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CGD > Examples of cancer > Flashcards

Examples of cancer Flashcards

1
Q

What tumours are common in paediatric cancer?

A

Leukaemia and CNS tumours
Leukaemia is common in young children whilst germ cell tumours are common in young children and again in teenagers and young adults - a range of ages

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2
Q

What is Ewings tumour?

A

A tumour of the bone (or soft tissue ¼). Is rare, and found in teenagers/young adults. Is clinically diverse in the site of origin. Is aggressive (rapidly increased swelling and pain), the bone expands with cystic spaces within it.

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3
Q

What does Ewings tumours show?

A

Unlike most solid tumours (but like haematological malignancies) shows that chromosomal translocations are important in the initiation of paediatric cancer

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4
Q

What is the histological appearance of Ewings tumour?

A

Sheets of homogenous small round blue cells, undifferentiated with normal staining - is common in paediatric cancers. Means is hard to diagnose - look for differentiation in the neuroectoderm (indicated by expression of CD99)

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5
Q

What is the cell of origin of Ewings tumour?

A

Is controversial. Could be bone progenitors or mesenchymal stem cells

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6
Q

What is the genetic cause of Ewings tumour?

A

Fusion genes from chromosomal translocations, resulting in expression of aberrant transcription factors that drive tumour formation. These are essential for cell survival and progression so are good therapeutic targets

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7
Q

What is the classical translocation found in Ewings tumour?

A

Reciprocal translocation between 11 and 22. Get fusion of 5’ EWS (22) and C terminus of FLI1 (11) from derivative 22 chromosome. FLI1 binds DNA and N terminus of EWS is an RNA binding protein of the TET family (adaptors between RNA transcription and splicing, critical processing molecule, normally regulated). In the fusion gene, FLI1 directs EWS to parts of the genome where it isn’t regulated. FLI1 is part of ETS family (includes ERG) and has a role in cell proliferation and development

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8
Q

What other translocations are found in Ewings tumour?

A

Other members of the ETS family can substitute for FLI1 e.g. EWS:ERG and EWS:ETV-1

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9
Q

How can Ewings tumour translocation be detected?

A

With FISH to 5’ and 3’ end of EWS (would expect 1 colocalised and one split)
Primers that only give a product if Ewings tumour is present

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10
Q

How does the fusion protein in Ewings tumour lead to an aggressive malignant tumour?

A

EWS has a transactivation domain which is a binding site for other transcriptional activators e.g. RNA pol II, CREB, RNA helicase. These act at targets directed by FLI1. Get activation of cancer associated pathways (WNT, EGF etc) due to aberrant transcription across the genome. Also get epigenetic modifiers such as JARID2 (targets PRC2 to DNA) and EZH2 and ncRNAs produced by the fusion protein which inhibit tumour suppressors.

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11
Q

How can Ewings tumour be treated?

A

Radiotherapy
Chemotherapy
Targeted therapy prospect is getting closer - hard to target the fusion gene, attempts with antisense cDNA and siena to repress transcription. Looking at targeting protein-protein interactions with EWS to RNA helices A. HDAC inhibitors/inhibitors of DNA methylation to switch on genes that have been repressed by the fusion protein

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12
Q

What is Wilms tumour?

A

A tumour of the kidney (normally just 1, can be both) due to aberrant development of normal tissue. Affects 1/10,000 births and is found in young children. Is a soft, homogenous fleshy tumour with a necrotic centre which presents as an abdominal mass and pain due to haemorrhage of the tumour/hypertension.

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13
Q

What are the risk factors for Wilms tumour?

A

WAGR - wilms, aniridia, genitourinary abnormalities, mental retardation
Denys-Drash - gonadal and renal abnormalities
Beckwith-Wiedemann - errors in imprinting

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14
Q

What is the histopathology of Wilms tumour?

A

Triphasic appearance - epithelial, stratal, primitive cells. Epithelial structure are tubules, stromal/mesenchymal structure can develop into things that aren’t kidney and are elongated fibroblasts, primitive cells dominate and are small round blue cells (are often the only visible feature making diagnosis difficult)
Tumour is often associated with nephrogenic rests (embryonic structures that remain in post-natal kidneys and thought to be precursor structures)

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15
Q

What are the genetic mutations in Wilms tumour?

