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FRCPath > Tumorigenesis and Leukaemias > Flashcards

Tumorigenesis and Leukaemias Flashcards

1
Q

Name the common rearrangement associated with Burkitt Lymphoma

A

t(8;14)(q24;q32) MYC-IGH

(also see t(2;8)(p12;q24) MYC-IGK and t(8;22)(q24;q11) MYC-IGL

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2
Q

Name the common rearrangement associated with Follicular Lymphoma

A

t(14;18)(q32;q21) - IGH-BCL2

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3
Q

Name the common rearrangement associated with Mantle Cell Lymphoma

A

t(11;14)(q13;q32) - IGH-CCND1

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4
Q

Name 2 rearrangements associated with Diffuse Large B Cell Lymphoma

A

t(14;18)(q32;q21) - IGH-BCL2

t(3;14)(q27;q32) - IGH-BCL6

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5
Q

Name 2 rearrangements associated with MALT Lymphoma

A

t(11;18)(q21;q21) - BIRC3-MALT1

t(14;18)(q32;q21) - IGH-MALT1

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6
Q

What is characteristic of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma?

A

Double Hit involving MYC

Commonly BCL2+/MYC+, also BCL6+/MYC+ or BCL2+/BCL6+/MYC

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7
Q

Name 4 rearrangements with a POOR prognosis in ALL

A

t(9;22)(q34;q11) BCR-ABL1
t(4;11)(q21;q23) AFF1-KMT2A
Hypodiploidy
t(17;19)(q22;p13) HLF-TCF3

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8
Q

Name 2 rearrangements with a FAVOURABLE prognosis in ALL

A

t(12;21)(p13;q22) ETV6-RUNX1

High Hyperdiploidy

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9
Q

Name a rearrangement with an INTERMEDIATE prognosis in ALL

A

t(1;19)(q23;p13) PBX1-TCF3

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10
Q

Name the commonest ALL rearrangement associated with:

a) Infant ALL
b) Childhood ALL
c) Adult ALL

A

a) KMT2A rearrangement
b) ETV6-RUNX1
c) BCR-ABL1

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11
Q

Name 3 partner genes for KMT2A in B-Cell ALL

A

t(4;11)(q21;q23) KMT2A-AFF1 (40-50% infant ALL, i7q common secondary abn)
t(9;11)(q22;q23) KMT2A-MLLT3 (10% infant ALL)
t(11;19)(q23;p13.3) KMT2A-MLLT1 (10% infant ALL)

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12
Q

Describe the t(12;21) seen in childhood ALL

A

Fusion protein acts in dominant negative fashion to interfere with normal TF RUNX1
t on its own not enough to cause cancer, often lose functional RUNX1 too or have secondary abns

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13
Q

Name 4 significant prognostic indicators in adult B-Cell ALL

A 
t(9;22)(q34;q11) BCR-ABL1 - POOR
t(4;11)(q21;q23) KMT2A-AFF1 - POOR
Complex karyotype (5 or more abns) - POOR
Ploidy - High hyper - FAVOURABLE
           - hypo - POOR
t(17;19)(q22;p13) TCF3-HLF - POOR
iAMP21 - POOR
ETV6-RUNX1 fusion - GOOD
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14
Q

Where is TCF3? Name two partners in B-Cell ALL

A

19p13.3
t(1;19)(q23;p13) PBX1-TCF3
t(17;19)(q22;p13) HLF-TCF3

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15
Q

Where is KMT2A? What does the gene do?

A

11q23.3 - Histone demethylase
Encodes nuclear protein thought to be positive regulator of gene expression in early embryonic development and haematopoeisis. Over 80 partners described so far.

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16
Q

Describe RUNX1T1-RUNX1 Rearrangement in AML

A

t(8;21)(q22;q22) - 5% AML - FAB Class M2
Associated with Auer rods - seen predom in younger patients
GOOD prognosis with high dose cytarabine in consolidation phase

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17
Q

Describe abnormalities associated with t(8;21) in AML

A

5% have complex translocation
70% have secondary abns, -X, -Y, del(9q)
KRAS/NRAS mutns
KIT mutns

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18
Q

Describe CBFB-MYH11 rearrangement in AML

A

inv(16)(p13.1q22) or t(16;16) - 5-8% AML - FAB Class M4
Myeloid sarcomas may be present at diagnosis/relapse
GOOD prognosis with high dose cytarabine in consolidation phase
+22 as secondary abn improves outcome

