Cancer Flashcards
what is our central concept of cancer
it is a disease caused by alteration of a cell’s genes
why do we say gene changes instead of just mutations
these may be any of the following
- Mutations, in the most general sense: any kind of alteration of DNA sequence
- Epigenetic change, such as aberrant DNA methylation or histone modification
- Tumour viruses bringing extra genes into the cell
How many critical gene changes are needed for adult cancer
> 10
what is metastasis
formation of new colonies of tumour in other parts of the body, by the of seeding cells into the circulation
what is the primary tumour
original tumour is called the primary tumour and a metastasis may be called a secondary.
what are malignant tumours
those capable of
metastasis.
A tumour doesn’t have to have formed any metastases to be
malignant: the actual formation of
metastases is very slow and inefficient
and may not actually have happened yet
what are benign tumours
Incapable of metastasis (unless subsequent mutation may turn the benign tumour into a malignant one).
where do the following cancers often metastasize to:
breast
colorectal
breast to lymph nodes and bone
colorectal to liver via HPV
why is metastasis important clinically and intellectually
most deaths from cancer are caused by metastases;
important intellectually because they are the key mechanisms of pathogenesis
and we don’t understand them.
what does a benign tumour look like down a microscope
confined to their original site in the body;
they have clearly defined boundaries, and can often be physically separated from surrounding tissue;
often surrounded by a capsule of connective tissue, which can be peeled away
what do malignant tumours look like down the microscope
ragged edges, infiltrating into
surrounding tissue, and growing there.
Malignant tumours often show other morphological differences, eg abnormalities of nuclear size and shape, and alterations or loss of differentiation;
but ‘invasion’ is the most important.
what is the classical idea of development of a colorectal tumour
Often a polyp/adenoma precedes the malignant tumour, and the polyp may progress through various degrees of abnormality. Polyps may well be preceded by less visible abnormalities.
True or false
Malignant tumours often develop via visible benign precursors
true but not all benign can become malignant
eg benign smooth muscle tumour of the uterus rarely if ever turns malignant; the rare invasive tumours in this tissue appear to develop via a different set of mutations.
can benign tumours kill
yes
for example meningiomas growing in the brain, or hormone-producing benign tumours of the pituitary or adrenal.
what are the broad rules for naming a benign tumour
eg
tissue name + - oma
e.g.
lipoma = benign fat tumour
Leiomyoma = benign smooth muscle tumour
Papilloma = wart
adenoma [of the colon] = benign glandular lump, including glandular polyp
nomenclature of malignant tumours from mesenchyme
[name of tissue] sarcomas
E.g.
osteosarcoma (malignant bone tumour),
leiomyosarcoma (malignant smooth muscle tumour)
nomenclature for malignant tumours of mesenchyme
[name of tissue] carcinoma
e.g. breast carcinoma, colorectal carcinoma
give some exceptions to the naming rules of cancer
malignant melanoma (‘melanoma’ is not used for benign moles, which are called
nevi (singular nevus))
Neuroblastoma, glioblastoma (malignant neural tumours)
how do you name cancers of the haemopoietic system
Leukaemias liquid haemopoietic neoplasms
lymphoma solid haemopoietic (usually lymphocytic) neoplasms
give examples of how cancer can interfere with normal function (4)
Pressure: enlarged prostate obstructing ureter, meningioma on brain
Erosion/destruction e.g. of bone -> fractures and pain
Epithelial ulceration: bleeding from colorectal tumours (picture) -> anaemia
Competition with normal: failure of normal bone marrow in leukaemia
what are some of the metabolic effects of cancer
general, systemic wasting – ‘cachexia’
