This document contains a summary of all the course material of theme 1A and B of the subject Mechanisms of Disease 2. DISCLAIMER: this summary consists of practice questions. These questions are not old exam questions, they are purely to see how well you understand the course material. These questi...
Content
Content in details (all added course material).......................................................................................2
Theme 1A – Cancer biology and genetics..............................................................................................3
Cancer biology: the hallmarks of cancer............................................................................................3
Cancer genetics..................................................................................................................................5
Cancer aetiology................................................................................................................................8
Cancer and genome integrity...........................................................................................................10
Clinical relevance of genetic repair mechanisms.............................................................................12
Hereditary aspects of cancer...........................................................................................................14
Hereditary breast cancer.................................................................................................................16
Hereditary colorectal cancer............................................................................................................18
Concepts of cancer heterogeneity...................................................................................................19
General principles: invasion and metastasis....................................................................................20
Cancer immunology and immunotherapy.......................................................................................23
Cancer and immunity.......................................................................................................................26
Cancer and the genome...................................................................................................................27
BAP1 cancer syndrome....................................................................................................................29
Theme 1B – Cancer diagnostics...........................................................................................................31
Biomarkers: diagnostic and therapeutic relevance..........................................................................31
General principles: diagnostic pathology.........................................................................................33
General principles: molecular diagnostics.......................................................................................35
Diagnostics at work: case discussion................................................................................................37
1
, Theme Course material
Theme 1 – Neoplastic disorders LT 2 – Cancer biology: the hallmarks of cancer
LT 3 – Cancer genetics
Theme 1A – Cancer biology and LT 4 – Cancer aetiology
genetics LT 5 – Cancer and genome integrity
LT 6 – Clinical relevance of genetic repair mechanisms
LT 7 – Hereditary aspects of cancer
PD 1 – Breast cancer
XL 1 – Hereditary breast cancer
STA 1 – Hereditary cancer
SSA 1 - Hereditary colorectal cancer
LT 8 – Concepts of cancer heterogeneity
LT 9 – General principles: invasion and metastasis
LT 10 – Cancer immunology and immunotherapy
WG 1 – Cancer and immunity
STA 2 – Cancer and genome
SSA 2 – Cancer and genome
CA 1 – Cancer and genome
PD 2 – BAP1 cancer syndrome
Theme 1B – Cancer diagnostics LT 11 – Biomarkers: diagnostic and therapeutic relevance
LT 12 – General principles: diagnostic pathology
LT 13 – General principles: molecular diagnostics
IS 1 – Diagnostics at work: case discussion
Content in details (all added course material)
LT = lecture; PD = patient demonstration; XL = extra lecture; STA = small teaching activity; SSA = self
study assignment; WG = workgroup; CA = computer-assisted assignment; IS = interactive session
2
,Theme 1A – Cancer biology and genetics
Cancer biology: the hallmarks of cancer
What are the hallmarks of cancer?
o Sustaining proliferative signalling
o Evading growth suppressors
o Avoiding immune destruction
o Enabling replicative immortality
o Tumour promoting inflammation (not only typical of cancers)
o Activating invasion & metastasis
o Inducing angiogenesis
o Genome instability & mutation (not only typical of cancers)
o Resisting cell death
o Deregulating cellular energetics
What happens in cancer with the hallmark ‘sustaining proliferative signalling’?
o Normally there is activation of signalling pathways
A growth factor binds to a growth factor receptor (often a tyrosine kinase)
The tyrosine kinase phosphorylates and leads to a cascade and activation of
a transcription factor
Transcription is activated when this factor binds to genes
Often these are genes that stimulate cell growth/proliferation
o In a tumour cell there could be
Overexpression of growth factors (EGF, VEGF)
Overexpression of cell surface receptors and/or activating mutations (EGFR,
HER2)
Overexpression of intracellular signalling molecules or activating mutations
(KRAS, BRAF)
Overexpression of transcription factors (MYC, β-catenin)
What happens when there is overexpression of MYC?
o The cell doesn’t need the pathway at all, it becomes independent of the signalling
pathway
How is RAS activated?
o GDP bound to inactive RAS is exchanged for GTP by GEF, creating active RAS
o (When GTP is hydrolysed to GDP by GAP, RAS becomes inactive again)
What are proto-oncogenes?
o Genes that can stimulate cancer development
Activating mutations/amplifications of EGFR and ERBB2 (HER2) are common in which
cancers?
o EGFR: lung cancers
o ERBB2 (HER2): breast cancers
What happens in cancer with the hallmark ‘evading growth suppressors’?
o Growth suppressors are like breaks, they will dominate in a healthy cell but in cancer
cells the growth promotors are dominant
o Normally all stages of the cell cycle are checked, though this is dysregulated in
cancer
Which types of function mutations are there when it comes to evading growth suppressors?
o Loss-of-function (tumour suppressors): mutations of growth inhibitors (TGFβ
receptor, p16)
o Gain-of-function (oncogenes): mutations of growth factors (Cyclin D, CDK4)
What happens to retinoblastoma (RB) protein when growth factors or inhibitors activate?
