1
Q
Deficiency in the terminal components of complement predisposes patient to which type of infections?
A
Neisseria bacteria infections
2
Q
Deficiency in C1 inhibitor of the complement system results in what disease?
A
Angioedema
3
Q
Deficiency in glycophosphtatidylinositol (GPI) anchors results in what disease?
A
Paroxysmal Nocturnal Hemoglobinuria (PNH)- complement-mediated red cell lysis)
Decay accelerating factor and CD59 (plasma membrane proteins that attach to GPI anchors.
DAF - prevent formation of C3 convertase
CD59 inhibits formation of MAC
4
Q
Complement Factor H inherited defects results in what disease?
A
Atypical form of Hemolytic Uremic Syndrome
5
Q
Polymorphisms in Factor H gene is linked to what disease?
A
Age-related macular degeneration - important cause of vision loss in older adults
6
Q
What syndrome occurs from gain-of-function of NOD-like receptors of loss-of-function of inflammasomes?
A
Autoinflammatory syndromes (Periodic fever syndomes)
7
Q
How do you classify colonic polyps and what is included in each classification?
A
Colon polyps can be classified into:
- Non-neoplastic and Neoplastic
Non-neoplastic:
Hyperplastic polyps
- Inflammatory polyps
- Hamartomas
Neoplastic:
- Adenomas: Tubular, Tubulovillous, Villous, Sessile Serrated, Traditional Serrated
- Adenocarcinomas
8
Q
Discuss hyperplastic polyps and the variants.
A
Hyperplastic polyps are non-neoplastic polyps that are a result of benign proliferation of the colonic epithelial cells and decrease cell turnover and delayed epithelial shedding.
Epidemiology: M>F ; 6th - 7th decade of life
Gross: Most commonly occurs in rectum and sigmoid, may be single or multiple (multiple common in rectum)
Size: Small <5mm ; occurs on crest of mucosal folds
Microscopic:
Serrated architecture limited to upper 1/3 or 1/2 of crypts.
No crypt dilation, branching or horizontal spreading
No dysplasia
Variant:
1. Microvesicular variant (May have BRAFV600E mutations)
- Abundant microvesicles within the apical portion of absorptive cells with variable goblet cells.
2. Goblet cell rich variant ( May have KRAS mutations)
- Serrations limited to surface, abundant goblet cells (seen on surface as well)
- Round glands more abundant than stellate shaped glands
Clinical significance:
There is no malignancy potential of hyperplastic polyps.
BUT: Must be distinguished from sessile serrated adenomas which have similar histological features and have risk of malignant progression.
9
Q
What mutations may be found in hyperplastic polyps?
A
BRAFV600E mutations
10
Q
What genetic abnormalities may be found in sessile serrated adenomas?
A
BRAFV600E mutations and CpG Island Methylation Phenotype (CIMP) resulting in microsatellite instability.
MLH-1 mutations (DNA mismatch repair genes)
11
Q
What genetic mutations are associated with Juvenile Polyposis Syndrome?
A
SMAD-4 (Encodes signal intermediate in TGF-B pathway)
BMPR1A (A kinase that is a membrane of TGF-B superfamily)
***These two mutations account for few than half of patients with JPS. Therefore other genes responsible for AD JPS remain to be discovered.
12
Q
What chromosome is SMAD4 located on?
A
Chr 18q21.1
13
Q
What chromosome is BMPR1A located on?
A
Chr 10q23.2
14
Q
What chromosome is TP53 located on?
A
Chr 17p13
15
Q
What chromosome is retinoblastoma gene located on?
A
Chr 13q14
16
Q
What are the gross and histological features of Juvenile Polyps?
A
Gross: Polyps <3cm, pedunculated, smooth surfaced and reddish lesions with cystic spaces
Microscopic:
Polypoid lesion with cystically dilated glands filled with mucin and inflammatory debris.
- Lamina propria expanded by mixed inflammatory infiltrates
- Normal or attenuated muscularis mucosae
17
Q
What % of people develop colorectal cancer and by what age is this usually seen in Juvenile Polyposis Syndrome?
A
30-50% of persons develop CRC by 45 years of age
18
Q
What is the lifetime risk of malignancy in Peutz-Jegher Syndrome?
A
40%
19
Q
What are the types of malignancies associated with Peutz-Jegher Syndrome?