specific – tumour specific products, e.g. peptide hormones ACTH, ADH secreted by small cell lung
cancer
what causes cachexia
Its mechanism, other
than competition for metabolic resources, is not known
how do you generally die from liver cancer
- Liver overwhelmed by metastatic colon cancer -> liver failure
how does leukaemia usually kill you
Failure of normal bone marrow -> infection through lack of neutrophils; or haemorrhage through lack
of platelets
how can pain from cancer kill you
Pain management -> analgesia -> respiratory depression
how common are benign tumours and malignant tumours of mesenchyme
Benign tumours:
very common in all tissues
e.g. Leiomyoma of uterus, lipoma, wart, mole …
Malignant tumours from mesenchyme:
generally rare but often rapidly lethal, e.g. osteosarcoma (malignant bone tumour)
how common are malignant cancers of epithelium
Common – the most important cancers
eg breast, colorectal, lung, prostate
which cancers have low incidence in the west but high elsewhere
Nasopharyngeal (in Chinese populations), Liver
how do cancers present
Tumour may be visible/palpable:
e.g. melanoma, breast carcinoma
but often indirect, through effect of tumour:
prostate: blockage of ureter
colorectal: obstruction of bowel, anaemia due to bleeding
how is colorectal cancer usually first noticed
patient is anaemic due to chronic bleeding of the ulcerated tumour, or because s/he is losing weight, or has altered bowel habit due to partial obstruction of the bowel
how is breast cancer usually spotted
unusual in that the tumour is often detected directly as a lump in the breast, but occasionally the first indication is bone pain or pathological fracture caused by metastatic tumour growing in bone.
what is the object, ideal, and draw backs of screening for cancer
Object: Find cancer earlier
Ideal: Find before malignant
But: have to be able to do something useful
what is the ideal screen for cancer
find benign precursors of cancer and remove them even before they turn malignant
eg cervical cancer where benign precursor lesions can be detected by the cervical smear test—cells from the cervix are sampled by brushing—and removed. The fall in cervical cancer in countries that screen strongly suggests that it is very successful
How is screening for colorectal cancer usually done
what is a draw back
how could this be improved
by detecting blood in stool collected at home—
reasonably convenient but
only able to detect tumours that have
already ulcerated.
Endoscopy for polyps would be
better, detecting the benign precursor, but is much more expensive and much more demanding on the patient.
How can breast cancer be detected by test
by X-ray, ‘mammography’, slightly earlier than it would be detected by palpation.
why is breast cancer screening controversial
expensive and demanding for patients, especially as many patients who do not have tumours are recalled for further investigation, and some cancers are discovered and treated unnecessarily
why do we not screen for prostate cancer
currently we could screen for malignant prostate cancers but screening is considered counterproductive, because the tumours are often so indolent that they may never cause a problem; and surgery has a very high morbidity—incontinence and/or impotence.
what are the stages of the cell cycle
G0+G1 (diploid state),
S (DNA synthesis),
G2 (tetraploid state, tidying up at the end of S phase and preparing for M),
M (mitosis).
How does Rb control the cell cycle
e by inhibiting the
initiation of DNA replication, i.e. holding the cycle at the G1/S checkpoint.
How is the cell cycle inhibition by Rb relieved
when CDK4-Cyclin D1 phosphorylates Rb1
What inhibits CDK4-cyclin D
p16 (aka CDKN2A) or p21 (aka CDKN1A)
what has to happen to Rb to promote cancer
how does this compare to CDK4-cyclin D
has to be inactivated, for example by deletion of all or part of the RB1 gene
overactivity mutations of CDK4 or CyclinD1 can keep Rb-1 phosphorylated.
