Genetics- Cancer Flashcards
cancer
a genetic disease caused by abnormal expression of normal gene products or by gene products expressed from mutant genes. Some mutated genes may be inherited but most are mutated by environmental factors
what causes cancer?
caused by a series of genetic changes
Cancer step 1
most cancers originate in a single cell- a cancerous growth can be considered to be clonal
cancer step 2
at the cellular and genetic levels, cancer is usually a multistep process that begins with a precancerous genetic change ( a benign growth) like a missense mutation affects a protein function. Then, as cell division increases, additional genetic changes occur that cause progression to malignant tumor growth
cancer step 3
once a cellular growth has become malignant, the cells are metastatic, they are also invasive
invasive
can invade healthy tissue cells
benign vs malignant
benign is noncancerous and malignant is cancerous
why don’t all cells become cancer cells?
growth factors often stimulate cells in Go to re-eneter the cell cycle by activating cell signaling pathways –there are three checkpoints in cell cycle
what are the go signals for the cell cycle?
cyclins and Cdks & they have a cyclic pattern
what stops cells from continually dividing?
crossroads at the checkpoint in G1 @ this checkpoint there is a crossroad of proceeding to S phase or withdraw and go to G0
What are the stop signals in the cell cycle?
checkpoints– there are three
what are the three checkpoints ?
G1/S checkpoint: (most important) cell monitors size and DNA integrity
G2/M checkpoint: cell monitors DNA synthesis and damage
M checkpoint: cell monitors spindle formation and attachment to kinetochores (prevents aneuploidy)
Cell cycle control system is a combination …
of positive factors (GO signals) that push cells through the cell cycle and negative regulators (STOP signals, checkpoints)
Cancer is uncontrolled cell division
1) activate positive regulators = oncogenes
2) inhibit checkpoint regulators = tumor suppressors
How to turn a proto-oncogene into an oncogene
Many proto-oncogenes function in growth factor signaling pathways and oncogenes are their hyper-active versions. Proto-oncogenes are turned into oncogenes by activating them with:
a) missense mutation in the coding sequence
b) gene amplification
c) chromosomal rearrangement that increases expression
d) chromosomal rearrangement that forms a hyperactive fusion protein
e) viral integration
Function of changing proto-oncogene into an oncogene
gain of function so only need one allele to be activated into an oncogene to make cell cancerous
Loss of herterozygosity
lose the other functional gene so no functional tumor suppressor proteins – inherit one mutant & environment mutates the other –tends to be inherited in a dominant fashion and can result from a point mutation in the normal allele or occurs if chromosome carrying good copy is lost
two-hit model
ways to lose the only good copy of a tumor suppressor gene
two-hit model ways
a) mitotic non-disjunction (=aneploidy) causes the chromosome with the wild type gene to be lose
b) duplication of chromosome with mutated gene
c) mitotic recombination can lead to two mutant genes
d) gene conversion where WT becomes mutant
e) deletion of the normal gene
f) point mutation in normal gene
Another two hit model
any genetic or epigenetic mutations that inhibit expression of the wild type tumor suppressor gene may lead to cancer
p53
is a tumor suppressor gene
considered the “guardian of the genome” kills any cells with DNA damage, telomere shortening, hypoxia, and hyper proliferative signals
dominant mutation
gain of function, where single mutation event in proto-oncogene creates oncogene by activating mutation enables oncogene to stimulate cell survival and proliferation
-only need one copy
recessive mutation
loss of function, BUT inherited in a dominant fashion, where the two mutation event inactivates tumor suppressor gene so the two inactivating mutations functionally eliminate the tumor suppressor gene, stimulating cell survival and proliferation
-need both copies inactivated
cancer is usually…
a result of multiple genetic changes
metastasis
ability to leave surrounding cells»_space; invade blood vessels» invade a different tissue»_space;grow and proliferate there (=secondary/tertiary tumors)
angiogenesis
cancer cells secrete factors that stimulate the growth of blood vessels (to feed growing cancer cells)
COSMIC
catalog of somatic mutations in cancer
Hallmarks of cancer
a) sustained proliferation of cells
b) evasion of growth suppressors
c) avoid destruction by immune system
d) immortality of cells
e) cause tumor-promoting inflammation
f) activate metastasis
g) angiogenesis
h) genome instability
i) resist cell death
j) deregulate cellular energetics
Treat hallmark of sustained proliferation of cells
inhibit mitosis, block growth hormone receptors & inhibit kinases
Treat hallmark of evasion of growth suppressors
inhibit cell-cycle promoting proteins
Treat hallmark of avoid destruction by immune system
activate immune system (immunoncology)
Treat hallmark of immortality of cells
inhibit telomerase
Treat hallmark of cause tumor-promoting inflammation
some anti-inflammatories
Treat hallmark of activate metastasis
inhibit invasion of other tissues
Treat hallmark of angiogenesis
inhibit angiogenesis
Treat hallmark of genome instability
PARP inhibitors (recently successful) easier to make drugs that inhibit rather than activate
Treat hallmark of resist cell death
pro-apoptotic drugs
Treat hallmark of deregulate cellular energetics
aerobic glycolysis inhibitors
cancer is a disease characterized by …
characterized by uncontrolled cell division
•It is a genetic disease at the cellular level
•More than 100 kinds of human cancers are known
–These are classified according to the type of cell that has become cancerous
not a single disease but a collection of diseases & not really inherited
What makes a cell cancerous?
