Neoplasia Flashcards
1
Q
In tubulovillous adneoma, cervical intraepithelial neoplasia, solar keratosis - what is the pathological process that has occured?
A
It is dysplasia which is a diseased change in the cells. Opposed to metaplasia (such as in Barrett’s) which is a change to the shape and arrangement of the cells, or hyperplasia which is overproduction of cells with maintained structure.
2
Q
What does carcinoma refer to?
A
Malignancies that originate from epithelial tissues.
3
Q
What does sarcoma refer to?
A
Malignancies that orginate from connective tissues, muscles, bones and other non-epithelial tissues.
4
Q
What does leyimyoma refer to?
A
Malignancy originating from smooth muscle
5
Q
What is the technical name for uterine fibroid?
A
Uterine leiyomyoma
6
Q
What IHC staining is likely to be absent in patients with lynch syndrome?
A
MLH1 and MSH2 from a gut biopsy.
Interestingly, if these and other mutations (e.g. PMS2) was seen from a skin lesion it would be called Muir-Torre synsdrome.
7
Q
Other than breast cancer, what do BRCA1 mutations increase the risk of?
A
Ovarian cancer, fallopian tube cancer, primary peritoneal cancer, pancreatic cancer and prostate cancer.
8
Q
Other than breast cancer, what do BRCA2 mutations increased the risk of?
A
Ovarian cancer
Prostate cancer
Pancreatic cancer
Melanoma
9
Q
What virus is associated with Kaposi sarcoma?
A
HHV8
10
Q
What strains of HPV are most commonly associated with oropharyngeal and cervical carcinomas?
A
16 and 18
11
Q
What cancer is associated with EBV?
A
Burkitt lymphoma
Nasopharyngeal carcinoma
Hodgkin’s disease
Other B-cell lymphomas
12
Q
HBV and C are associated with what cancer
A
HCC
13
Q
HLTV-1 is associated with what cancers?
A
Lueukaemia and lymhoma
14
Q
What does ‘stary sky’ correlate to?
A
Burkitt lymphoma
15
Q
What is coilocytosis?
A
The empty looking cells of HPV infection
16
Q
What industrial exposure leads to baldder ca?
A
Analine dyes
17
Q
Arsenic predisposes to what cancer?
A
Lung, skin cancer
18
Q
Other than mesothelioma, what cancers does asbestosis increased the risk of?
A
Many, but lung, larynx, oropharyngeal stand out.
19
Q
What is the gene usually assocaited with Li-Fraumeni syndrome?
A
TP53
20
Q
How is Li-Fraumeni syndrome inherited?
A
Autosomal dominant
21
Q
Familial adenomatous polyposis is associated with a mutation in what gene?
A
APC
22
Q
What is the most relevant factor for grading melanoma?
A
Breslow thickness
23
Q
Sertoli-Leidig tumours of the testicles produce what paraneoplastic hormone?
A
Oestrogen - so men develop gynaecomastia.
24
Q
Paraneoplastic cushiing’s is caused most commonly by what?
A
Lung Ca
25
What cancer classically causes osteoblastic sclerotic bone malignancies?
Prostate cancer.
26
What are the vasoactive substances that are produced by carcinoid tumours that cause sympoms?
Kallikrin and serotonin
27
What Cancers commonly produce both CA125?
Breast, pancreatic, ovarian, lung
28
What cancers commonly produce CEA?
Colon, stomach, breast, pancreatic, lung and ovarian.
29
What cancers commonly produce AFP?
Liver
Testicular
30
What cancers commonly produce PSA?
Prostate
31
What cancers typically produce beta-HCG?
Ovarian, testicular, choriocarcinoma
32
What cancers typically produce Ca19.9?
Pancreatic cancer, cholangeocarcinoma, stomach ca, HCC, CRC
33
What is desmoplasia?
It's when the tumour causes extensive formation of collagenous stroma.
34
What is scirrhous tissue?
Stoney hard tissue formed around a tumour - a form of desmoplasia.
35
What is a pleomorphic adenoma?
A tumour of glandular origin that is capable of differentiting into multiple cell lines.
36
What is a hydatidofrm mole to a choriocarcinoma?
The benign form of the other. Placental neoplasms
37
What is anaplasia?
Loss of cell differentiation
38
What does the word pleomorphism mean?
Different shape and size. If a biopsy is reported to have pleomorphic appearance, it means the cells shape and size are all different.
39
Why do benign tumour capsules of ECM form?
Pressure from the mass causing hypoxia. Happens in most benign tumours, except for haemangiomas that form in penetrating branches.