A
Birth: Sex-cord tumours of the testes
Late childhood: Gastric and small intestinal cancers
2nd to 3rd decade of life: Colon, pancreatic, breast, lung, ovarian and uterine cancers.
20
Q
What gene is mutated in Peutz-Jegher Syndrome?
A
STK11
21
Q
Which chromosome is STK11 found?
A
Chr 19p13.3
22
Q
What are the gross and microscopic features of Peutz-Jegher Syndrome polyps?
A
Gross:
Site: Small bowel (most common), stomach and colon; less frequently: lung and bladder
Large pedunculated with lobulated contours
Microscopic: Arborizing network of smooth muscle, connective tissue within the lamina propria, with glands lined by normal appearing intestinal epithelium
23
Q
What are the GI polyposis syndromes and their genetic abnormalities?
A
- Juvenile Polyposis Syndrome - SMAD4 ; BMPRA1 ; TGF-B signaling pathway
- Peutz-Jegher Syndrome - STK11 ; AMP -kinase related pathway
- PTEN Hamartoma Tumour Syndrome (Cowden Syndrome and Bannayan-Ruvalcaba-Riley Syndrome) - PTEN ; PI3K/AKT pathway
- Cronkhite-Canada Syndrome - Nonhereditary; unknown cause
- Tuberous sclerosis - TSCI (hamartin), TSC2 (tuberin), mTOR pathway
- FAP
-Classic FAP, Attenuated FAP, Gardner Syndrome, Turcot Syndrome APC
- MUTYH-associated polyposis - MUTYH
24
Q
Which chromosome is PTEN located on?
A
Chr 10q23
25
What gene/protein is abnormal in tuberous sclerosis and which chromosome are they found on?
TSC1 -- Hamartin ; Chr 9
TSC2 -- Tuberin ; Chr 1-
mTOR pathway
26
How do you distinguish Cronkhite-Canada Syndrome from Juvenile Polyps?
Microscopically:
Juvenile polyps and Cronkhite-Canada Syndrome have classic features of a Juvenile Polyp, however, Cronkhite-Canada also has these features extending into the nonpolypoid mucosa; while Juvenile polyps have normal adjacent mucosa.
27
What is the lifetime risk of cancer in PTEN Hamartoma Tumour Syndrome?
9-16%
28
What is the lifetime risk of cancer in Cronkhite-Canada Syndrome?
15-25%
29
What % of the architectural component of the colonic adenoma is needed to classify as tubular/tubulovillous/villous?
75% Tubular architecture = Tubular adenoma
75% Villous architecture = Villous adenoma
At least 25% of each - Tubulovillous adenoma
30
What is the most important characteristic of a colonic adenoma correlates with risk of malignancy?
Size [Adenomas >10mm (1cm)]
Cancers are rare in adenomas <1cm
~40% of lesions >4cm contain invasive foci
31
Which chromosome is APC gene located?
Chr 5q22.2
32
What are the genetic defects of colon cancer and what % do they account for sporadic cases?
APC/WNT pathway defects - 70-80% ; left sided tubular/villous adenoma and typical adenocarcinoma
DNA MMR defects - 10-15% (MLH1, MSH2) - right sided - SSA / Mucinous Adenocarcinoma
Hypermethylation of MLH1, BRAF - 5-10% - Right sided - SSA / Mucinous Adenocarcinoma
33
Which syndrome is the most common cause of colorectal carcinoma?
Hereditary Non-polyposis Colorectal Carcinoma (HNPCC) - 2-4%
34
Which chromosome is K-RAS found on?
Chr 12p12
35
What are the pathways for colorectal carcinoma formation?
1. Adenoma-Carcinoma Sequence
- APC mutations/epigenetic alteration (Early driver mutation)
- Acquisition of additional mutations: KRAS, SMAD2/4 , TP53; OR Genetic silencing by methylation of CpG islands
+ Telomerase expression
- Carcinoma
2. DNA MMR deficiency --> Microsatellite instability (MSI-H)
- Mutations in Type 2 TGF-B Receptor (TGFBR2) -> Increase proliferation
+ Loss of pro-apoptotic factors (eg. BAX) --> Increase survival
--> Carcinoma
3. Microsatellite unstable without DNA MMR deficiency
- CpG island hypermethylation phenotype (CIMP) of MLH1 promoter region.