- Growth self-sufficiency
- Protection from apoptosis (death)
- Angiogenic Capacity (growing blood vessels to feed itself)
- Limitless division (biggest hallmark)
- Invasion and metastasis
normal control of cell division
• Cell cycle is HIGHLY REGULATED • Many CHECKPOINTS to ensure the cell and its DNA are normal before continuing through division • Mutations to checkpoint genes are often involved in cancer
G2 checkpoint
check for cell size & DNA replication
Spindle Assemble Checkpoint
check for chromosome attachment to spindle
G1 checkpoint
check for cell size, nutrients, growth factors, DNA damage
Cancers arise when critical genes are mutated causing.. .
unregulated proliferation of cells. These rapidly dividing cells pile up on top of each other to form a tumor
once malignant
the cells are invasive
cells have a great many defects by the time they …
become cancerous
Cancer cells are clones of the initial cell gone bad
- a cell is predisposed to proliferate at an abnormally high rate
- a second mutation causes the cell to divide rapidly
- after a third mutation, the cell undergoes structural changes
- a fourth mutation causes the cell to divide uncontrollably and invade other tissues
cancer has a clonal origin
Cancer results from cells in a single lineage
accumulating enough mutations to outgrow
normal cells.
Most cancers originate in a single cell
cancer is a result of multiple mutations
• A single mutation usually does not result in cancer
• Usually several genes that regulate cell growth are
mutated before a cancerous state results.
tumor
a clonal group of cells that arose from a prerecessor
inherited predisposition
only 5-10% of cancers
BRCA1 or BRCA2 mutations lead to breast cancer
spontaneous or induced mutation
90-95% of cancers
about 80% are related to exposure to mutagens
about 20% are spontaneous & not a response to something external
Model
a small # of initial mutations»_space;increased mutation frequency ‘genetic instability’»_space; more mutations»_space;cancer
predisposition for developing cancer
often the result of being heterozygous for one of these genes
types of cancer-causing genes
1) tumor suppressor
2) proto-oncogene
3) repair gene
tumor suprresor
normal function: suppresses cell division when mutated fails to suppress division ( loss of function mutation)
–growth factor inhibitors (type of protein)
proto-oncogene
normal function is to promote division but when mutated promotes division at abnormal levels or in cells that shouldn’t divide (gain of function mutation)
–growth factors (types of protein)
repair genes
normal function is to repair DNA mutations but when mutated fail to repair DNA mutations (loss of function)
–enzymes (type of protein)
work with the other two to cause cancer
when p53 is on
tumor suppressor gene
inhibits cell cycle/excessive proliferation & must lose BOTH copies to lose inhibition
–loss of function
–recessive
the two hit hypothesis
two mutation in the same tumor suppressor gene are required to initiate cancer
- sporadic
- familial
sporadic cases
the cancer begins with two somatic mutations (in a gene like retinoblastoma, or APC)
familial cases
the cancer begins with only a single somatic mutation, because the individual has inherited a mutation in a cancer causing gene (predisposes you more)
consequence of two hit hypothesis
if they get another mutation in the same gene, that cell now has a chance to begin dividing out of control, and accumulating more mutations. Eventually this can lead to cancer
tumors suppressor gene can appear to be dominant at the organismal level BUT
at the cellular level be recessive
proto-oncogenes act dominantly at the cellular level
Genes that promote cell division when mutated, become
“oncogenes”
• Cancerous situations:
• Expression of oncogene at the wrong time or in the wrong cell type
• Mutation (dominant) causes
protein to be always “ON”= GAIN OF FUNCTION MUTATION!