40
Define a sentinel lymph node?
The first lymph node to receive lymphatic drainage from an area with a primary tumour.
41
Arsenic exposures is associated with what cancers and professions?
Lung and skin carcinoma. Metal smelting, herbicide and fungicide use, animal dips.
42
Asbestos exposure is associated wit what cancers?
Lung carcinoma
Oesophageal carcinoma
Gastric carcinoma
Colon carcinoma
Mesothelioma
43
Benzene exposure is a risk facotr for what cancers, and where is it found?
Acute myeloid leukaemia
Light oil, printing, paint, rubber, dry cleaning, adhesives and coatings, detergents
44
What cancers does Beryllium exposure predispose to? Where is it found?
Lung carincoma
Missile fuel and space vehicles, hardener fo metal alloys (esp aeorspace), nuclear reactors
45
Cadmium exposure predisposes to what type of cancer? Where is it found?
Prostate cancer.
Used in yellow pigments, is in metal platings and coatings.
46
What cancer does cadmium exposure increase the risk of? Where is it found?
Lung cancer
Metal alloy component, paints, pigments, preservatives.
47
What cancer does nickel exposure increase the risk of? Where is it found?
Lung and oropharyngeal cancer
Nickel plating, alloy component, ceramics, batteries, by product of stainless steel arc welding.
48
What cancers does Radon exposure classically pre-dispose to? How is it encountered?
Lung carcinoma
Quaries and mining
49
Vinyl chloride predisposes to what cancer classically? Where is it encountered?
Hepatic angiosarcoma
Refrigerant, adhesive for plastics, aerosol propellants in pressurised containers.
50
What cancer does liver fluke infection pre-dispose to?
Cholangiocarcinoma
51
What cancer does schistosomiasis increase the risk of?
It causes chronic cystitis, so baldder carcinoma risk is increased.
52
What are the 4 different gene types that can be mutated to contribute to cancer cell formation?
Tumour suppressor gene
Proto-oncogene
Genes that regulate cell death
DNA repair genes
53
What is the natural growth factor for the EGFR receptor?
TGF-alpha
54
What protooncogene family is common to Lung adenoca and breast ca?
EGFR - referred as this in lung Ca, referred to as HER2 in breast Ca.
55
After tyrosine kinase receptors activate RAS, what are the two arms of activation that follow?
The MAPK and PI3K/AKT pathways
56
What family of genes is the most commonly mutated oncogene found in cancers?
RAS
57
What are the three families of RAS genes?
HRAS, KRAS and NRAS
58
Which cancer almost always has RAS mutations?
Pancreatic adenocarcinomas (90% of the time)
59
RAS usually associates with GTP to activate, and has an endogenous GTPase that cleaves GTP to GDP to return the RAS back to it's normal baseline status. GTPase function of RAS is accelerated by what family of proteins?
GAPs (GTPase activating proteins). In this way, deactivation of RAS is a GAP dependent process.
60
What has RAS signalling got to do with neurofibromatosis type 1?
NF1, the defective protein in neurofibromatosis type 1, is a GAP (GTPase activating protein) that acts on RAS GTPase to return it from its GTP active form to its GDP bound inactive form. Defective NF1 (tumour suppressor gene) therefore allows constituitively active RAS.
61
RAS activation leads to MAPK and PI3K pathway activation. Where does BRAF fit into this paradigm?
BRAF is one of the RAF family kinases that are downstream of RAS on its way to activating the MAPK pathway.
62
What is PTEN?
PTEN is a negative regulator of the PI3K, one of the key kinases downstream of the RAS pathway. If PTEN is defective, the PI3K is constituitively activated. PTEN is therefore an important tumour suppressor gene that is mutated in many malignancies.
63
Which cancer is PTEN most commonly mutated in? (PTEN is a tumour suppressor gene that normally regulates the activity of PI3K, and imporant downstream growth promoting kinase in the tyrosine kinase/RAS pathway)
Endometrial cancer
64
AKT is a prolific phosphorylator for the growth promotion - it has more than 150 targets! Including mTOR, which is the major protein syntheis rate controller. What activates AKT?
Tyrosin kinase -> RAS -> PI3K -> AKT
65
What does ABL (involved in chronic myeloid leukaemia when part of the BCR:ABL t9:22 translocation) encode?
ABL encodes a non-receptor tyrosine kinase - the BCR promotor on the front causes a constantly active version of it.
66
BCR:ABL (philadelphia) CML is a common translocation related malignancy. What is the t(8:14) associated with?
Burkitt lymphoma.