- BRAF mutations (NOT KRAS or TP53)
4. Increased CpG island methylation in the absence of MSI
- KRAS mutations (uncommon BRAF and TP53)
36
Which types of colon adenocarcinoma are associated with worse prognosis?
Mucinous and poorly differentiated carcinoma
37
What are the two most important prognostic factors for colon cancer?
1. Depth of invasion (invasion into muscularis propria significantly reduces the probability of survival)
2. Presence of lymph node metastasis
38
What is the most common site for distant metastasis of colon cancer?
Liver
39
What are the risk factors for haemorrhoids?
Staining at defecation (eg. in constipation)
Pregnancy - venous stasis
Portal hypertension (pathogenesis similar to oesophageal varices)
40
What is the pathogenesis of haemorrhoids?
Persistently elevated venous pressures within the haemorrhoidal plexus.
41
What age is haemorrhoids normally seen?
Generally older than 30 years old, except in pregnancy.
42
What three factors may be affected in haemorrhagic disorders?
1. Blood vessels (eg. vWF)
2. Platelets
3. Coagulation factors
43
How do defects in platelets or vessel wall manifest in hemorrhagic disorders?
Petechiae or Purpura of the skin and mucosa
(Petechiae - 1-2mm ; Purpura >/= 3mm)
Mucosal bleeding may result in epistaxis, GI bleed or menorrhagia
Intracranial bleeds may occur which is may be life threatening
44
How do defects in secondary hemostasis manifest?
Bleeding into soft tissue and joints (hemarthrosis) following minor trauma which is characteristic in hemophilia.
45
How do defects involving small vessels present?
Palpable purpura and ecchymosis (1-2cm) ; which may for hematoma
Characteristic of systemic disorders that disrupt blood vessels (eg. vasculitis) or lead to blood vessel fragility (amyloidosis and scurvy)
46
Rapid loss of approximately how much blood volume is needed to result in haemorrhagic (hypovolemic) shock in health adults?
>20% of blood volume
47
What is the most important factor in Virchow triad?
Endothelial integrity
48
What are the factors that predispose patients to thrombus formation? Provide examples
Virchow Triad
-Endothelial injury (eg. Inflammation or hypercholesterolemia)
- Abnormal blood flow (eg. Stasis - AF, Bed red; Turbulence - Atherosclerotic vessel narrowing)
-Hypercoagulability (eg. Inherited - factor V Leiden; Acquired DIC)
49
What is the prerequisite for thrombus formation under high shear stress (i.e arteries)?
Platelet adherence and activation
50
What are the factors that cause endothelial activation/dysfunction?
1. Endothelial injury (physical)
2. Infectious agents
3. Abnormal blood flow
4. Metabolic abnormalities, eg. hyperccholesterolemia, homocysteinemia and toxins from smoking cigarettes
51
What are the antithrombotic properties of the endothelial cells and the components of each?
1. Platelet inhibitory effects
- Barrier that shields platelets to subendothelial vWF and collagen
- Produces factors that inhibits platelet activation and aggregation
(Prostacyclin (PGI2), NO, ADPase)
2. Anticoagulation effects
- Thrombomodulin (Binds Thrombin and inactive it, also activates Protein C)
- Endothelial Protein C Receptors (Protein C/S complex is a potent inhibitor of cofactor Va and VIIIa)
- Heparin-like modules (Activates antithrombin III - inhibits Thrombin and Factors IXa, Xa, XIa, XIIa)
- Tissue factor pathway inhibitor (TFPI) (Inhibits tissue factor (TF) / factor VIIa complexes - with cofactor Protein S)
3. Fibrinolytic effects
- tPA
52
What are the most important endothelial inhibitors of platelet activation and aggregation?
Prostacyclin (PGI2)
NO
ADPase
53
What is a major regulator of NO and PGI2 production?
Blood flow
54
How does inflammation promote thrombus formation?
Activated endothelial cells have two major changes:
1. Procoagulant changes:
- Downregulation of thrombomodulin and other anticoagulants (eg. Protein C and TFPI)
2. Antifibrinolytic effects:
- Activated endothelium secretes plasminogen activator inhibitor -downregulates the expression of t-PA - factors thrombus formation
55
What are the most common inherited causes of hypercoagulability?
Factor V Leiden and Prothrombin gene mutations
56
What is Factor V Leiden?
