Haem Onc Flashcards
(150 cards)
1
Q
What prognostic scoring system is used in mds
A
Greenberg et al 2012 ipss-r
2
Q
Ipss-r good cytogenetic risk group
A
Normal Del 5q Del 12p Del 20q Double with del 5q
3
Q
Ipss-r very good cytogenetic risk
A
-y
Del 11q
4
Q
Ipss-r intermediate cytogenetic risk group
A
Del 7q \+8 \+19 I(17q) Any other single or double
5
Q
Ipss-r poor cytogenetic risk group
A
Complex - 3 abns
-7
Inv(3) etc
Double inc -7/del 7q
6
Q
Ipss-r very poor cytogenetic risk group
A
Complex >3 abns
7
Q
Main type of Cato abnormality seen in mds
A
Mostly numerical abnormalities, structural rearrangements rare
8
Q
What is 5q- syndrome (mds)
A
Macrocyctic anaemia
Older females
Good survival
Treat with lenalidomide
9
Q
What is minor cytogenetic response in cml
A
> 35% ph cells
10
Q
What is partial cytogenetic response in cml
A
1-35% ph cells
11
Q
What additional cyto abnormalities are seen at blast crisis CML
A
+der 22, i(17q), +8, ,+19
12
Q
What is imatinib
A
Tki, tightly holds tk fusion in inactive state and blocks ATP
13
Q
Imatinib side effects
A
Cramps,nausea, diaroeah. Anaemia
14
Q
How many cml patients show clonal evolution at blast crisis
A
80%
15
Q
What is the outcome of Bcr-abl fusion product
A
Elevated and disregulated TK leads to uncontrolled proliferation and inhibition of apoptosis
16
Q
A response to imatinib would be shown by what kind of monitoring of Mrd response? Ie: when expect mmr etc
A
CHR in 3 months, PCyR 6 months, CCyR 12 months, cMR 18 months
17
Q
Standard dose of imatinib
A
400mg
18
Q
How do you ‘cure’ cml
A
SCT- offered those unresponsive to TKI or in AP or BC
19
Q
Differences between binding properties of nilotinib and dasatinib on Bcr-abl fusion
A
Nilotinib bind inactive protein, dasatinib bind active conformation
20
Q
What is benefit of dasatinib over imatinib and nilotinib
A
Not as stringent therefore can be used for all TKD mutations seen except T315L
21
Q
Side effect of nilotinib
A
Cardiac rhythm, glucose regulation, MDT, MDN,A
22
Q
Side effects dasatinib
A
Pleural effusions in 25%, MDN
23
Q
What are NICE cml treatment recs
A
Imatinib or nilotinib first line, nilotinib fir imatinib resistant patients, dasatinib not rec
24
Q
What is the most resistant TKI mutation
A
T315L
25
What level Mrd can rq Pcr detect down to
5 log reduction
26
What can Mrd monitoring in cMl indicate
Treatment resoonse and compliance
27
When is Abl kinase domain mutation status testing rec?