67
The Burkitt lymphoma t(8:14) apposes what genes to create an oncogene?
Immunglobulin gene and the MYC gene, leading to constituitviely active MYC - downstream from the tyrosine kinase/RAS/RAF/MAPK --> MYC pathway.
68
Is JAK2 a receptor or non-receptor tyrosine kinase?
Non-receptor
69
What do janus kinases (JAK) do?
They allow tyrosine kinase activity to cytokine receptors that don't have access to it normally by associating with the intracellular domains of these receptors.
70
What is meant by the JAK/STAT pathway?
JAKs bind to cytokine receptors intracellularly, then recruit STATs, which once phosphorylated enter the nucleus and act as a trascription factor for target genes related to the cytokine receptor that was activated.
71
Which JAK is only expressed in the bone marrow, lymphatic system, endothelial cells and vascular smooth muscle cells?
JAK3. The other members of the family (JAK1/2/TYK2) are expressed almost everywhere.
72
Which JAK is critical to erythropoesis as it transmits the intracellular signal from the EPO receptor to lead to red cell proliferation?
JAK2
73
Which JAK is often implicated in hematopoetic malignancies as an oncogene?
JAK2 - responsible for downstream activation in response haematopoetic growth signal. Leads to cancer when constituitively active.
74
What tdo the MUC, MUB, JUN, FOS and REL genes all have in common?
They are all genes that encode transciption factors that when constituitively activated, are oncogenes.
75
MYC is a transcription factor that is often mutated in malignancies. It upregulates the expression of many malignancy related genes. How is MYC activated in the physiologically well patient?
It is downstream of the tyrosine kinase -> RAS -> RAF -> MAPK pathway.
76
MYC activation, seen in many cancers in an uncontrolled way, directly activates the Warburg effecct. What is this?
Aerobic glycolysis. Cancer's, and other rapidly replicating cells do this so they gain access to the intermediates of glycolysis needed for protein building.
77
MYC activation, seen in many cancers, increase the production fo cyclin D. What does this do?
Drives the cell cycle forward in combination with CDKs.
78
What is common about all cancers that have MYC mutations?
They are fast growing - MYC is seen as the master transcription regulator of cell growth.
79
MYC is upregulated as the result of Tyrosine kinase receptor -> RAS -> RAF -> MAPK pathway. What other pathways lead to MYC upregulation?
NOtch signaling, Wnt signalling, Hedgehog signalling.
80
Which cylcin and CDK is the G1/S checkpoint regulated by?
Cylcin D and CDK4 or CDK6
81
Which cyclin and CDK are often mutated in cancers?
Cyclin D and CDK4 or CDK6 leading to increased likelihood of progression throught the first (G1/S) checkpoint
82
Gain of function mutations in cyclins and CDKs can lead to malignancy. Which CDK inhibitors are commonly subject to loss of function mutations that allow the cell cycle to freely progress?
RB and TP53, but also
p16 (aka CDKN2A) - germline mutation in a large number of melanoma patients, and a somatic mutation in many cancers (75% of pancreatic carcinomas, 40% to 70% of glioblastomas, 50% of oesophageal cancers, 20-70% of acute lymphoblastic leukaemia, and 20% of non-cmall cell lung carcinomas, 20-70& of all ALL, and 20% of NSCLC soft tissue sarcomas and bladder TCC).
83
Do patients with familial retinoblastoma have homozygous mutations in their RB genes at birth? (germline)
No they are heterozygotes. Retinoblastoma develops with the normal allele mutates.
84
What is the function of normal adenoomatous polyposis coli (APC) protein?
Suppressing WNT signalling.
85
What condition is associated with mutations in the APC protein?
Familial adenomatous polyposis (FAP). Increased risk of colon, pancreas, stomach carcinoma, as well as melanoma.
86
What does the neurofibromin-1 protein normally inhibit?
It is a GAP (GTPase activating protein) that usually acts on the GTPase associated with RAS. This causes the GTPase to cleave GTP to GDP and RAS inactivation. When mutated it leads to constituitively active RAS pathway.
87
Which type of neurofibromatosis is associated with meningioma's and scwhannomas?
Neurofibromatosis 2.
88
What gene is mutated in NF2?
Merlin
89
What is the thing about retinoblastoma gene? Why is it discussed with regard to every cancer?
Hold onto and the releases E2F, required for G1->S cell cycle transition, when phosphorylated by CDK/4/6-D complexes, or CDK2-E complexes. Mutations in RB, CDK or cyclin, or cyclin inhibtiros (namely p16) are involved in EVERY human cancer as the free movement through checkpoint one is needed for ALL tumours.