Inherited Autosomal Dominant hypercoagulability disorder caused by point mutations in Factor V Leiden gene making it resistant to cleavage and inactivation by protein C.
- Heterozygotes have 5-fold increase in venous thrombosis
- Homozygotes have 50-fold increase
57
At what age should you consider inherited causes of hypercoagulability?
Ages <50 years, despite acquired risk factors
58
What is the mutation in Factor V Leiden?
Point mutation - Arg to Gln substitution in amino acid residue 506
- leading to resistance to activated protein C
59
What is the mutation in Prothrombin mutations?
Point mutation in G20210A noncoding sequence variant
- leading to increased prothrombin levels
60
What is the most common manifestation of Heparin-Induced Thrombocytopenia (HIT) Syndrome?
Thrombocytopenia
61
What is the most serious manifestation of Heparin-Induced Thrombocytopenia (HIT) Syndrome?
Thrombosis
62
What is antiphospholipid antibody syndrome (APS) characterized by?
1. Presence of one or more antiphospholipid (aPL) autoantibodies
2. Venous or arterial thromboses OR pregnancy complications such as recurrent miscarriages, unexplained fetal death and premature birth
63
What is the fate of the thrombus?
1. Propagation
2. Embolization
3. Dissolution
4. Organization and recanalization
64
What is a embolus?
A detached intravascular solid, liquid or gaseous mass that is carried by the blood from its point of origin to a distant site, where it often causes tissue dysfunction or infarction.
65
What the types of emboli?
1. Thromboembolism
2. Fat embolism
3. Air embolism
4. Amniotic fluid embolism
5. Foreign body embolism
66
What are the consequences of pulmonary embolus?
1. Most are clinically silent (60-80%)
2. Sudden death, acute right heart failure (cor pulmonale) or CV collapse (occurs when emboli obstruct >/=60% of the pulmonary circulation.
3. Embolic obstruction of medium-sized arteries with subsequent vascular rupture can result in pulmonary haemorrhage without infarction (unless bronchial arteries are compromised eg. left heart failure)
4. Embolic obstruction of small-end arteriolar pulmonary branches with pulmonary haemorrhage or infarction
5. Multiple emboli over time may cause pulmonary hypertension and right ventricular failure
67
Where do most systemic emboli originate from?
80% arise from intracardiac mural thrombi (2/3 associated with LV wall infarcts and 1/4 with LA dilation and fibrillation)
- Remainder originates from aortic aneurysms, atherosclerotic plaques, valvular vegetations, or venous emboli (paradoxical emboli) 10-15% of unknown origin.
68
Where do most systemic emboli lodge?
75% lodge within the lower extremities
10% within the brain
69
What is fat embolism syndrome?
It is characterized by pulmonary insufficiency, neurological symptoms, anemia, and thrombocytopenia and is fatal in 5 - 15% of cases
70
What external finding may be suggestive of a fat embolism?
A diffuse petechial rash (seen in 20 - 50% of cases) is related to rapid onset of thrombocytopenia and can be a useful diagnostic clue.
71
What special technique is needed to demonstrate fat microglobules in tissue and why?
Frozen section with stains for fat (Oil Red O)
- Because lipids are dissolved out of tissue preparation by solvent routinely used in paraffin embedding
72
Approximately what volume of air is needed to produce a gas embolus?
More than 100ml OR Introduction of 300 to 500ml of air at 100ml/sec
73
Explain decompression sickness
Inhalation of air at high pressures (eg. during deep sea diving) results in increased amount of gas (particularly nitrogen) are dissolved in the blood and tissue. With sudden decrease in atmospheric pressure (eg. during rapid ascent from diving - depressurizes) the nitrogen comes out of solution in the tissue and the blood
74
What are the manifestations of air within tissue?
Rapid formation of gas bubbles within skeletal muscles and supporting tissue in and about joints results in 'the bends'
In the lungs - gas bubbles in the vasculature causes oedema, haemorrhage, and focal atelectasis or emphysema - leading to the chokes (form of respiratory ditress)
Chronic: Caisson disease - persistence of gas emboli in the skeletal system leads to multiple foci of ischemic necrosis - (common site: femoral heads, tibia and humeri)
75
What is the classic autopsy finding in amniotic fluid embolism?
Presence of squamous cells shed from fetal skin, lanugo hair, fat from the vernix caseosa and mucin derived from the fetal respiratory or gastrointestinal tract in the maternal pulmonary microvasculature.
