Cancer Genetics Oct 8 Flashcards
What is the protoypical complex genetic disease?
cancer
What is the prevalence of cancer in the US?
1 in 4 in the US will die of cancer
1 in 2 peple will develop some form of cancer in their life time
(higher if you count preneoplastic tumors)
What percentage of cacners arise initially from environmental causes?
70%
REgardless of initiating factor, what do ALL cancers involve?
multiple genetic (and epigenetic) changes that occur insequence over time
this is why most cancers are diseases of old age
Where are sporadic mutations most worrisom?
if they’re in stem cells, the accidental mutation will be passed on to all daughter cells
What are the two basic ways a gene can be silenced in epigenetics?
it can accedentally be packaged into heterochromatin
It can accidentally be methylated
What are some of the barriers metastatic cells need to overcome in order to form a met?
They need to be able to escape from th eparent tissue, survival in circulation, be able to stop at a specific tissue, enter the tissue, survive in a foreign tissue, initiate growth in a foreign tissue and keep the growth up
most mesastatic cells are killed
What kind of cancer affects the intestine, breast and lungs?
carcinomas
What cancers affect the blood and immune system?
leukemias and lymphomas
What tumors affect the bone, muscle and connective tissue?
sarcomas - mesenchymal in origin
Most cancers are thought to arise from what?
Why should this make sense?
a stem cell tumor precursor cell
this makes sense because cancers are more common as mutations accumulate over time; therefore, they should be more common in the cells that live for a long time - stem cells
Describe the concept of tumor natural selection?
It’s the idea that neoplastic cells become malignant by acquiring features that permit them to evade cell constaints on growth and proliferation
these characteristics are acquired over time and are the result of new mutations or the selection for cells with phenotypically silent mutations
in this case, the genetic changes are not harmful - they confer selective advantage and therefore are selected for
What is the clonal evolution hypothesis?
In this hypothesis, EVERY TUMOR CELL is equally capable of initiating neoplastic growth
the genetic changes occur over time in individual cancer cells and if the change gives selective advantage, clonal expansion of that cell will occur, and it will outcompete other cells and expand
This model is underpinned by the new acquisition of genetic changes, but epigenetic and microenvironmental influences probably play a role
What is the cancer stem cell hypothesis?
This promoses that the growth and progression is cancer is driven by a small subpopulation of CSCs
So here the mutation or epigenetic change causes the normal stem cell to become a malignant cancer stem cell which can self renew just like normal stem cells
these then give rise to all the other cells of the tumor
What evidence is in favor of the cancer stem cell hypothesis?
- There is a small fraction of cells within a tumor that actually possess the ability to cause the formation of a new identical tumor
- tumors that enter remission often come back after time even though it appear to be cured
Why are cancer stem cells thought to be resistant to current chemotherapies?
Normal stem cells have innate multidrug resistance already, plus they’re resistant to apopotisis.
Thus, cancer stem cells are also likely to be resistant to drugs and apoptosis
If the cancer stem cell hypothesis is accurate, what should be the drug target?
Instead of targeting the bulk of the proliferating tumor cells (which is what we do now), we should target the CSCs
we an induce the differentation of the CSCs
We can block the signalling pathways for the CDCs
etc.
What are some indicators of familial cancers?
several close relatives with a common cancer
several close relatives with related cancers
two family members with the same rare cancer
unusually early age of onset
bilateral tumors in paired organs
synchronous or successive tumors
tumors in two different organ systems in one individual
How do inherited vs.sporadic cancers need in terms of the # of “hits” required to initiate a neoplasm?
An inherited cancer typically only requires one more hit - either mutation or epigenetic. This is because all the cells are already heterozygous and therefore just need to lose that last wild type allele.
Sporadic cancers require two hits
Wat are the three classifications of cancer genes by FUNCTIONAL alteration?
gain of function (oncogenes)
loss of function (tumor suppressor genes)
Crhomosomal translocations (cause misexpression of genes or chimeric genes with novel properties)
In cancer genetics, what is a dominant gene and what is a recessive gene?