A

Most (⅔) don’t have a common mutation
Of those that do, see mutations in WT1 (20%), WTX (20%) (a negative regulator of the Wnt pathway - tumour suppressor), beta catenin (CTNNB1) (15%) and occasionally p53 (5%)

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16
Q

What are the molecular abnormalities in Wilms tumour?

A

70% have loss of heterozygosity or loss of imprinting at 11p15 (near WT1) where the IGF2-H19 gene cluster is found. IGF2 (growth factor) is normally imprinted on the maternal chromosome, whilst H19 (lncRNA) is imprinted on the paternal chromosome. Same alterations found in Beckwidth-Wiedermann syndrome

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17
Q

What is the structure of WT1?

A

10 exon gene with a protein interaction domain at the N terminus and 4 zinc fingers at the C terminus. Alternative splicing leads to 4 isoforms - can not have exon 5 or can have an insertion of 3 amino acids (KTS) in-between exon 9 and 10

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18
Q

What is the function of WT1?

A

Is known to bind nucleic acids, dependent on the presence of the KTS sequence. If KTS is present, it binds DNA and is involved in transcriptional regulation. If it is absent, it binds RNA (including IGF2 transcripts) and controls processing (e.g. splicing and degradation)
Allows cells to switch between epithelial and mesenchymal cells.

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19
Q

What is the function of WT1 in nephrogenesis?

A

Can switch cells between epithelial (involved in formation of coronary blood vessels from epicardium) to mesenchymal (in formation of nephrons, involves control of Wnt4 expression). WT1 forms the intermediate mesoderm in the embryo

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20
Q

Describe the process of neurogenesis?

A

From the intermediate mesoderm in the embryo. Interactions between the ureteric bud (containing epithelial structures) and the mesenchymal cells around it. The epithelial structures cause the mesenchyme to be dense which in turn causes branching and proliferation of the epithelium.

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21
Q

How does Wilms tumour arise?

A

Thought to be from metanephric mesenchyme - instead of forming normal kidney, get formation of a disorganised tumour - histology resembles derivatives of metanephric mesenchyme but are disorganised.

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22
Q

Is WT1 a tumour suppressor or an oncogene?

A

Both! In Wilms tumour acts as a tumour suppressor - 2 hit hypothesis (either sporadic or due to inherited deletion in WAGR). Mutations are all across the gene and are nonsense/frame shifts that truncate the protein
In adult tumours e.g. some acute myeloid leukaemia get missense mutations (oncogenic) or over expression. In these cases it is associated with the epithelial to mesenchymal transition pathway.

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23
Q

What is the result of the loss of WT1?

A

Depends on the different stage of kidney development. In general, loss or over expression results in disturbance of normal differentiation. Consequence is dependent on cell type, differentiation state, genetic abnormalities and microenvironment.
If it is lost in mature cells (lineage committed) get prevention of maturation - WT1 is driving differentiation.
If it is lost in early cells, get apoptosis and no formation of the kidney - is pro survival.

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24
Q

What is neuroblastoma?

A

A tumour often in the adrenal gland. Is the most common extra cranial solid tumour (is pretty common). Is an aggressive c cancer and amounts to 15% of all childhood cancer deaths (7% of childhood cancers). Is found in under 4s as a mass in the adrenal gland hear the kidney.

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25
Q

What does Wilms tumour show?

A

That tumorigenesis can occur through aberrant development

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26
Q

What does neuroblastoma show?

A

How genetics can determine clinical management

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27
Q

What are the classical features of neuroblastoma?

A

A supra-renal mass in under 4s. See calcification and necrosis on a CT scan and elevated levels of VMA (A metabolite of catecholamines) in the urine. Is a fleshy red tumour with regions of necrosis and flecks of calcificaiton

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28
Q

Describe the clinical behaviour of neuroblastoma

A

Is very variable - genetics are used to help determine. Can spontaneously regress in infants or mature in older children and need no treatment OR be very aggressive and response to no treatment.

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29
Q

How can the prognosis of neuroblastoma be predicted?

A

Age - 18 months + is high risk
Histology - mitosis-karryohexis index (combination of proliferation/apoptosis)
Stage - spread
DNA index - policy
MYCN copy number (linked to mitosis-karryohexis index)
Chromosomal aberrations

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30
Q

What is the cell of origin of neuroblastoma?