76
What is infarction?
An infarct is an area of ischemic necrosis caused by occlusion of either the arterial supply or venous drainage
77
How do you classify infarcts?
Based on the color: Red (Haemorrhagic) or white (anemia)
Based on presence of absence of infection: Septic or bland
78
In what conditions do red infarcts occur?
1. Venous occlusion (eg. testicular torsion)
2. In loose spongy tissue where blood can collect in the infarcted zone (eg. lung)
3. In tissue with dual circulation (eg. lung and small intestines)
4. In tissue previously congested by sluggish venous outflow
5. When flow is reestablished to a site of previous arterial occlusion and necrosis (eg. following angioplasty of an arterial obstruction
79
What are the factors that influence the development of an infarct?
1. Anatomy of vascular supply:
- Tissue with end arteries vs tissue with dual blood supply
2. Rate of occlusion (eg. slowly developing occlusion - provides time for collateral formation)
3. Tissue vulnerability to hypoxia
Irreversible ischemic damage to:
- Neurons in 3 to 4 minutes
- Myocardial cells in 20 to 30 minutes
- Fibroblast within myocardium in many hours
4. Hypoxemia
- Low blood oxygen content regardless of cause increases both the likelihood and extent of infarction
80
What are the two most important causes of aortic aneurysms?
Atherosclerosis and Hypertension
81
What is the most common cause of ascending aortic aneurysms?
Hypertension
82
What is the greatest risk factor for abdominal aortic aneurysms?
Atherosclerosis
83
What is the risk of rupture per year of an abdominal aortic aneurysm based on size?
<4cm - Nil
4-5cm - increases by 1% per year
5-6cm - increases by 11% per year
>/=6cm - 25% per year
84
What is the rate of aneurysm expansion per year?
0.2 - 0.3cm / year
but 20% expand more rapidly
85
At what size are abdominal aortic aneurysms managed aggressively?
>/=5cm
86
What is the most important risk factor for aortic dissection?
Hypertension
87
How are aortic dissections classified?
Stanford A - Involving the ascending aorta
Standford B - Involving only the descending aorta
DeBakey I - Ascending aorta and descending aorta involvement (tear in ascending aorta)
DeBakey II - Only ascending aorta involvement (tear in ascending aorta)
DeBakey III - Only descending aorta (tear in descending aorta)
88
Which aorta dissections require surgical management?
Stanford A or DeBakey I and II.
- All ascending aorta dissections require urgent surgical management
89
Which aortic dissections can be managed medically?
Stanford B or DeBakey III
90
What is the steps of angiogenesis?
1. Vasodilation (NO and increased vascular permability by VEGF)
2. Separation of pericytes - from abluminal surface and breakdown of the basement membrane to allow formation of a vessel sprout
3. Migration of endothelial cells towards to area of injury
4. Proliferation of endothelial cells - behind leading front of migrating cells
5. Remodeling into capillary tubes
6. Recruitment of periendothelial ceclls to form mature vessesl
7. Suppression of endothelial proliferation
91
What is shock?
Shock is a state of circulatory failure that impairs tissue perfusion and leads to cellular hypoxia
92
What are the different types of shock?
Major types:
1. Cardiogenic shock
2. Hypovolemic shock
3. Septic shock
Other types:
4. Neurogenic shock
5. Anaphylactic shock
93
How is Sepsis defined?
Based don the Third International Consensus Definitions for Sepsis and Septic Shock (2016)
Sepsis: a life-threatening organ dysfunction caused by a dysregulated host response to infection.
94
How is Septic Shock defined?
A subset of sepsis in which particularly profound circulatory, cellular and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone
95
How is systemic inflammatory response syndrome (SIRS) defined?
Sepsis-like condition associated with systemic inflammation that may be triggered by a variety of nonmicrobial insults such as burns, trauma and/or pancreatitis
96
List 5 examples of cardiogenic shock and state the principle mechanism
1. Myocardial infarction
2. Ventricular rupture
3. Arrhythmia
4. Cardiac tamponade
5. Pulmonary embolism
Principle Mechanism:
- Failure of myocardial pump result from intrinsic myocardial damage, extrinsic compression, or obstruction of outflow.