If milestones for response not reached or acquire secondary resistance
28
Who 2008 has how many classifications of lymphoma
>50
29
Definitely difference between hodgkins and non Hodgkins lymphoma
Reed steinberg cells present in hodgkns
30
2 subtypes of NHL and percentage of each
Low grade/indolent 20-40% and high grade/aggressive 60-70%
31
3 subtypes of burkitts
Sporadic, endemic and immunodeficiency derived
32
IgH gene breakpoint
14q32
33
Rea seen in burkitts lymphoma
(8;14)(q24;q32) in 85%
34
Rea seen in FL
T(14;18)(q32;q21) in 80%. IgH-bcl2
35
What is clinical course of FL
Mostly indolent but 60-80% can progress to DLBCL
36
What is the status of neoplastic cells expressing bcl2
Resistant to apoptosis
37
Which additional cyto abns in FL indicate poor prognosis
6q23-26 abn and 17p abn and 9p21 (p16) abn
38
Rea seen in MCL
T(11;14)(q13;q32). IgH- Ccnd1
39
Result of IgH-ccnd1 fusion in MCL
IgH enhancer stimulate ccnd1 exp -> accelerate passage through G1-> cells divide before mature
40
Secondary abns in MCL with IgH-ccnd1 fusion
Gain/rea of Myc : aggressive. Del13q14, delp53, del ATMgain 3q26
41
Difference between IgH-Myc translocation X seen in BL and DLBCL
BL usually simple karyotype, DLBCL complex karyotype
42
Rea seen in DLBCL
T(14;18)(q32;q21) IgH-bcl2 , t(3;14)(q27:q34),IgH-bcl6, t(8;14)(q24;q34) IgH- Myc
43
3 subtypes of MzL
MALT (see after H.pylori infection), splenic (spleomrgaky,BM involvement), nodal (advanced stage disease)
44
Rearrangements seen in MALT
Birc3-malt1 t(11;18), IgH-malt1 t(14;18), IgH-bcl10 t(1;14)
45
Abnormalities seen in splenic MZL
Gain or partial gain of 3,12, del 17p
46
Rea seen in ALCL
T(2;5) Alk-npm and t(1;2) tpm3-alk
47
Example of a T cell nhl
Anaplastic large cell
48
Which cell fraction is affected in HCL
Cd19+
49
What is myeloma
Clonal expn of transformed plasma cells
50
Myeloma is seen increased incidence in which sex and in which ethnic population
Males and 2x higher in African American than Caucasian
51
What is mgus
Precursor state to MM, non malignant, assymptomatic, risks of progression to MM
52
What is smouldering myeloma
Inbetween MM and mgus, stable plasma cells no lesions
53
Which 2 primary genetic events seen in MM?
In either/or category over disease duration. 1. Hyperdiploidy : elderly, favourable. 2. Non hyper diploid: more unfavourable IgH-ccnd1 (neutral prog) IgH-fgfr3, IgH-maf (both poor prog)
54
What scone art genetic events seen in MM
P53 loss: v poor, Chr 1 abnormalities: poor, del 12p: poor, del 13q (associated with IgH-fgfr3)
55
% mds that are cyto genetically abnormal
50%
56
Disadvantage of snp arrays in mds
Not detect balanced EG Mecom rearrange to which are poor risk. Not distinguish separate clones, low level mosaic missed
57
Examples of genes mutated in mds
Haferlach et al 2014- deep sequencing and aCGH found 47 genes sit mutated , 90% mds had at least 1 mutation- eg tet2, asxl1, runx1, dnmt3a
58
In AML what is defined as complex karyotype
3 or more abns
59
% AML in adult with abnormal cyto
55%
60
% child AML with abnormal cyto
78%
61
What happens in CBF AML?
The fusion proteins still bind but activation is lost via Dom-neg inhibition -> increased survival
62
Which treatment used for t(8;21) in AML
Cytarabine
63
Effect of cKIT mutation in CBF AML
Poor prognosis
64
Fab type for t(8;21)
M2
65
Rea seen in APML
T(15;17)(q24;q21) pml-rara
66
Which rara rea are resistant to ATRA
T(11;17)(q23;q21) plzf-rara, t(11:17)(q13;q21) and t(5;17)
67
How does pml-rara fusion act?
Inhibit differentiation and increase cell self renewal. Rara Binds DNA and represses transcription of target like normal RARA action but does NOT respond to signal induction of genes so they remain repressed. PML is also disrupted. PML normally blocks cell growth -> apoptosis but fusion PML does NOT do this.
68
What is diagnosis of DIC in APML?
Disseminated intravascular coagulation -> activation of clotting cascade which forms blood clots in small vessels-> damage and bleeding (consumes clot factors)
69
What is ATRA?
Bind PML-rara -> diassociate-> down regulate
70
What is the gene fusion seen in t(9;11) in AML
Mllt3-mll
71
Which mll Rea has better prognosis (int) in aml?