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19
Q

Describe abn associated with APML

A

t(15;17)(q24;q21) PML-RARA - GOOD prognosis, very sensitive to ATRA

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20
Q

Describe APML resistant to ATRA

A

Variant RARA translocations
t(11;17)(q23;q21)
t(5;17)(q35;q21)
t(11;17)(q13;q21)

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21
Q

Describe PML-RARA Fusion protein

A

Dominant negative form of RARA - binds to DNA and represses transcription of retinoic acid target genes but doesn’t respond to the transcriptional signal induction of the genes - gene remains repressed. Function of PML disrupted - normally blocks cell growth/proliferation and induces apoptosis

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22
Q

How does ATRA work in APML

A

Ligand for RARA - binds to fusion protein with co-repressor complex, engagement of co-activation complexes by the chemical receptor and subsequent degredation of the fusion protein PML-RARA

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23
Q

What is the most common KMT2A rearrangement in AML?

A

t(9;11)(p22;q23) MLLT3-KMT2A

INTERMEDIATE prognosis, better than AML with other KMT2A rearrangements

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24
Q

What is the prognosis of t(6;9)(p23;q34) in AML

A

Generally POOR

DEK-NUP214

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25
Q

Describe the 3 phases of CML

A

Chronic - 3-4 yrs but can last 10, 40% asymptomatic
Accelerated - Accumulate further mutations, cell proliferation increases, symptoms more severe
Blast crisis - >20% blast cells in blood/BM. Infiltrate other tissues

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26
Q

Describe the BCR-ABL1 fusion protein

A

5’ end of BCR fuses with 3’end of ABL1 - fusion oncogene on der(22) has elevated and disregulated tyrosine kinase activity –> uncontrolled cellular proliferation and inhibition of apoptosis

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27
Q

Describe clinical aspects of CLL

A

Proliferation and accumulation of monomorphic b-lymphocytes in PB, BM, spleen and lymph nodes - prevents haematopoeisis of other normal blood cells –>cytopaenias

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28
Q

Describe the FISH investigations carried out in Liverpool on CLLs and their prognostic significance

A

ATM deletion - 11q23 - POOR prognosis
TP53 deletion - 17p13.1 - POOR prognosis
Trisomy 12 - INTERMEDIATE prognosis
13q14.3 deletion (mono/biallelic) - FAVOURABLE prognosis

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29
Q

20% CLL have IGH rearrangement - give some examples

A 
t(11;14)(q13;q32) IGH-CCND1
t(14;19)(q32;q13) BCL3 locus often with +12
t(2;14)(p13;q32) IGH-BCL11A
t(14;18)(q32;q21) IGH-BCL2
t(8;14)(q24;q32) IGH-MYC
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30
Q

Describe the clinical presentation of Multiple Myeloma

A

Bone disease (lytic bone lesions, hyperCalcaemia, fractures, osteoporosis)
Impaired Renal function - proteinuria
Anaemia
CRAB

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31
Q

What are the two broad categories of MM?

A

Hyperdiploid - 48-75 chrms, more favourable prog (often gains of odd numbered chrms)
Non-hyperdiploid - 75 chrms - generally unfavourable

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32
Q

Name the 5 major IGH rearrangements in MM

A 
4p16.3 FGFR3 - POOR
11q13 - CCND1 - GOOD
16q23 - MAF - POOR
6p21 - CCND3 - GOOD
20q11 - MAFB - POOR (may be very poor)
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33
Q

Give 3 genetic changes associated with disease progression in MM

A

Monosomy/del13q - close associated with t(4;14)
Del17p/TP53 - rare, late event, very poor prognosis
Loss 1p/Gain 1q
Translocations +/- amplifications of MYC - late events in tumour progress

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34
Q

What are the three main checkpoints in cell cycle regulation?

A

1) G1/S (restriction) checkpoint
2) G2/M checkpoint
3) Metaphase/Spindle checkpoint

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35
Q

How does the G1/S (restriction) checkpoint work?

A
  • Cell growth enables CDK-cyclin D formation
  • Phosphorylates Rb protein
  • Relieves inhibition of E2F transcription factor
  • Cyclin E now expressed - binds to CDK2
  • Allows G1-S transition
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36
Q

How does the G2/M checkpoint work?