tranformation
the process of converting a normal cell into a malignant (cancerous) cell
Oncogenes were found because of their
ability to “transform” cells
Rous Sarcoma virus, sarcoma in chickens needs a vial oncogene, “ v-src ” (viral sarcoma) Nobel 1966 for Rous (virus discovery) Bishop and Varmus found a cellular version called c–src (for cellular src) Nobel 1989 c-src is incorporated into viral genome during infection and becomes v-src
the most famous oncogene
activated RAS
oncogenic RAS is active even if no EGF present
when Ras is active we get cell division & mutation prevents RAS from being regulated always active
Chromosomal rearrangements can result in cancer
A chromosomal translocation turns abl into an oncogene
-normal order of gene is disrupted
The chromosomal rearrangement changes when and where the abl gene is expressed: abl now active all the time, in white blood cells
strategies for battling cancer
- surgical intervention (confined tumor)
- radiotherapy (targeted radiation)
- chemotherapy (most used-only one generally useful for invaded or metastatic cancers)
- immunotherapy (new and shows a lot of promise)
immunotherapy
generating T cells that specifically target cancer cell–will not work in immune-compromised patients
why genetics makes treatment so hard
Hallmarks of cancer: predictable phenotypes in the progression of cancer
- clonal origin so mutation A occurs randomly in a single cell & expansion creates local population of A’ cells
- Polyclonal tumor
polyclonal tumor
layers of mutation/expansion
treating a tumor like an infection
Successful treatment requires separation of tumor from host cells Less similar cells are easier to target More “druggable targets” - Specific to infection - Consistent within infection
Bacterial infection
Infecting cells are very different from host Side-effects of antibiotics few, except for misuse and development of resistance
Fungal infection
Both host and infection are
eukaryotic cells
Side-effects of antifungals
More common, varying
cancer infection
Host and infection are same species and same individual Side-effects of anticancer therapy Extremely common and severe!
Chemotherapies DNA as a target
Most cancer cells use their DNA more than most normal cells
Fast division = high levels of flux
through DNA pathway
Doxorubicin drug
fragment the DNA
Cisplatin drug
glue the strands together
Methotrexate drug
attack the supply chain
Taxol drug
prevent separation of replicated DNA
traditional chemotherapy
targets production and common manipulations of DNA
Side effects of Chemotherapy on any replenishing (stem) cell
Bone marrow, skin, hair, intestine, germ line All these cells look like cancer cells in terms of DNA use The drugs are doing EXACTLY what they are supposed to do! DNA use is inadequate for specific targeting to cancer
Side effects of Chemotherapy on some other cell type
Drug-specific interactions cause toxicity
in some other tissue
Often unpredictable for new drugs
Unique for each drug or class of drugs
Cardiac toxicity, deafness, liver toxicity,
neuropathy
Chemotherapy success
moderately successful strategy
different tissues, different results in overall survival and in stage-specific survival
we are great at breast cancer but not good in pancreatic
why difference in success?
accessibility to cancerous cells
localized
regional invasion
Rational drug design
target something that is unique about cancer cell
use genetics of the tumor to direct the treatment
-Targeted therapy
-Prodrug therapy
Leukemia (CML)
Gleevec treats it and has a high survival rate
other possible cancer treatment approaches
• Block receptors for growth factors that make cells divide
–angiogenesis
–Her-2/neu breast cancer (cells have extra growth factor receptors):
drug Herceptin
• Engineer viruses that can only replicate or infect cancer cells;
when the viruses replicate they will kill the cancer cells
molecular profiling to classify tumors
identifying the genes involved in making a cancerous cell. • Use microarrays to identify up regulation or down-regulation • Look for correlations between genes that are mis-regulated • Sequencing cancer cells!
cancer genome challenge
individual scientists from all over sequencing as many cancers as possible (profiling)