which cyclin complex is often overactive in breast cancer
CCND1/CyclinD1 gene as a result of gene amplification
what has to happen p16/INK4A to cause cancer
inactivation (as p16 inhibits CDK4 cyclin D1)
define oncogene and tumour suppressor gene
Oncogene mutations are overactivity mutations - requires 1 mutation
Tumour Suppressor Gene mutations are loss of function mutations - requires 2 mutations
what is an intermediate case of oncogene vs tumour suppressor
some tumour suppressor gene
mutations, have a significant effect on the cell when only one copy of the gene is mutated, but losing both copies has a stronger effect. These are usually cases where the mutant protein complexes with the normal protein (eg p53)
It functions as a
tetramer, so mutating half the copies of the gene means that most tetramers are faulty
what is clonal expansion
A normal cell acquires a mutation/gene change that means that, over time, its progeny compete with neighbouring cells so that they take over more than their normal share of a tissue
why is there heterogeneity to a tumour
may contain not just the latest clone but also preceding clones and dead-end branches of the evolutionary tree
how did Jones et al demonstrate clonal expansion
They put a mutation and a
fluorescent marker into a few cells in mouse oesophageal epithelium in vivo; over a year the mutant cells’ progeny took over almost the entire epithelium.
what is the evidence for tumours being clones
all cells have the same gene changes, except for the most recent ones. Precursor clones, having some of the mutations seen in a tumour, can sometimes be detected in flanking tissue that is superficially normal.
How do we know that most cancers have specific defects that make them genetically unstable, and it’s not just that they are cycling so fast they mess up their DNA?
individual cases of cancer show different kinds of genetic instability
eg in colon cancers where there are at least two obviously different types of instability - sequence instability vs chromosome instability
How many cancers display sequence instability
15% - stable chromosomes but unstable sequences
poor function of what system leads to colorectal cancer 15% of the time
mismatch repair (leading to sequence instability)
Is sequence instability the most common cause of colorectal cancer
no
, most
cases have a lot of rearranged chromosomes, chromosomal instability or ‘CIN’,
while generally having a near-normal rate of point mutation
what kind of mutation leads to CIN
mutations in managing or repairing chromosomes
What are the different types of DNA repair for single strand breaks
NER
BER
MMR
What damage does MMR deal with
mismatched bases and also small loops that occur where polymerases slip while replicating repeats and add or delete a copy of the repeat, generating a tiny mismatched loop
What happens to mismatched loops when MMR machinery is defective
slippage loops persist, and a striking effect is
shrinkage or expansion of short repeats known as microsatellites
What technique are microsatellites used for
forensic DNA fingerprinting
Give 2 ‘symptoms’ of faulty MMR
microsatellite instability
higher point mutation rate
what usually causes the MMR failure in 15% of colon cancers
inactivation of MLH1 or MSH2, key components of mismatch repair
how does the mutation rate in colon cancers with dodgy MMR compare with the rate in a normal cell
roughly hundred-fold increased rate of small mutations including both single base changes (mismatches) and frameshifts caused by elongation or shortening of repeats such as AAAAAAA.
Both TGFbetaRII and Bax suffer such mutations
How does inactivation of MLH1 often occur
by epigenetic change, methylation of
the DNA of its promoter
which repair system is lost in Lynch Sydrome
MMR
What does HR repair of DSB require
Which proteins are important in this repair system
there being 2
copies of the genome: it uses the other copy of the broken sequence—usually the
sister chromatid—as a template to resynthesise the broken bit
BRCA1/2
What are the BRCA genes infamous for
hereditary breast cancer
Which repair system deals with crosslinked DNA
HR
mutations in which protein account for a few percentage of colon cancers
mutations in DNA polymerase epsilon proof-reading domain can cause an extremely high error rate
what is a source of chromosome instability other than defects in repair mechanisms
defects in mitosis
eg multiple centromeres, in some cancer cells, chromosomes sometimes get left behind or broken during anaphase
why does a mutation of p53 lead to instability
If DNA is damaged or replication encounters a problem, the cell cycle should be halted at a checkpoint, so defects in checkpoints may leave problems unresolved
what is the Vogelstein model of colorectal cancer
model of the development of colorectal cancer (revised 2008), trying to relate genes mutated to stages in cancer development. The model is speculative and oversimplified—e.g. only some colorectal cancers have these particular mutations, and the list of mutations is not complete
What is the sequence of mutations in the Vogelstein model of colorectal cancer
1) APC or beta-catenin;
2) CDC4 or CIN;
3) KRAS or BRAF;
4) PIK3CA or PTEN;
5) p53/TP53 or BAX;
6) SMAD4 or TGF-beta.
why are the APC and beta-catenin mutations interchangable in the Vogelstein model of colorectal cancer
both may be required for adenoma formation—mutating either gene has much
the same effect so these are alternatives
how high is the risk of developing cancer if you have a hereditary predisposition
(not including weak predispositions that increase risk by 1.3x eg)
e.g. hereditary predisposition to breast cancer, the affected individual has a high risk, usually at least 50% and often higher, of developing cancer.