A
  • CDK1 activated by phosphorylation and dephosphorylation of specific amino acids by cyclin-activating kinases (CAKs) and the wee1 protein
  • Enables CDK1-cyclinB production (aka MPF)
  • Allows G2/M transition
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37
Q

How does the Metaphase/Spindle checkpoint work?

A
  • Chromosomes assemble on metaphase plate
  • Anaphase promoting complex (APC) activated
  • Degrades cyclin B-MPF disassembly
  • Relieves inhibition of ‘separase’ - spindles cut
  • Sister chromatid separation - anapahse entry
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38
Q

What are the heterodimeric protein kinases that regulate cell cycle control made up of?

A

1) Cyclins - No catalytic activity

2) Cyclin dependent Kinases (CDKs) - Inactive without cyclins, catalytic

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39
Q

How does the heterodimeric protein kinases that regulate cell cycle control work?

A

Heterodimer phosphorylates target proteins to orchestrate coordinated entry into next phase of the cell cycle

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40
Q

Describe the expression of CDKs and cyclins

A

CDKs - Constitutively expressed

Cyclins - synthesised at specific stages in response to stimuli

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41
Q

In simple terms - what prevents tumourigenesis?

A

Arrest of cell cycle proliferation where the genome has been compromised

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42
Q

Where do oncogenes generally exert the most influence?

A

Over G1 phase progression

  • During G1 cell responds to extracellular signals moving it towards division or back to G0
  • Cancer cells abandon controls and remain in cell cycle - tend to lose exit pathways too
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43
Q

What does overexpression of Cyclin D1 lead to?

A

Inappropriate activation of CDKs - can be induced by Ras and P13 kinase signalling pathways - force cell through G1 checkpoint

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44
Q

What is the location of TP53 and what does it do (in simple terms)?

A

17p13.1 - encodes p53 - Tumour supressor gene that regulates cell cycle - GUARDIAN OF THE GENOME!

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45
Q

When is TP53 activated?

A

Potent transcription factor activated in response to stressors –> cell cycle arrest/apoptosis/senescence

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46
Q

How is the level of p53 maintained?

A

Kept at low level in double negative feedback loop by MDM2.

p53 –> Induces expression of MDM2 –> promotes degredation of p53

47
Q

Name 3 anti-cancer mechanisms of p53

A

1) Activate DNA repair proteins when damage sustained
2) Arrest growth by holding cell cycle at G1/S in DNA damage
3) Initiate apoptosis if DNA damage too severe

48
Q

What percentage of human cancers possess a mutated form of TP53?

A

50% - MDM2-p53 interaction major target for cancer therapies

49
Q

What percentage of tumours exhibit MDM2 amplification?

A

17% - MDM2-p53 interaction major target for cancer therapies

50
Q

What disease is associated with constitutional mutations of TP53?

A

Li Fraumeni Syndrome

51
Q

Describe Li Fraumeni Syndrome

A

Multiple primary tumours, typically soft tissue carcinomas, osteosarcomas, tumours of breast, brain and adrenal cortex, and leukaemia

52
Q

What is the location of RB1?

A

13q14.2

53
Q

How is RB1 activated and what is its role?

A

Activated by dephosphorylation - binds and inactivates cellular transcription factor E2F1

54
Q

Are you going to pass this exam?

A

HELL YES!!!

55
Q

Describe the role of RB1

A

2-4 hours before cell enters S-Phase pRB is phosphorylated which releases inhibition of E2F1 and allows cells to progress through to S Phase

56
Q

What governs the phosphorylation of RB1?

A

Cascade of cyclins, CDKs and CKIs

57
Q

RB1 gene mutations produce what?

A

Sporadic/inherited retinoblastoma - most often frameshifts/dels –> premature introduction of stop codon

58
Q

What is the location of CDKN2A and what does it encode?

A

9p21.3

Encodes CDKN2A and ARF

59
Q

Where in the cell cycle does pCDKN2A function?

A

Upstream of RB1 protein - inhibiting kinases that phosphorylate pRB

60
Q

Was function does ARF serve in the cell cycle?

A

Mediates G1 arrest by destabilising MDM2

61
Q

What cancer do inherited mutations of CDKN2A cause?

A

Multiple melanoma

62
Q

How does blocking MDM2 expression work as a therapeutic target in cancer?

A

Limits interaction with p53 –> increased levels of p53 which is a tumour suppressor gene

63
Q

What difficulties are encountered inhibiting the MDM2-p53 binding as a therapeutic target in cancer?