A

From the neural crest cells (which originate from the neural fold near the neural tube) - migrates around the body to form adrenal gland and cells of ganglia of CNS. Differentiation is mimicked in the cancer - it resembles development of fatal adrenal gland but is disorganised

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31
Q

What is the histology of neuroblastoma?

A

Have undifferentiated, poorly differentiated and differentiating tumours. Undifferentiated tumours have the worst outcome - show no maturation of cells, all are small round blue cells. Best outcome is diffenretating - at least 5% of tumours show differentiation to mature products (ganglion cells) which are big cells with lots of cytoplasm and a large nucleolus

32
Q

How does genetic heterogeneity drive clinical outcome in neuroblastoma?

A

One of the only tumours where cytogenetics is used for prognosis and to direct treatment outside of a clinical trial. Look at copy number gains on locus of short arm of chromosome 2 (region of MYCN and ALK). MYCN amplifications (in 25% of cases) is a severe adverse prognostic factor. In high risk cases without MYCN amplification, often have over expression of MYCN, CMYC and genes in the MYC pathway.

33
Q

What is the normal expression of MYCN?

A

In adult - MYCN is low or absent (CMYC expressed in proliferating tissues)
In embryo - MYCN is high in neuroepithelium and low elsewhere (CMYC is expressed in many tissues but is low/absent in the neuroepithelium)

34
Q

How can MYCN be amplified?

A

As double minutes - ORI in the middle with a copy of the gene on each side. Can replicate itself and harbour copies
Chromosome gains many repeats or translocates to a different chromosome - get a homogenous stain across that region of the chromosome

35
Q

What is the structure of MYCN?

A

Has 3 exons but only 2 and 3 are translated. An N terminal transactivation domain and a C terminal basic domain (helix loop helix and a leucine zipper). Dimerises with MAX (same as MYCN but without transactivation domain). This allows MYCN to bind DNA at an E box consensus sequence.

36
Q

What do MAX-MYCN dimers do?

A

Activate transcription at MYCN genes (containing an E box in the DNA) by recruiting things to the MYCN transactivation domain to activate genes involved in proliferation, metabolism, apoptosis, differentiation.
Can also sequester other transcription factors and recruit HDACs. DNA methylasese and suppress genes that interfere with proliferation.

37
Q

What is the result of over expression of MYCN and CMYC?

A

Get lots of proliferation - shortening of G1 and reduced attachment to the ECM
Also get more apoptosis - cells are sensitised. However, not all cells die, suggesting that apoptosis isn’t fully functional in neuroblastoma - a high mitotic-karryohexis ratio suggests MYCN amplification

38
Q

What are the pro-proliferative targets of MYCN?

A

SKP2 (component of an E3 ubiquitin ligase that targets CDKis)
E2F (G1-S transition)
MDM2 (negative regulator of p53)
ID2 (inhibitor of Rb)
MCM7 (pre replication complex)
Inhibits DKK3 (a secreted antagonist of WNT)
And others

39
Q

What are the pro-apoptotic targets of MYCN?

A

p53

p14 (stabilises and activates p53 response following oncogenic activation)

40
Q

What are the anti-differneation targets of MYCN?

A 
PAX3 (promotes proliferation and inhibits differentiation of neuronal progenitors)
CDC42 is inhibited (involved in cytoskeletal remodelling in neuronal differentiation)
Nm23 genes (negative regulators of CDC42)
41
Q

How is MYCN regulated?

A

By miRNAs - miR-34a. Is often deleted in acne and is an example of how can have adverse MYCN effects with no amplification. Returning miR-34a to cells can switch of MYCN effects and restore normality

42
Q

What are the miRNA targets of MYCN?

A

Act on proliferation, inhibit apoptosis and differentiation. If these are deregulated get loads of deregulation

43
Q

What are the genetic events in neuroblastoma apart from MYCN?

A

Expression of neurotrophin receptors
ALK receptor is expressed/mutated to become an oncogene
Large chromosomal changes

44
Q

How does expression of neurotrophin receptors lead to neuroblastoma?

A

They bind extra cellular molecules. E.g. TrkA binds a growth factor NGF, resulting in autophosphorylation and activation of MAPK and AKT - survival effects. TrkA expression negatively correlates with MYCN amplification whilst TrkB positively correlates

45
Q

How does mutation/exprerssion of the ALK receptor lead to neuroblastoma?