The individual inherits one of the mutations required to get a cancer, and so is one step down the road to cancer.
What is an inherited mutation predisposing cancer usually in
why does this increase their chances of cancer
usually (but not always) in one copy of a tumour suppressor gene rather than an oncogene
In a normal individual—known as a ‘sporadic’ case—2 mutations, in the same cell, one on each copy, would be required to inactivate this tumour suppressor gene.
In the predisposed person, all their cells start with one copy inactivated, but one intact so that cells behave normally, and the second mutation occurs in occasional cells during life to alter the cell’s behaviou
Why are hereditary predispositions to cancer important
(a) Because they are among the commonest genetic diseases,
(b) They provided an important route to discovery of tumour suppressor genes including APC and RB1.
How common are hereditary predispositions to cancer
among the commonest potentially-lethal hereditary diseases, i.e. are more common than most of the well-known non-cancer genetic diseases that are potentially lethal.
At least a few percent of cancer is due to such predispositions and the individuals affected may have a very high probability of developing the particular cancer, e.g. BRCA2 mutation gives a lifetime risk of around 40-80% of breast cancer
true or false
inhereditary predisposition to cancer mutations are always in genetic instability genes
false
can either be in growth control genes (e.g. APC, RB1) or in genetic instability genes (MLH1, MSH2, BRCA2).
what are the 2 best known examples of hereditary predisposition to colon cancer
Familial Adenomatous Polyposis
Lynch Syndrome
What are the other names for familial adenomatous polyposis
how common is it
Adenomatous Polyposis Coli or just polyposis coli
1/10,000
What happens in familial adenomatous polyposis
individuals develop ~1000 polyps
(adenomas) in colon in late adolescence
associated with mutation in tumour suppressor APC gene
How common is APC mutation in sporadic colorectal cancer
Around 80% of sporadic colorectal cancers also have this mutation, but both copies have to be damaged after birth
what proportion of colon cancers are from Lynch Sydrome
What are the mutations in
what do these genes encode
1%
(one copy of) MLH1 and MSH2, both encoding components of DNA mismatch repair
How common are MLH1 and MSH2 mutations in sporadic cases of colon cancer
15% have mutation
What is Lynch Sydrome also called
old name Hereditary Non-Polyposis Colon Cancer, HNPCC but it afffects other tissues as well
How much of breast cancers are in individuals with an inherited predisposition
what genes are often involved in inheritance
5%
Perhaps half of these have a mutant copy of BRCA1 or BRCA2.
How are BRCA 1 and 2 related
unrelated proteins but are both components of DNA strand break repair, and loss of both copies of the genes gives genetic instability.