A

Targeting protein-protein interactions problematic - simple framework of 3 amnio acid residues used to design therapeutic molecules

64
Q

Name three targets of the MDM2-p53 pathways for cancer therapies

A

1) Blocking MDM2 expression
2) Inhibiting the MDM2-p53 binding
3) Curtailing E3 ubiquiting ligase activity of MDM2

65
Q

Give 4 characteristics of myelodysplastic syndromes

A

1) Clonal expansion of BM myeloid cells with
2) Impaired differentiation
3) Development of peripheral cytopenias
4) Increased risk towards development of AML

66
Q

Why do we see development of peripheral cytopenias in MDS?

A

Ineffective haematopoeisis and dysplasia of one or more myeloid lineages - ineffective blood cell production

67
Q

How does the bone marrow present in MDS?

A

Hypercellular, dysplastic features, may involve multiple lineages +/- blasts

68
Q

Name the 3 myeloid lineages involved in MDS

A

Erythrocytic, granulocytic and megakaryocytic

69
Q

Where is EVI1 and what is its significance in MDS?

A

3q36 - associated with poor survival and high risk of transformation to AML

70
Q

Describe the significance of 5q- in MDS

A

Proximal 5q31.2 assoc with high risk of transformation, distal 5q33.1 - lower risk of transformation, RPS14 (5q33) found to contribute to abnormal erythroid differentiation and apoptosis. Long survival when isolated finding - low risk of transformation

71
Q

What is the prognosis of Monosomy 7 and -7q in MDS

A

POOR

72
Q

What is the only recurrent amplification in MDS? What is its significance?

A

+8 - Intermediate risk factor

73
Q

What is the risk of progression of MDS in 20q-?

A

Low risk of progression

74
Q

What is the risk of progression in MDS of complex karyotypes? (>/= 3 abn’s)

A

High risk of transformation

75
Q

How do myeloproliferative neoplasms distinguish themselves from MDS?

A

Increased number of mature cells in BM - normal proliferation and effective maturation

76
Q

What is constitutively activated in MPN?

A

Tyrosine kinase/similar –> abnormal proliferation

77
Q

What is the role of JAK2?

A

Non-receptor tyrosine kinase involved in JAK/STAT signalling pathway. Acts as signal transducer and activator for the MAPK and P13K pathways to promote transformation and proliferation

78
Q

What at the most common mutations seen in JAK2?

A

V617F - gain of function releasing inhibition - also see mutations in exon 12 and LOH of 9p

79
Q

Name 2 MPNs associated with CALR mutations?

A

ET and MF - generally considered mutually exclusive of JAK2 mutations

80
Q

Name 3 types of Burkitt Lymphoma

A

Sporadic - global and usually presents with abdominal masses,
Endemic - equatorial Africa - predominantly affects jaw and other facial bones,
Immunodeficiency related - AIDS patients

81
Q

Describe the function of the MYC protein

A

Involved in regulation, differentiation and apoptosis

82
Q

How is Burkitt Lymphoma caused?

A

Juxtaposition with regulatory elements of immunoglobulin loci –> constitutive expression of MYC oncogene or mutns in MYC 5’ regulatory regions - AA substituted in exon 2

83
Q

What is the cytogenetic characteristic of Burkitt Lymphoma?

A

Genetically simple - no complex karyotypes

84
Q

Give 3 favourable abnormalities in adult AML

A

t(8;21)(q22;q22) RUNX1T1-RUNX1
inv(16)(p13q22) CBFB-MYH11
t(15;17)(q21;q24) PML-RARA

85
Q

Give 2 examples of therapy related AML

A

5/7 years post irradiation/alkylating agents with abn 5q/abn 7q, 2/3 year post therapy targeting topoisomerase II often associated with translocations associated with KMT2A or RUNX1

86
Q

Name 2 therapies used in MDS

A

Lenalidomide in cases with isolated del(5q) and Azacitidine with chromosome 7 abnormalities

87
Q

What translocation is commonly associated with Ewing’s Sarcoma?

A

t(11;22)(q24;q12) EWS/FLI

88
Q

Name the 3 types of Rhabdomyosarcoma

A

Embryonal (ERMS), Alveolar (ARMS) and Pleomorphic (PRMS)

89
Q

What are the recurrent chrm gains seen in Embryonal Rhabdomyosarcomas?