A

Is close to MYCN and is an RTK which phosphorylates down stream kinases upon dimerisation and phosphorylation in the kinase domain and is required for neural development. Is either amplified or mutated in the kinase domain or over expressed. Results in constituent signalling

46
Q

What are the common mutations in the ALK receptor

A

R127Q
F1174L - is associated with poor response to treatment and often coexists with MYCN amplification (is likely to be a selective advantage). Potentiates the effect of MYCN

47
Q

How can expression of ALK be treated?

A

Cells are addicted - so if take away they die. Is therefore a good target, especially as expression is normally restricted to the brain after development. There are small molecule inhibitors available (as well as ALK directed immunotherapy and ALK siRNA nanoparticles). Can use in conjunction with therapies that target the downstream effects.

48
Q

What common large chromosomal changes are seen in neuroblastoma?

A

Loss on chromosome 1 (contains a putative TSG and miRNA for MYCN), loss on chromosome 11 (inverse correlation with MYCN amplification and contains a putative TSG), gain on chromosome 17 (unbalanced translocation with 1 or 11, contains putative oncogenes). In the absence of MYCN amplifications, presence of these changes are a poor prognosis indicator

49
Q

How can the DNA index of neuroblastoma guide prognosis?

A

If have 2n or 4n tend to have aggressive tumour (though if no MYCN or segmental aberrations will do better)
If have 3n/near triploid will do better (unless have MYCN and segmental aberrations)

50
Q

What are the prognosis indicators used in neuroblastoma?

A

MYCN amplifications - bad, especially if have these in structural aberrations
Segmental aberrations - not good if have without MYCN (if don’t have do well)
TrkA is good, TrkB is bad.

51
Q

What are the risk factors of Barrett’s Oesophagus?

A

Obesity
50-60 years old
Male

52
Q

What is the normal histology the oesophagus?

A

Inner mucosa made of 3 layers (epithelium, lamina propria, muscle mucosae), then the sub mucosa then the muscular propria. At the gastro-oesophageal junction have a change in histology from epithelial to glandular.

53
Q

What is GERD?

A

Gastroesophageal reflux disease. Have mucosal damage caused by reflux of gastric contents into the oesophagus (or beyond - oral cavity including larynx or lung). Can leat to erosive reflux disease - oesophagitis

54
Q

How can Barrett’s oesophagus be detected?

A

Endoscopy - is salmon pink instead of white. Histology is metaplasia - squamous to columnar

55
Q

How does Barrett’s oesophagus develop into cancer?

A

Is a pre-malignant condition but risk of cancer is low - 0.3%
Cancer developed through a progression of low to high dysplasia - once have dysplasia risk of cancer is high

56
Q

What are the types of oesophageal cancer?

A

Squamous carcinoma - in eastern countries from alcohol, smoking, hot food and beverages
Adenocarcinoma - from Barrett’s oesophagus, western countries, related to GERD and obesity

57
Q

Describe the outcome of adenocarcinoma

A

Has a high incidence which is growing, however 5yr survival rate is 13% (30% if can offer curative treatment). Presents at a late stage so screening and surveillance is challenging.

58
Q

Why do we study Barrett’s oesophagus?

A

Adenocarcinoma develops from it - if we can study Barrett’s, might do better at predicting adenocarcinoma, allowing early treatment and improved survival rates

59
Q

What is the genetic difference between Barrett’s oesophagus and adenocarcinoma?

A

Used next generation sequencing. When looking at point mutations there were no differences - only recurrent mutation was p53. Went on to look at copy number - big differences. Found rearrangements of the genome, losses and gains. Also found that Aneuploidy is an indicator of progression of Barrett’s oesophagus - can do flow cytometry with DAPI to find out how much DNA is present

60
Q

What large scale genome events occur in adenocarcinoma progression?

A

Chromothripsis
Breakage fusion bridges cycles
Whole genome doubling
These can accelerate the progression of Barrett’s oesophagus to invasive adenocarcinoma (otherwise get progression in a step wise manner)

61
Q

What is Chromothripsis?

