Cancer Genetics Oct 8

Question 1

What is the protoypical complex genetic disease?

Answer 1

cancer

Question 2

What is the prevalence of cancer in the US?

Answer 2

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)

Question 3

What percentage of cacners arise initially from environmental causes?

Answer 3

70%

Question 4

REgardless of initiating factor, what do ALL cancers involve?

Answer 4

multiple genetic (and epigenetic) changes that occur insequence over time

this is why most cancers are diseases of old age

Question 5

Where are sporadic mutations most worrisom?

Answer 5

if they’re in stem cells, the accidental mutation will be passed on to all daughter cells

Question 6

What are the two basic ways a gene can be silenced in epigenetics?

Answer 6

it can accedentally be packaged into heterochromatin

It can accidentally be methylated

Question 7

What are some of the barriers metastatic cells need to overcome in order to form a met?

Answer 7

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

Question 8

What kind of cancer affects the intestine, breast and lungs?

Answer 8

carcinomas

Question 9

What cancers affect the blood and immune system?

Answer 9

leukemias and lymphomas

Question 10

What tumors affect the bone, muscle and connective tissue?

Answer 10

sarcomas - mesenchymal in origin

Question 11

Most cancers are thought to arise from what?

Why should this make sense?

Answer 11

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

Question 12

Describe the concept of tumor natural selection?

Answer 12

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

Question 13

What is the clonal evolution hypothesis?

Answer 13

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

Question 14

What is the cancer stem cell hypothesis?

Answer 14

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

Question 15

What evidence is in favor of the cancer stem cell hypothesis?

Answer 15

1. There is a small fraction of cells within a tumor that actually possess the ability to cause the formation of a new identical tumor
2. tumors that enter remission often come back after time even though it appear to be cured

Question 16

Why are cancer stem cells thought to be resistant to current chemotherapies?

Answer 16

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

Question 17

If the cancer stem cell hypothesis is accurate, what should be the drug target?

Answer 17

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.

Question 18

What are some indicators of familial cancers?

Answer 18

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

Question 19

How do inherited vs.sporadic cancers need in terms of the # of “hits” required to initiate a neoplasm?

Answer 19

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

Question 20

Wat are the three classifications of cancer genes by FUNCTIONAL alteration?

Answer 20

gain of function (oncogenes)

loss of function (tumor suppressor genes)

Crhomosomal translocations (cause misexpression of genes or chimeric genes with novel properties)

Question 21

In cancer genetics, what is a dominant gene and what is a recessive gene?

Answer 21

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

Question 22

What are proto-oncogenes typically>

Answer 22

growth factors

receptor tyrosine kinases

transcription factors

Question 23

What are the 5 ways in which a proto-oncogene can be converted to an oncogene?

Answer 23

1 .deletion or point mutation in the coding sequence which results in hyperactive protein made in normal amounts

2. Regulatory mutation - so normal protein is greatly overproduced
3. Gene amplification - too much normal protein made
4. Chromosome rearrangement which places the gene downstream of an active promoter causing normal protein to be overproduced
5. Chromosome rearrangement causing the fusion of two chromosomes leading to the production of an overative fusion protein

Question 24

In order for a mutation in an oncogene to result in cancer, there must also be a mutation in a ____.

Answer 24

tumor suppressor gene

otherwise it would just turn the bad cell off in sensscence.

Question 25

WHat is Knudson’s Two-Hit Hypothesis?

Answer 25

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

Question 26

Why are inherited tumor suppressor mutations considered dominant at the level of the organism, but recessive at the level of the cell?

Answer 26

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

Question 27

What is loss of heterosygosity?

Answer 27

This is when you lose the function in the second allele, resultin in cancer

Question 28

What are the possible ways to lose heterozygosity?

Answer 28

1. nondisjunction causes chromosome loss
2. chromosome loss, then chromosome duplication (of the bad one)
3. Mitotic recombination where the bad allele gets recombed onto the chromosome that used to have the good allele
4. Gene conversion
5. Deletion of the good allele
6. A point mutation altering the good allele
7. epigenetic silencing

Question 29

What is the difference between microinstability and chromosomal instability?

Answer 29

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

Question 30

Colon cancer ariving from a mustion of APC will display microinstability or chrmosome instability?

Answer 30

chromosome instability - you get many gross chromosome abnormalities like aneuploidies and translocations

Question 31

Will a cancer with microinstability have an obviously abnormal karyotype?

Answer 31

No - MIN arises from DNA repair defects, so they’re harder to see on the karyotype level.

Question 32

In what kinds of cancer are translocations common?

Answer 32

hematopoietic cancers mostly, but not found in eithelial cancers too

Question 33

How can you detect a microinstable cancer?

Answer 33

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

Question 34

What is APC’s normal role in the cell?

Answer 34

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

Question 35

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?

Answer 35

APC is the “gatekepper” of the GI tract and will suppress growth even if other mutations occur first

Question 36

What happens in patients who have FAP?

Answer 36

they get thousands of colon adenomas in their teens, need to have their colons removed, and then die early from other GI cancers

Question 37

How does new genetic classification of diffuse large B-cell lymphomas imprive treatment?

Answer 37

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