90
What is the protein that inhibits p53 when the cell is healthy and replicating normal?
The protein is called MDM2 - it ubiquinates p53 for proteosomal degradation. It is expressed in normal healthy cells, but it becomes over expressed in cancer cells that have not got mutated TP53, allowing p53 to be inhibited anyway.
91
What are ATM and ATR? What do they have to do with p53?
These are DNA damage sensing molecules. When DNA damage are detected, they phosphorylate p53 which prevent it being ubiquinated by its regulator MDM2, allowing it to accumulate.
92
What is the role of p14 in regulating cancer cell development?
p14 is prodcued in signficant quantities when there is sustained overactivity of growth pathways, as seen in cancerous cells. p14 (aka ARF) binds to the inhibitor of p53 called MDM2, allowing p53 to accumulate.
93
How does p53 normally stop cancer cells from progressing?
p53 is a transciption facotr than binds DNA and causes the increased transciption of 100s of genes. These mostly participate in cell cycle arrest, apoptosis and catabolism.
94
What are the key pro-apoptotic enzymes that accumulate during p53 initiated apoptosis?
BAX and PUMA - contribute to intrinsic apoptosis.
95
What is the name of the p53 induced DNA repair enzyme?
GADD (growth arrest and DNA damage) 45
96
What CDK inhibitor is produced when p53 accumulates?
p21 - causes cell cycle arrest
97
What is the interaction between Beta-catenin, e-cadherin, WNT and APC?
At rest APC inhibits beta-catenin released from e-cadherin preventing it from travelling the nucleus to act as a proliferation growth factor. When the WNT receptor is activated, downstream signalling prevents APC binding to the beta-catenin, releasing it to influence proliferation. In many cancers, APC is mutated so that it can't inhibit beta-catenin ever, or WNT is mutated so it constantly inhibits APC, or beta-catenin is mutated so it can't be stopped by APC.
98
What proteins are produced when cells are exposed to TGF-beta to reduce cell proliferation?
SMAD protein family. SMAD and TGF-beta receptors are often mutated in cancer.
99
Von Hippel-Lindau syndreom is associated with mutations in the VHL gene. What does the normal gene do and what cancers do these patients usually develop?
VHL encodes VHL ubiquitin ligase which is in the presence of oxygen bound to hypoxia inducible trasncription fator (HIF1alpa) preventing its release and causing its proteosomal destruction. When hypoxia arises, VHL-UL releases HIF1alpha to travel to the nucleaus and activate angiogenesis related genes (e.g. VEGF). Mutations in VHL lead to constituitive HIF1alpha activity and cancer. Most commonly renal cell carcinoma.
100
Which familial benign polyp associated syndrome is associated with mutations in STK11?
Peutz Jeghers syndrome.
101
Genetic studies revealed that isocitrate dehydrogenase (a Krebs cycle enzyme) was mutated in many cancers - what does IDH normally do, and how is it implicated in cancer?
IDH normally, in the Krebs cycle, catalyzes the oxidative dearboxylation of isocitrate to alphaketoglutarate and CO2.
When mutated in cancer, it acquires a new function - instead producing 2-hydroxyglutarate (2-HG). 2-HG then inhibits these TET family proteins that normally control DNA methylation, leading to silencing of tumour suppressor genes and overexpression of oncogenes.
Important, as abnormal IDH is targetable with drugs.
102
Follicular B-cell lymphomas are characterised by t(14;18) translocation that apposes BCL2 to the Ig promotor region. What is the significance of this translocation?
It causes constiutive production of BCL2 - the key anti intrinisc apoptosis agent that stabilised the mitochondrial membrane. In this way, the cells avoid death by instrinsic apoptosis.
103
What to cancer cells about to metastasise produce to get throught he basement membrane?
Type IV collagenase - just one of many matrix metalloproteases made by tumours.
104
E-cadherin is often mutated to allow cancer cells to metastasise. Sometimes, cancers with unmutated E-cadherin metastasise. How do they breakfree of their neighbours?
Epithelial mesenchymal transition. This process mediated by transcription facotrs SNAIL and TWIST transiently silence E-cadherin, and allow the cell to wriggle free.
105
What is anoikis?
Apoptosis triggered by detachement of key integrins from the extracellular matrix. Cancer cells subvert this
106
CD44 is expressed by many cancer cells. What does it do?
It's used normally by lymphoctyes to adhere to the endothelial cells in lymph nodes. This could explain why so many cancers spread and grow in lymph nodes.
107
What are neoantigens?
Protein components from mutated cancer driver and passenger genes expressed on MHCI and targetd by CD8 T cells.