97
List 5 causes of hypovolemic shock
Fluid loss
1. Haemorrhage
2. Vomiting
3. Diarrhea
4. Burns
5. Trauma
98
List 5 causes of Shock associated with systemic inflammation and the principle mechanism
1. Overwhelming microbial infection
2. Superantigens (eg. toxic shock syndrome)
3. Trauma
4. burns
5. pancreatitis
Activation of cytokine cascade resulting in peripheral vasodilation and pooling of blood, endothelial activation/injury; leukocyte induced damage, DIC.
99
What is septic shock most commonly caused by?
Gram-positive bacterial infections, followed by gram-negative and fungi
100
What are the stages of shock?
There are 3 stages:
1. An initial nonprogressive stage - Reflex compensatory mechanisms result in maintained perfusion
2. A progressive stage - Tissue hypoperfusion and onset of worsening circulatory and metabolism derangement (including acidosis)
3. An irreversible stage: in which cellular and tissue injury is so severe that even if the hemodynamic defects are corrected, survival is not possible.
101
What are the hall marks of cancer?
There are 8 hallmarks of cancer
1. Self-sufficiency in growth signaling
2. insensitive to growth-inhibitory signals
3. Altered cellular metabolism
4. Evasion of apoptosis
5. Limitless replicative potential (immortality)
6. Sustained angiogenesis
7. Ability to invade and metastasize
8. Ability to evade the host immune response
102
PDGF-B overexpression leads to which type of cancer?
Astrocytoma
103
Overexpression of HST1 (FGF) is associated with which type of cancer(s)?
Osteosarcoma
104
Amplification of FGF3 is associated with which type of cancer(s)?
Stomach, bladder, breast cancers and melanoma
105
Overexpression of TGF-alpha is associated with which type of cancer(s)?
Astrocytoma
106
Overexpression of HGF is associated with which type of cancer(s)?
Hepatocellular carcinoma and Thyroid cancers
107
ERBB1 (EGFR) mutations is associated with which type of cancer(s)?
Adenocarcinoma of lung
108
ERBB2 (HER) Amplification is associated with which type of cancer(s)?
Breast carcinoma
109
FMS-like tyrosine kinase 3 (FLT3) point mutation or small duplications is associated with which type of cancer(s)?
Leukemia
110
Receptor for neurotrophic factors (RET) point mutations is associated with which type of cancer(s)?
MEN2A and 2B, Familial Medullary Thyroid Carcinoma
111
PDGF-Receptor (PDGFRB) amplification or translocation is associated with which type of cancer(s)?
Gliomas and Leukemias
112
Receptor for KIT ligand (KIT) point mutations is associated with which type of cancer(s)?
Gastrointestinal stromal tumours, seminomas, leukemias
113
ALK receptor translocation is associated with which type of cancer(s)?
Adenocarcinoma of the lung, certain lymphomas
114
ALK receptor point mutation is associated with which type of cancer(s)?
Neuroblastoma
115
KRAS point mutations is associated with which type of cancer(s)?
Colon, lung and pancreatic tumours
116
HRAS point mutations is associated with which type of cancer(s)?
Bladder and kidney tumours
117
NRAS point mutations is associated with which type of cancer(s)?
Melanomas, hematologic malignancies
118
GNAQ point mutations is associated with which type of cancer(s)?
Uveal melanoma
119
GNAS point mutations is associated with which type of cancer(s)?
Pituitary adenoma, other endocrine tumours
120
BRAF point mutations is associated with which type of cancer(s)?
Melanomas, leukemias, colon carcinoma and others
121
NOTCH1 point mutations/translocation is associated with which type of cancer(s)?
Leukemias, lymphomas, breast carcinoma
122
JAK2 point mutations/translocation is associated with which type of cancer(s)?
Myeloproliferative disorders, acute lymphoblastic leukemia
123
ABL translocation is associated with which type of cancer(s)?
Chronic Myelogenous Leukemia, Acute Lymphoblastic Leukemia
124
MYC translocations is associated with which type of cancer(s)?
Burkitt Lymphoma
125
NMYC Amplifications is associated with which type of cancer(s)?
Neuroblastoma
126
Cyclin D1 Translocation is associated with which type of cancer(s)?
Mantle cell lymphoma, multiple myeloma
127
Cyclin D1 Amplification is associated with which type of cancer(s)?
Breast and esophageal cancers
128
CDK4 Amplification of Point mutation is associated with which type of cancer(s)?
