get diverse types of cancers
- Cancer occurs at early age, survivors of 1st cancer develop a second independent tumor of a different type
p53?
- mutations in this gene cause Li-Fraumeni (ATG–> AGC)
- an important regulator of cell proliferation and apoptosis
- Loss of p53 function is advantageous to some cancer cells
What is the most common mutation that causes malfunctioning in p53?
- most p53 mutations are single AA substitutions
- almost always occur in a few well-defined locations in the p53 gene
- some mutations are DOMINANT NEGATIVES
Dominant negative mutations
-when have an altered gene product that acts antagonistically to the wild-type allele
p53 and dominant negative mutations?
-if p53 tetramer has 1 subunit w/ dominant negative mutation, the tetramer is not functional
p53 in healthy individual?
- damage is detected, p53 activated, binds dan then:
1) can modify cell cycle
2) can repair DNA damage
3) can signal for apoptosis
p53 mechanism when mutated?
-DNA damage occurs, p53 isn’t activated, no apoptosis, accumulation of mutant cells, damage and mutations begin to accumulate
loss of p53 has what cancer hallmarks?
1) insensitivity to antigrowth signals
2) genomic instability
3) evasion of apoptosis
Oncogenes & mutations that cause them?
- operate as dominant gain of function mutations
- require only one mutated gene to be cancerous
- mostly somatic mutations (not germline/inherited)
- these mutations cause hyper activation of the gene or gene products
3 ways you can go from proto-oncogenes to oncogenes?
1) Deletion or point mutation in coding sequence
2) Gene amplification
3) Chromosome rearrangment
Deletion or point mutation in coding sequence & oncogenes?
- have hyperactive protein made in normal amounts
- ex: RAS
- can’t turn off the protein (RAS) so have constant cell proliferation
Gene amplification & oncogenes?
- have a normal protein, but is greatly overproduced
- usually due to excessive trxn making extra mRNAs that turn into extra proteins
Chromosome rearrangment & oncogenes? (2 ways)
1) nearby regulatory DNA sequence causes normal protein to be overproduced
2) proto-oncogene DNA is fused to actively trxned gene which causes fusion protein to be overproduced OR causes the fusion protein itself to be hyperactive
oncogenes and inheritence?
- until recently assumed all oncogenes were somatic; never inherited
- Paton Raus discovered retrovirus (RSV) that can be passed from human to human (hen to hen)
Paton Raus discovered what? How?
- the first oncogene
- isolated RSV (Rous Sarcoma Virus ) from hen tumor, put in other hen and found it caused tumor to develop
- the hen cells infected w/ RSV virus were “transformed”
What does it mean when say cells are transformed?
-cells change from normal shape/configuration to changing their appearance and proliferated abnormally
How does RSV direct tumorigenesis?
- SRC gene present in virus also present in hen/human cells
- w/o virus, it is a proto-oncogene in humans. Has beneficial role
- w/ virus changed into oncogene (hyperactive gene) which leads to cancer
Who discovered how RSV direct tumorigenesis?
Bishop & Varmus
How other oncogenes identified?
- done by Bob Weinberg
- DNA isolated from bladder cancer, introduced into immortalized but not transformed mouse cells
- causes occacional colonies of transformed (rapid growth) cells
- Among clones he found RAS
immortalized cells mean?
- cells had lost their clock of how many times they can divide before dying
- but ARE NOT transformed/ not cancerous
RAS? in proto-oncogene form?
- example of an oncogene
- located near membrane; activated by growth factors that bind to receptor & modify affinity of RAS from GDP to GTP -once have GTP Ras is activated & can activate trxn factors like MAPk to enable progression of cell cycle
How RAS go from proto-oncogene to oncogene?
- single nucleotide substation (G–>T) changes glycine–> valine,
- caused change in affinity for GTP
- RAS can no longer hydrolyze GTP to GDP, RAS is constantly activated responding to growth factors
Consequences of RAS being activated indefinelty?
- means RAS can activate it’s downstream proteins at all times
- causes many trxn factors & modulators of several responses (including the cell cycle) to be engaged at all times
- alters many molecules explains why directly linked to so many cancer
Ras has what hallmarks of cancer?
- self-sufficiency in growth signals
- point mutations in RAS genes cause constitutive activation of signaling pathways normally regulated by growth factors