A

2 8 11 12 13 and 20

90
Q

Name the two chromosome rearrangements associated with Alveolar Rhabdomyosarcomas

A

t(1;13)(p36;q14)(PAX7;FOXO1) (20%)

t(2;13)(q35;q14)(PAX3;FOXO1) (60%)

91
Q

Name 4 alternate Ewing Sarcoma translocations

A

t(21;22)(q22;q12)(EWS;ERG) (5%)
t(7;22)(p22;q12)(EWS;ETV1) (1%)
t(17;22)(q12;q12)(EWS;ETV4) (

92
Q

What are the common losses seen in Oligodendrogliomas?

A

1p/19q

93
Q

Name 4 common genetic findings in Glioblastoma

A

Gain of 7p (EGFR at 7p11.2)
Loss of 9q (CDKN2A at 9q21.3)
Loss of 10q (PTEN at 10q23.31)
Loss of 13q (RB at 13q14)

94
Q

Name 3 common epigenetic findings in Glioblastoma

A

Hypermethylation of MGMT, GATA6 and CASP8

95
Q

What are the treatment options in Glioblastoma with hypermethylated MGMT?

A

Cells more sensitive to alkylating agents - silenced MGMT that repairs DNA damage post alkylating agent damage

96
Q

What are the outcomes of glioblastoma with Hypermethylated:
CASP8
GATA6

A

CASP8 - Worse outcome

GATA6 - Increased survival

97
Q

What can you tell me about Glioblastoma?

A

Most common primary brain tumour, very poor outcomes, median survival months from diagnosis

98
Q

Discuss 5q- in MDS

A

Better prognosis, high rate of response to lenalidomide

99
Q

Discuss -7/7q- in MDS

A

Poor prognosis, more common in therapy related MDS

100
Q

Discuss +8 in MDS

A

Can help predict response to immunosuppression, some evidence as a marker of progression to AML

101
Q

Discuss -20q in MDS

A

Better prognosis

102
Q

Discuss -Y in MDS

A

May be a useful as a marker of clonal haematopoiesis - always consider age-related Y chromosome loss

103
Q

Discuss complex karyotypes (3 or more abnormalities) in MDS

A

Poor, may be very poor, often include abnormal chromosome 17 - TP53

104
Q

Common chromosome considerations in MDS

A

1q, 3q36 (EVI1), 5q-, monosomy 7 and 7q-, +8, KMT2A, del(12p) (loss of ETV6), del(13q), 17p- (TP53), 20q-, -Y, complex karyo

105
Q

Name 3 Myeloproliferative Neoplasms other than CML

A

Polycythemia Vera
Essential Thrombocytopenia
Primary Myelofibrosis

106
Q

What is PCV?

A

Polycythemia Vera

Expansion of the erythrocytes lineage characterised by high peripheral blood red cell count numbers

107
Q

What is Essential Thrombocytopenia?

A

Sustained increase in platelets with associated effects

108
Q

What is PMF?

A

Primary Myelofibrosis

Colonial disorder cause by transformation of early haematopoietic progenitor cells resulting in bone marrow fibrosis

109
Q

What 3 genes are commonly mutated in PCV, ET and PMF?

A

JAK2 - V617F and exon 12
CALR - Frameshift mutns, 5bp insertion (50%) and 52bp del (35%)
MPL - Hotspot at W515 but others exist

110
Q

What rearrangements do the European Myeloma Network recommend FISHing for?

A 
t(4;14) - IGH/FGFR3
t(14;16) - IGH/MAF
17p13 deletions - TP53
1p/1q telomeres
Extended:
t(11;14) - IGH/CCND1
t(14;20) - IGH/MAFB
Ploidy status
Chrm 12 and 13 abn’s
111
Q

Give 3 Personalised Medicine examples

A

Herceptin - HER2 amplification in breast cancer
PARP Inhibitors - BRCA1 and BRCA2
Gefitinib - EGFR Over expressed in lung cancer
Crizotinib - EML4/ALK rearrangement in lung cancer
ATRA - PML/RARA in AML
Cytarabine - RUNX1T1/RUNX1 in AML

112
Q

What are some of the issues associated with convention needle biopsies for tumour profiling?

A

High failure rate (10-30% fail to yield suitable DNA for genomic profiling)
Genetic heterogeneity of tumour missed
Tumours hard to get to in some cases
Invasive procedure

113
Q

What genes would you include on MPN NGS panel

A

JAK2, CALR, MPL, ASXL1, TET2, SRSF2

FRCPath (9 decks)

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