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PATH 310 Study Guide - Midterm Guide: Tumor Suppressor Gene, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia

Pathology and Molecular Medicine
Course Code
PATH 310
Christine Hough
Study Guide

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Lifetime risk of cancer is increasing, but death rate due to cancer is slowly declining
o Extending lives but not curing
Cancer = disease in which abnormal cells divide without control and are able to invade or spread to
other tissues, a malignant neoplasm
Neoplasm = a collection of abnormal cells that divide without control
o Benign neoplasms do not invade or spread, malignant neoplasms do spread
Metastasis = spreading of cancer to distant sites, usually through the blood stream
Cancer is a genetic disease, risk factors that could increase damage include
o Radiation (UV or other)
o Tobacco
o Western Diet
o Age
Clonality in cancer
o A successful clone (one that has mutations that provide selective advantages to the cell) will
be over-represented in the selected population
o Individuals with advantageous trait will produce more progeny and will come to dominate
The hallmarks of cancer
o Cell sufficiency and growth signals
o Insensitivity to anti-growth signals
o Tissue invasion and metastasis
o Limitless replicative potentials
o Sustained angiogenesis (ability to attract blood vessels to nourish growing tumour)
o Evading apoptosis
Benign tumours differ in that there is no tissue invasion and metastasis other hallmarks are the
Retinoblastoma is a rare cancer that arises in the retinal layer of the eye (4% of all pediatric
Sporadic retinoblastoma is when there is no family history
o Unilateral tumour
o When it is removed, a second does not arise
o Non-linear kinetics
Familial retinoblastoma is when it has been inherited
o Bilateral (tumours can present in both eyes)
o One parent had retinoblastoma and survived
o It is inherited in a dominant pattern, since one allele is already mutated in all cells only one
more hit is required to induce a tumour
Two-hit hypothesis
o Only one working tumour suppressor gene is required for its function
o On the cellular level, the gene is recessive (so both copies need to be lost before cancer
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o For familial tumours: one allele is already mutated, so one more hit required to induce a
tumour (cancers occur with linear kinetics)
o For sporadic tumours: non-linear kinetics, cell needs to lose both copies to become cancer
o Second hit: removal of the second allele is associated with loss of the normal difference
between chromosome pairs (loss of heterozygosity, which confers a selective advantage)
Tumour suppressor genes are guardians and governors of the genome
o Loss of function leads to cancer
o A gene whose inactivation contributes to cancer development, encode tumour suppressor
proteins (TP53 encodes p53)
Rb as a governor of the cell cycle
o Cells without Rb can enter at any time, it is a governor because it puts a limit on the speed at
which cells can replicate
Rb in sporadic cancer
o Mutations are common, one of the most frequently mutated genes in cancer
o Rb holds E2F, a transcription factor that can be inactivated by mutation or phosphorylation
of Rb
TP53 germline mutation
o Associated with familial cancer
o Has same 50% penetrance rate as Rb, leads to more common adult cancers
o Tend to manifest at earlier ages with familial than with sporadic
o TP53 is thought to be the guardian of the genome, as it monitors the health of the genome
o In response to stress signals it shuts down cell proliferation
o Mutation here causes cells with damage that can proliferate
o A gene that in certain circumstances can transform a cell into a tumour cell
o Dominant gain of function leads to cancer
o Cancer-inducing gene, they encode oncoproteins
Oncogenic activation of EGFR
o Activation of receptors occurs with phosphorylation of tyrosine
o There is a conformational change that facilitates phosphorylation, so there are hyper
activating mutations that hold on to ligands more avidly, or signal moderately without the
ligands (EGF) being present
EGFR activating mutations are dominant gain of function
o Responds to targeted therapies with drugs that inhibit these tyrosine kinases
Normal function of EGFR receptors is to activate growth in a defined way, some survive and some
undergo programmed cell death
Tumour heterogeneity
o Each tumour has many different cells within it
o Tumour cells, and tumour variant cells
o Transformation of normal cell into tumour cell (carcinogen induced change) tumour cell
progression proliferation of genetically unstable cells clonal expansion of surviving cell
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Biopsy sites and regional distribution of mutations
o Full genome sequencing of each part of tumour and remote metastases
o Plot of detected mutations, only the ones that hit key regulators of the hallmark pathway
are important
Intratumor heterogeneity
o Can lead to underestimation of the tumor genomics landscape portrayed from single tumor-
biopsy samples and may present major challenges to personalized-medicine and biomarker
o Associated with heterogeneous protein function, may foster tumor adaptation and
therapeutic failure through Darwinian selection
Critical mutations come from a limited number of pathways (certain systems that have to be
deregulated in cancer)
o There are plenty of passenger mutations in cancer, but the drivers matter more
o Caretakers are passengers, like MLH1, MSH2
o Gatekeepers are the regulators of the key pathways (p53 and Rb), and they are proteins
involved in maintaining genomic stability and keeping mutation rates low
o Loss of these leads to massive amounts of random mutations at an accelerated rate
Cell cycle (for CyclinD-Cdk4)
o Step 1 is external signal that tells cell to divide, allowing for transcription, accumulation and
expression of cyclin D, an oncogene (regulatory cyclinD binds to Cdk4 to turn the kinase on)
o Rb has a protein-protein interaction with E2F (when bound E2F can not perform function),
cdk4 phosphorylates Rb, so that E2F can dissociate and become the transcriptional regulator
o E2F transcribes a bunch of replication proteins needed for S phase, DNA polymerases, and
dNTP synthesis giving cell ability to replicate
o When enough E2F is free, we get formation of cyclin E, that binds to Cdk2 and activating the
kinase (complex phosphorylates and activates many replication proteins), to maintain signal
independent of growth factors (synergistic!)
o How do we turn it off? Another cyclin-cdk complex (CycA-Cdk2) that phosphorylates and
inactivates proteins including E2F
Restriction point is a critical point where the decision to proliferate or undergo apoptosis occurs
(between G1 and S phase)
P53 is the key linker between DNA damage and apoptosis (it tips balance in presence of DNA
damage towards apoptosis rather than S phase)
o Mdm2 is a ligase, and it sticks a small protein onto p53 (becomes unstable)
o When DNA damage happens, a signal gets sent to ATM, which phosphorylates p53 such that
it can no longer bind to mdm2
o P53 levels then rise, and it becomes stable as it is no longer being degraded or uniquitinated
o P53 activtes Bax, then Bcl-2 (both tumour suppressors) which ultimately triggers apoptosis
o P53 loss of function has net effect that cell can no longer undergo apoptosis when DNA is
damaged, instead it proliferates
o When p53 is intact, S phase population disappears in presence of DNA damage
o When p53 is mutated (at the G1-S checkpoint), the ability to halt replication in presence of
DNA damage is bypassed proliferation tumour growth
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