3
, o Growth factors: hyperphosphorylated
o Growth inhibitors: hypophosphyorylated
What is E2F?
o E2Fs are critical regulators (transcription factors) of the cell cycle, they regulate every
phase of the cell cycle by controlling the transcription of numerous target genes
involved in DNA replication and cell cycle progression
What is TP53?
o It’s a major tumour suppressor, it recognizes when something is wrong with the cell
and causes cell-cycle arrest, senescence and apoptosis
o It’s mutated in more than 50% of human tumours
o P53-related pathways affected in more than 90% of all tumours
What happens when there is a loss of P53?
o Loss of cell cycle checkpoints and proliferation of cells with DNA damage
What is Li-Fraumeni syndrome (LFS)?
o An inherited familial predisposition to a wide range of certain cancers due to a
change (heterozygous mutation) in TP53
o Development of multiple primary tumours of various kinds at young age (dominant
inheritance)
What is WNT signalling?
o It starts with the binding of WNT ligand to a WNT receptor
o This binding inhibits the destruction complex (includes APC)
o Inhibition of the destruction complex leads to the stabilization of β-catenin
o Stabilized beta-catenin accumulates in the cytoplasm and translocates into the
nucleus
o In the nucleus, β-catenin interacts with transcription factors
o This leads to the activation of target genes involved in cell proliferation,
differentiation and other cellular processes
What is APC?
o Adenomatous polyposis coli, it’s a main tumour suppressor in colorectal cancer
What happens when there is a mutation in APC?
o B-catenin is able to reach the nucleus and keep inducing transcription
o This can lead to familial adenomatous polyposis (FAP)
What is β-catenin?
o It’s a transcription factor and it’s also part of the cytoskeleton of the cells
o So some beta-catenin is associated with E-cadherin (E-cadherin maintains cell-to-cell
contact on epithelial cells)
o When E-cadherin is targeted/destroyed, cells become detached and β-catenin can
get loose and go to the nucleus
Are E-cadherin and β-catenin tumour suppressors or oncogenes?
o E-cadherin is a tumour suppressor
o β-catenin is an oncogene
o (the oncogene stays in the cell and increases its activity, tumour suppressors need to
be absent/inhibited in order to cause cancer)
What happens in cancer with the hallmark ‘avoiding immune destruction’?
o There is a loss of HLA/MHC class I molecules, tumour cells won’t present peptides to
the T cells
What happens in cancer with the hallmark ‘enabling replicative immortality’?
o Normal cells have limited proliferative capacity, they enter a state of (replicative)
senescence (they have lost the ability to re-enter the cell cycle)
o Telomerase is required for cell replication, but it becomes shorter every time
4
Voordelen van het kopen van samenvattingen bij Stuvia op een rij:
Verzekerd van kwaliteit door reviews
Stuvia-klanten hebben meer dan 700.000 samenvattingen beoordeeld. Zo weet je zeker dat je de beste documenten koopt!
Snel en makkelijk kopen
Je betaalt supersnel en eenmalig met iDeal, creditcard of Stuvia-tegoed voor de samenvatting. Zonder lidmaatschap.
Focus op de essentie
Samenvattingen worden geschreven voor en door anderen. Daarom zijn de samenvattingen altijd betrouwbaar en actueel. Zo kom je snel tot de kern!
Veelgestelde vragen
Wat krijg ik als ik dit document koop?
Je krijgt een PDF, die direct beschikbaar is na je aankoop. Het gekochte document is altijd, overal en oneindig toegankelijk via je profiel.
Tevredenheidsgarantie: hoe werkt dat?
Onze tevredenheidsgarantie zorgt ervoor dat je altijd een studiedocument vindt dat goed bij je past. Je vult een formulier in en onze klantenservice regelt de rest.
Van wie koop ik deze samenvatting?
Stuvia is een marktplaats, je koop dit document dus niet van ons, maar van verkoper StudieSteffen. Stuvia faciliteert de betaling aan de verkoper.
Zit ik meteen vast aan een abonnement?
Nee, je koopt alleen deze samenvatting voor €6,00. Je zit daarna nergens aan vast.