what is the major difference between the genes associated with inherited predisposition to breast rather than colon cancer
APC, MSH2 and MLH1 are found in both predisposed and sporadic colon cancers
BRCA1/2 are rarely mutated in non hereditary breast cancer
what are BRCA1 and 2 involved in normally
so what happens if they are lost
both components of DNA strand break repair, and loss of both copies of the genes gives genetic instability
what is retinoblastoma
a rare tumour arising in the immature retina, in children under a few
years old. About 40% of cases are hereditary, and on average predisposed individuals
develop 3 tumours (range 0 to many)
what cancers does a BRCA2 mutation lead to (3)
breast
prostate
ovarian
which part of the cell cycle does Rb control
g1/s checkpoint
What is the Knudson 2 hit hypothesis
The idea that typical tumour suppressor genes require two mutations to inactivate both copies
developed from studying retinoblastoma incidence
true or false
genetic instability may be separated from growth control
true
When cancers with BRCA2 mutations are treated with DNA-crosslinking agents, treatment selects for cells that can repair the lesions, so selects for revertants of the BRCA2 mutation. These revertants have lost genetic instability but go on to kill the patient
What are the hallmarks of cancer that are concerned with loss of growth control (5)
what is another key hall mark
independence of growth stimulating signals resistance to growth inhibitory signals differentiation block resistance to apoptosis immortality
genetic instability
What are the 4 more controversial hall marks of cancer
metabolic changes
metastasis
angiogenesis
evasion of immune response
Why is angiogenesis a controversial hallmark of cancer
arguably any growth in the body will grow extra blood vessels, not just tumours
Which receptor type are usually involved in growth factor pathways
RTK
name 3 types of signaling pathway in cancers
GFs
Wnts
TGF-beta
What does the TGF-beta family usually do in cancer
generally inhibit proliferation in epithelial cells.
Which of the 3 main types of cancer signaling pathways are involved in the Vogelstein model of colorectal cancer
pro-proliferation pathways—the Wnt pathway; and two pathways downstream of receptor tyrosine kinase signalling, the KRAS-BRAF MAP kinase pathway and the PI3 kinase-Akt pathway—and a growth-inhibitory pathway—TGF-beta signalling
Why is Wnt pathway of particular importance to the colorectal cancers
almost all colorectal cancers have a mutation in it, either in APC, beta-catenin, or, more recently discovered, other components such as a Tcf transcription factor
What is the most frequent mutation in the Wnt pathway in colorectal cancer
APC inactivation
What does beta catenin do
acting with Tcf transcription factors in the nucleus, drives cell proliferation and/or clonal expansion.
How do APC and Wnt relate to beta catenin
APC forms part of a complex that normally degrades beta-catenin, and Wnt signalling prevents the degradation.
Which type of mutations are required to make the Wnt pathway cancerous and pro-proliferative
inactivation of APC or activation of beta-catenin
How is activation of beta-catenin usually achieved
by preventing degradation, typically by point-mutating the motif on beta-catenin that the degradation machinery recognises.
What is the target of Herceptin in breast cancer treatment
HER2
Name 2 receptors in the ErbB family
EGFR
HER2
What are the 2 possible downstream pathways from ErbB receptors
1) MAPK (signals via RAS and RAF family members)
2) PIP3 (PI3K phosphorylates PIP2 to PIP3, which activates AKT, inhibiting apoptosis)
What dephosphylates PIP3
PTEN
What would have to happen PTEN to cause cancer
PTEN is a tumour suppressor (dephosphorylates PIP3 so stops inhibition of apoptosis) so must be deleted
What are the alternatives to PI3KCA and PTEN in Vogelstein’s colorectal cancer model
KRAS/BRAF
How do TGF beta family peptide GFs signal
via a transmembrane receptor to the SMAD family (which carry signals to nucleus)
How are TGF beta families implicated in cancer
Mutations in TGFbetaRII (TGFbeta receptor two), SMAD4 or SMAD2 are quite common in colon cancer.
All are tumour suppressor genes.
How does mutating RAF differ from mutating RAS in cancer
Mutating RAS has much the same effect as mutating RAF, so both mutations can be regarded as activating the RAS-RAF pathway
What is an example of differentiation block in the Vogelstein model
inactivation of APC (or activation of beta-catenin).
Mutating APC in the stem cell compartment of the
colon in an animal model blocks differentiation: the stem cell compartment expands and the proliferating cells are no longer able to migrate up the villi.
True or false
Leukaemias must arise as in full differentiated lymphocytes
false
Leukaemias can arise in stem cells or in fully differentiated lymphocytes (as in chronic B-lymphocytic leukaemia and also myeloma which arises in plasma cells).