108
Other than neo antigens, what other proteins can act as cancer antigens for the immune system?
Overly expressed antigens (e.g. tyrosinase, expressed by melanoma and by normal malnocytes, but in much higher quantities in melanoma).
Antigens normally only expressed in immunoprivalegded sites (e.g. cancer-testis antigen)
Oncogenic viral genes present in all cancer cells
109
What's it called when dendritic cells show their phagocytosed antigens on MHC class I so CD8 cells can act on them?
Cross presentation
110
What are the types of DNA repair that when dysfunctional lead to an increased risk of cancers?
Mismatched DNA repair (e.g. HNPCC)
Nucleotide excision repair facotrs (xeroderma pigmentosum)
Homologous recombination related protein dysfunction - helicase (Bloom syndrome), multiple (Fanconi syndreome), BRCA1/2 (familial breast cancer)
111
BRCA1 classically, causes an increased risk of breast cancer in men and women, and what other cancers?
Ovarian cancer in women, and prostate cancer in men.
112
What is chromothrypsis?
When a chromosome is shattered and then reassembled in a haphazard way.
113
How can cytochrome-450 pathways influence the carcinogeneis of a substance?
Because indirect carcinogens require metabolising before they are carcinogenic.
114
How do carcinogens primarily cause their damage?
Highly reactive electrophile groups that direcly damage DNA
115
UV radiation causes what problem with DNA?
Pyrimadine dimers.
116
Ionising radiation causes what type of DNA injury most frequently?
Chromosome breakage and translocations. Less frequently, it causes point mutations.
117
Which HTLV-1 genes are implicated in cancer?
Tax and HBX.
118
What cancer are HTLV-1 patients at increased risk of getting?
T-cell leukaemia/lymphoma
119
What are the viral oncoproteins encoded by HPV?
E6 and E7
120
HPV encodes oncogenes E6 and E7. What do they do to cause cancer?
E6 binds p53 and neutralises its function.
E7 binds to Rb and allows free flow through checkpoint 1.
121
What is the primary control mechnism that prevents B cells infected with EBV from becoming cancers?
Functional T cell surveillance. Clear in patients with HIV who develop B cell malignancy related to EBV.
122
HBV and HCV cause chronic inflammation in the liver that drives the development of HCC. There is one viral oncogene that is likely involved too. What is it?
HBx
123
What cancers are H. pylori gastric infections associated with?
Gastric adenocarcinoma and MALTomas
124
Which cancer most typically produces ACTH or ACTH like substances?
Small cell lung cancer
125
Which cancer is most classically associated with SIADH?
Small cell carcinoma. Also intracranial neoplasms though.
126
Which cancers are most typically associated with hypercalcaemia?
Squamous cell carcinomas. Due to production of PTH-related protein, TNF, TGF alpha and IL-1.
127
Which cancers are most typically associated with paraneoplastic hypoglycaemia?
Ovarian carcinoma
Sarcomas
Can produce insulin or insulin-like substances.
128
Which solid organ cancers can cause polycaethemia?
Renal carcinoma most commonly, but also cerebellar hemangioma and HCC, through the production of erythropoeitin
129
What cancers are most likely to cause myaesthenia gravis?
Thymoma and bronchogenic carcinoma.
130
Which cancers are associated with dermatomyositis?
Bronchogenic carcinoma
Breast cancer
131
Which cancers are associated with acanthosis nigracans?
Gastic, lung and uterine carcinoma
132
Which cancers are known to cause clubbing (hypertrophic oestoarthropathy)?
Bronchogenic carcinoma and thymic neoplasms
133
Human chorionic gandotropin is used as tumour marker. For which cancers is it beneficial?
Trophoblastic tumours
Nonseminomatous testicular cancers
134
Tumour marker to cancer matching: calcitonin
Medullary thryoid cancer
135
Tumour marker to cancer matching: alpha-fetoprotein (AFP)
HCC, nonseminomatous testicular tumours
136
Tumour marker to cancer matching: carcinoembryonic antigen (CEA)
Colon, pancreas, lung, stomach and cardiac carcinomas
137
Tumour marker to cancer matching: PSA
prostate cancer
138
What are CA-125/19-9/15-3?
They are mucins and other glycoproteins, noted to be in high concentrations in some cancers.
139
Tumour marker to cancer matching: CA19-9
Colon and pancreatic cancer primarily
140
Tumour marker to cancer matching: CA 125
Ovarian cancer primarily
141
Tumour marker to cancer matching: CA15-3
Breast cancer primarily
142