T(9;11) mllt3-mll
72
Fusion seen in AML with t(6;9)(p23;q34) and prognosis
Dek-nup214. Poor prognosis
73
Which recurrent Rea in AML is present in AML with trilineage dysplasia?
Mecom rearrangements
74
Fusion seen in AML with inv3
Rpn1-Mecom
75
Which Rea is seen in megakaryoblastic AML M7 and prognosis. Which syndrome is this increased in?
T(1;22) rbm15-mkl1. Int prognosis , Down syndrome
76
% AML classified as therapy related
1o-20%
77
What is myeloid sarcoma
Tumour mass of myeloid cells at site other than BM.
78
What is TAM
Transient abnormal myelopoiesis seen in 10% T21 neonates.
79
What is gene mutation seen in tAM
Gata1
80
Prognosis guidelines recommended for child AML
Harrison et al 2099
81
AML paediatric good prognosis markers?
T(8;21), inv(16)
82
AML paediatric intermediate prognosis markers?
All not in other categories
83
AML paediatric poor prognosis markers?
5q, -7, t(6;9), t(9;22), 12p abnormality
84
Adult AML good prognostic cyto markers
T(15;17), inv(16), t(8;21)
85
Adult AML poor prognostic cyto markers
Mecom, complex 4 or more, mll except t(9;11) and t(11;19), -5/5q, -7/7q, t(6;11), t(9;22), -17/17p
86
Molecular poor markers in AML
Flt3itd, mll-Ptd
87
Molecular good risk marker in AML
Cebpa, npm1 when flt3 negative
88
Where is flt3
13q12
89
What is fkt3
Receptor TK
90
Proportion normal AML with flt3 mutation
1/3
91
What is result of flt3-itd
In frame insertion exon 14+15. Loss structure->loss Of activation of flt3
92
Result of flt3 mutation
Folding out of activation loop -> constitutive action-unclear prog
93
Which cyto categories is flt3 abnormality most common in
T(15;17), ank, t(6;9)
94
Can flt3 be used to monitor Mrd
No- can be lost/gained in progression
95
Where is cKIT located
4q12
96
Disadvantages of using cyto in AML diagnosis
Not detect cryptic, resolution hard to determine bkpts, may be underlying molecular mech
97
Where is npm1 located
5q35.1
98
Example of familial AML
fAML mutated cebpa. AD. Near complete penetrance, good prog. Ank and M1 and M0 categories. Biallelic cebpa mutation-alternate 2nd hit- gata2. Approx 11% AML with cebpa mutation can be said to have 1 germ line mutation in cebpa.
99
Utility of using CTCs in cancer
Early rapid diagnosis, treatment response, drug targets, severity/spread, development of drug resistance, series monitor avoiding biopsies,
100
Example is CTCs system in clinical use
Cell search FDA approved for breast prostate colorectal cancer
101
Example of clinical app of CTCs
EGFR detection in lung cancer. Resistant mutations detected during therapy coinciding with refractory disease. BRAF in melanoma,
102
Prevalence of jak2 mutations in PRV,ET and MF
PRV 95%, ET 50% and MF 50%
103
Cyto findings in chronic neutrophilic leukaemia
90% cyto normal
104
% cyto abns in PRV
20%. +8, +9, del 20q, del 13q, del 9p
105
% PRV that progress to AML
20%
106
% cyto abn in MF
30%
107
Prognostic Scoring system used for MF
DIPSS-plus. System includes cyto (8 diff indicators)
108
Very high rates of death in MF seen with which cyto abns?