A dominant gene is one that only requires one mutation - these are the oncogenes OR they can be the tumor suppressor genes in people who have an inherited familial cancer syndrome
A recessive gene is one that requires both alleles to be knocked out - these are the tumor suppressors
What are proto-oncogenes typically>
growth factors
receptor tyrosine kinases
transcription factors
What are the 5 ways in which a proto-oncogene can be converted to an oncogene?
1 .deletion or point mutation in the coding sequence which results in hyperactive protein made in normal amounts
- Regulatory mutation - so normal protein is greatly overproduced
- Gene amplification - too much normal protein made
- Chromosome rearrangement which places the gene downstream of an active promoter causing normal protein to be overproduced
- Chromosome rearrangement causing the fusion of two chromosomes leading to the production of an overative fusion protein
In order for a mutation in an oncogene to result in cancer, there must also be a mutation in a ____.
tumor suppressor gene
otherwise it would just turn the bad cell off in sensscence.
WHat is Knudson’s Two-Hit Hypothesis?
Almost all tumor suppressor genes at recessivly at the cellular level, so all the function must be lost to cause cancer
cancer arises in cells that lose function in one allele and then later lose the function of the second allele
Why are inherited tumor suppressor mutations considered dominant at the level of the organism, but recessive at the level of the cell?
They’s autosomal dominant for the organism because the inherited germline utation is invariably followed by the loss of the wildtype allele in a subset of the cells
THey are considered recessive at the level of the cell because you need to lose function in both alleles of the tumor suppressor gene in order to get cancer
What is loss of heterosygosity?
This is when you lose the function in the second allele, resultin in cancer
What are the possible ways to lose heterozygosity?
- nondisjunction causes chromosome loss
- chromosome loss, then chromosome duplication (of the bad one)
- Mitotic recombination where the bad allele gets recombed onto the chromosome that used to have the good allele
- Gene conversion
- Deletion of the good allele
- A point mutation altering the good allele
- epigenetic silencing
What is the difference between microinstability and chromosomal instability?
Microinstability arises from defects in mismatch repair or nuclear excision repair
chromosomal instability are the bigger problems like translocations - they can arise downstram of defects in DNA damage checkpoints, chromatin condensation, separation or mitosis
Colon cancer ariving from a mustion of APC will display microinstability or chrmosome instability?
chromosome instability - you get many gross chromosome abnormalities like aneuploidies and translocations
Will a cancer with microinstability have an obviously abnormal karyotype?
No - MIN arises from DNA repair defects, so they’re harder to see on the karyotype level.
In what kinds of cancer are translocations common?
hematopoietic cancers mostly, but not found in eithelial cancers too
How can you detect a microinstable cancer?
Do PCR amplification of select microsatellite regions in the genome. The mroe bands you see, the more microinstability
this is because cells that can’t repair expansions of DNA repeat regions lik CACACACA will have extra bands
What is APC’s normal role in the cell?
It regulates cellular levels of the trx factor beta-catenin
it degrades beta catenin so it can’t get into the nucleus
if it isn’t degraded, the beta catenin will translocate to the nuclues and promote the expresion of genes required for proliferation
This is why APC is considered a tumor suppressor gene
Colorectal cancer develops over time and requires at least 6-10 genetic hits.
the order of these hits is critical.
Why does APC have to be lost first in APC-dependent cacners?
APC is the “gatekepper” of the GI tract and will suppress growth even if other mutations occur first
What happens in patients who have FAP?
they get thousands of colon adenomas in their teens, need to have their colons removed, and then die early from other GI cancers
How does new genetic classification of diffuse large B-cell lymphomas imprive treatment?
It has been found thatt here are actually two distinct cancers that were lumped together in DLBCL
One of them responds to treatment (those with germinal center DLBCL) and the other doesn’t (the activated B-cel-like DLBCL).
This was determined using microarray
Now there are 6 genes in a set that have predictive value for which type of DLBCL a patient has
based on this, new targeted therapies have been developed - like monoclonal antibodies - which will work for the activated B-cell-like version of the disease