A

A micronucleus is formed (a small nucleus in the cytoplasm containing 1 chromosome) - may be destroyed in the cytosol and induce the inflammatory response
If not, is replicated slowly and incompletely as unlikely to have all the machinery
Results in lag as chromosomes condense and chromosome shatters. Pieces rejoin the nucleus (only bits as have incomplete replication) and gets pieced together and incorporated into the nucleus

62
Q

What are breakage fusion bridges cycles?

A

Telomere get lost so the end of chromosomes become sticky
During replication, chromosomes join at the end
Get an anaphase bridge
When separate, chromosomes could break at any point
Certain points of breakages will result in 2 oncogenes on one chromosome and none on the other
Cycle repeats as have no telomere

63
Q

What is the advantage to cancer of whole genome doubling events?

A

Rapid evolution

Multiple redundant drivers are acquired together - can overcome senescence and growth inhibitors

64
Q

What are the mutational signatures of oesophageal cancer?

A 
APOBEC-mutation (DNA repair)
BRCA1/2
Acing
Stomach-like
Acid reflux
Found by looking at point mutations and the possible c causes (e.g. C>A is from smoking)
65
Q

How can patients with oesophageal cancer be classified?

A 
By looking at the overall mutational burden (passenger mutations)
Mutagenic (T>G dominant). Have the highest mutational load and neoantigen load. Treat with CHK/WEE1 inhibition and immunotherapy (as more neoantigens so more CD8 tumour rinfaltrate)
C>A/T: ageing as a factor, fewer large scale genomic events. Treat with chemotherapy and targeted ERBB2/MET inhibition
DDR impaired (DNA damage impaired, defects in homologous recombination and chromosome segregation pathways) Treat with DNA damaging agents and PARP inhibitors and proton irradiation with PARP inhibitors
66
Q

What is the lymphoma that develops from B cell precursors?

A

B-lymphoblastic leukaemia

67
Q

What is the lymphoma that develops from mature B cells

A

Many. Includes chronic lymphocytic leukaemia/small lymphocytic lymphoma, follicular lymphoma, burkitt lymphoma, mantle cell lymphoma, plasma cell myeloma, defuse large B cel lymphoma. Many are associated with specific translocations/mutations

68
Q

What is the lymphoma that develops from T cell precursors?

A

T lymphoblastic leukaemia

69
Q

What is the lymphoma that develops from mature T and NK cells?

A

Many. Includes anaplastic large cell lymphoma, enteropathy associated T cell lymphoma, angioimmunoblastic T cell lymphoma. Many are associated with specific translocations/mutations

70
Q

What are the types of hodgkin’s lymphoma?

A

Classical Hodgkin’s lymphoma (4 subtypes)

Nodular lymphocyte predominant Hodgkin lymphoma

71
Q

Where do B cell lymphomas originate from?

A

B cells develop from immature B cells in the bone marrow (B-lymphoblast) into the mantle zone (mantle cell lymphoma) through to the germinal centre (follicular lymphoma, burkitt lymphoma) out to marginal zone (marginal zone B cell lymphoma and plasma cell myeloma)

72
Q

How are oncogenes activated by chromosomal translocations?

A

Puts an oncogene under the transcriptional control of another gene e.g. same promoter but a different enhancer. Leads to aberrant and constitutive oncogene expression
Gene fusion of an oncogene to another protein (could be by translocation or gene inversion)

73
Q

What is the chromosomal translocation associated with Follicular lymphoma?

A

t(14;18)(q32;q21) - IGH-BCL2. Get BCL2 being expressed by IGH promoter. BCL2 is an apoptosis inhibitor, so increases cell survival

74
Q

What is the translocation associated with MALT lymphoma?

A

t(11;13)(q21;q21). API2-MALT1. Get a fusion gene which results in constitutive NFkB activation. Get cell survival and proliferation

75
Q

What are the general features of chromosomal translocations in lymphomas?

A

Often the primary genetic event, occurring during IGH VDJ recombination or class switch recombination
Often involve IG locus causing deregulated oncogene expression
Some result in novel oncogenes due to fusion
Get specific translocations with distinctive lymphoma subtypes
Different translocations in the same lymphoma may activate the same pathway
Translocation alone is insufficient to cause lymphoma

76
Q

What are the molecular mechanisms that cause lymphoma?

A 
Immunological stimulation (e.g. antigen receptor, other immune receptors)
Genetic abnormalities (chromosome translocation, somatic mutations, genomic copy number changes)

CGD (11 decks)

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