Inv(3) i(17q) >80% death
109
Which myeloid leukaemia suggested with uncreased megakaryocytes in BM
ET
110
% cyto abnormals in ET
10%
111
Rea seen in chronic eosinophilia leukaemia and treatment option
FIPL1-PDGFRA fusion on 4q - sensitive to TKI
112
Common mutations seen and Treatment for systemic mastocytosis
CKIT mutations- not respond to imatinib but do to other TKI such as dasatinib
113
What is jak2
Non receptor TK involved in JAK/STAT pathway leads to increased proliferation and survival of malignant cells
114
What is most common jak2 mutation
V617F gain of function -> release auto inhibition
115
Location of jak2
9p24
116
Which mpn disorders can have mpl mutations
3-4% et, 4-8% MF, not seen PRV
117
Mpl location and function
1p34 encode thrombopoeitin: regulates differentiation of Mega's and pltlets
118
Types of CALR mutation
36 types, ins and dels in exon 9
119
CALR location
19p13.3
120
Fgfr1 mutations seen in which eosinophilia syndrome
8p11 myeloproliferative syndrome.t(8;13) t(8;9) t(6;8). Not respond imatinib
121
Which mpn have pfgfrB rearrangements and which treatment is used
aCML, CMML, CEL. Respond TKI
122
What 2 disorders are classified as mds/mpn? What characteristic genetic abnormalities are seen?
CMML: cmml1 and 2, cyto abn 20-40% and RAS mutation in 30-40%. JMML: 30-40% cyto abn and RAS mutation common
123
Utility of cyto analysis in mpn?
Cyto not essential but useful to rule out AML, CML ph+ and mds. Can detect rare reas such as t(5;12) seen in cmml with eosinophilia. Fish useful to detect cryptic Rea in eosinophilia which resound to TKI
124
3 members of Ewings family of tumours
Ewings: ass with bones, PNET: brain and Askins: chest wall
125
Where is gene EWSR1
22q12
126
Rearrangement ass with Ewing sarcoma
T(11;22)(q24;q12). EWS-FLI1 in 85%
127
Result of ewsr1-fli1 fusion in Ewing sarcoma
constitutive exp from native ewsr1 promoter.
128
Example of non ETS fusion in Ewings
EWS-ZSG - intrachromosomal Rea para inversion of 22q12
129
Why is early diagnosis of Ewings so important
Many illnesses appear the same therefore difficult to detect in early stages and is v aggressive.
130
List techniques used in tumour mutation analysis
Ngs- panels eg CRUK lung cancer, mutation analysis Braf melanoma, egfr, ALK Rearrangements lung cancer. aCGH. Snp array. Expression arrays. CTCs
131
Example of mature B cell neoplasm
CLL
132
Haematological characteristics of CLL
Proliferation and accumulation of mono morphic small round b-lymphocytes. Mature yet disfunctional b cells : prevent haem of other normal cells
133
Clinical course of CLL
1 premalignant . 2. CLL 3. Richter's syndrome, DLBCL
134
Poor risk CLL markers
P53, ATM deletions,
135
What test is useful to investigate atypical CLL
Check for T(11;14) to exclude MCL. (Differential diagnosis)
136
Ngs has identified possible new genes important in CLL- examples
BIRC3, NOTCH1,
137
CLL trials currently running
RialtO, FLAIR
138
Phenotype f ALL
General weak/fatigue, anaemia, fever infections, wt loss bruising
139
% childhood leukaemia that is ALL
75%
140
ALL trials
Interfant, uKALL-2011, ALL14
141
Bcr-Abl fusion seen in ALL
P190 (75%)- only in de novo ALL p210(25%-also seen in cml blast crisis)
142
Number of chrs in HeH
51-65
143
Number chromosomes in near haploid
23-29
144
Number chromosomes in low hypodiploidy
30-39
145
Number chromosomes in high hypodiploidy
40-44
146
Where is TCF3 commonly rea in ALL
19p13
147
Most common IGH rearrangement in ALL
T(X;14) IGH-CRLF2 cryptic. Common with + sex chromosome
148
Describe ETV6-RUnX1 in ALL
Cryptic, often see loss of other Etv6 , fusion protein acts in don-Neg fashion and interferes with normal Runx1 transcription factor. Good prognosis. Common children
149
IAMP21 in ALL:describe
>5 copies, poor prog, ace age 9 years, rob(15;21) sees 2700 fold increased risk.
150
Prognosis of IKZF1 mutation/del in all
Poor, in 80% ph positive