Glioblastoma, melanoma and sarcoma
129
What translocation is associated with chronic myeloid leukemia?
t(9;22) - BCR-ABL fusion gene (Philadelphia Chromosome)
BCR - Chromosome 9
ABL Chromosome 22
130
t(9;22) is associated with which disease?
Chronic Myeloid Leukemia
131
What is the translocation associated with Burkitts Lymphoma?
t(8;14)
MYC oncogene - Chromosome 8
IG gene - Chromosome 14
132
t(8;14) is associated with which disease?
Burkitts Lymphoma
133
What are the effects of MYC transcription factor?
1. Targets cyclins (eg. Cyclin D) to cause cell cycle progression
2. Upregulated ribosomal (rRNA) RNA gene and rRNA processing (needed for protein synthesis)
3. Metabolic reprogramming - Warburg effect and Glutamine metabolism (To provide substrates for cell growth)
4. Upregulated telomerase expression
5. Reprogramming of somatic cells into pluripotent stem cells
134
Amplifications in NMYC is associated with which type of cancer(s)?
Neuroblastomas
135
Amplifications in LMYC is associated with which type of cancer(s)?
Small cell cancers in the lung
136
What cancer is the hedgehog pathway associated with?
Medullablastoma
137
What is a proto-oncogene and a oncogene?
Proto-oncogenes are normal cellular genes whose products promote cell proliferation
Oncogene: mutated or overexpressed versions of proto-oncogenes that function autonomously, having lost dependence on normal growth-promoting signals
138
Which is the major angiogenic factor for blood vessel development?
VEGF-A (Known as just VEGF)
139
Which of the VEGF family is associated with embryonic vessel development?
VEGF-B and Placental Growth Factor (PlGF)
140
Which of the VEGF family is associated with angiogenesis and lymphangiogenesis?
VEGF-C and VEGF-D
141
What is the most important inducer of VEGF production?
Hypoxia (through pathways involving transcription factor - Hypoxia inducible factor-1 (HIF-1))
142
Which receptor is highly expressed on endothelial and is the most important for angiogenesis?
VEGFR-2
143
Which fibroblast growth factor has all the activities necessary for angiogenesis?
basic FGF (FGF-2)
144
What chromosome is MYC gene on?
8q24.21
145
What chromosome is MYCN gene on?
2p23-p24
146
What is the most important genetic abnormality used in risk stratification of Neuroblastic tumours?
MYCN amplification
147
148
What epigentic changes occur in Acute Myeloid Leukemia?
DNMT3A = DNA Methylation
149
What epigenetic change occurs in Acute Leukemia in Infants?
Histone Methylation of MLL1
150
What epigenic change occurs in Follicular Lymphoma?
Histone methylation in MLL2
151
What epigentic change occurs in Diffuse Large B-Cell Lymphoma?
CREBBP/EP300 Histone methylation
152
What epigentic change occurs in ovarian clear cell carcinoma and endometrial carcinoma?
Nucleosome position/Chromatin remodeling of ARID1A
153
What epigenic change occurs in malignant rhabdoid tumour?
Nucleosome position/Chromatin remodeling of SNF5
154
What epigenic change occurs in renal cell carcinoma?
Nucleosome position/chromatin remodeling of PBRM1
155
What epigenic change occurs in Paediatric gliomas?
Histone H3 variants (nucleosome component) in H3F3A, HIST1H3B
156
Which mutations are seen in Thyroid Adenoma?
Functional Adenomas
Gain of Function in TSHR, GNAS and EZH1
Non-Functional Adenomas
Gain of Function in RAS and PPARy
157
Which mutations are normally seen in Papillary Thyroid Carcinomas?
RET translocation; most commonly with PTC1 and PTC 2
NTRK1 translocation - NTRK1 fusion protein
BRAFV600E - Valine to Glutamine - Tall cell variant
158
What mutations are associated with Follicular Neoplasms?
RAS point mutation
Unique (2;3)(q13;p25) translocation PAX8 and PPARG
PIK3CA gain of function
PTEN loss of function
159
What mutations are seen in poorly differentiated and anaplastic thyroid carcinomas?
Similar to those of well-differentiated papillary and follicular carcinoma.
+ Mutations in three genes: p53, Beta Catenin (CTNNB1) and TERT (Telomerase)
160
Pathology
flashcards
Decks in class (5)
# Cards
