Celebrating 20 years of the Database Joint UKCCG and CHO Annual Conference. 22 nd -23 rd March 2012 Newcastle upon Tyne
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1 Celebrating 20 years of the Database Joint UKCCG and CHO Annual Conference 22 nd -23 rd March 2012 Newcastle upon Tyne
2 The following years. FISH and genomics Christine Harrison Chair, UK Cancer Cytogenetics Group Professor of Childhood Cancer Cytogenetics
3 Royal Free Hospital, London University of Southampton Newcastle University Prof Andy Hall Prof Josef Vormoor
4 Programme Grant Application to LRF Remit of the group in 1997 Co-ordinate cytogenetics in UK acute leukaemia treatment trials Guarantee the accuracy of the karyotypes Provide interface between laboratories and trial co-ordinators Initiate research projects in genetics of acute leukaemia
5 At that time in 1997 There were around 2000 patients entered to Database with karyotype data Now more than 28,000 patients Trials: Childhood Adult UKALLXI UKALLXII ALL UKALL 14 now ALL Infants ALL2011 now Infant6 Interfant99 Interfant
6 Cytogenetics of childhood BCP-ALL ~10,000 cases 1% Normal 11% Other 11% t(9;22) 2% t(1;19) 4% t(12;21) 25% 3% t(17;19) 1% CRLF2-P2RY8 5% iamp21 2% Hypo (<40) 1% HeH 30% 11q23 2% t(4;11) 2%
7 Proportion of cases Age-specific frequency of chromosomal abnormalities 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% < Age group (years) T-ALL Other Hap/hypo Other MLL t(4;11) t(1;19) t(9;22) HeH ETV6-RUNX1
8 1997 Breakthroughs at that time Able to request fixed cells from cytogenetics laboratories Have access to survival data from trial patients
9 ALL97 High risk protocol: BCR-ABL1, MLL and near-haploidy
10 Action Cytogenetics was good >80% Success >80% Abnormality detection rate FISH in place in UK Interphase FISH screening Calculate accurate incidences Determine prognosis of cytogenetic subgroups
11 ..in UK ALL treatment trials to use FISH for the detection of known subgroups Poor risk BCR-ABL1 MLL Hypodiploidy Other significant prognostic groups ETV6-RUNX1 High hyperdiploidy
12 Interphase FISH in ALL Triple-Test on all patients Centromeric probes on normal and fail BCR-ABL1 MLL ETV6-RUNX1 Harrison et al 2005 Br J Haematol 129:
13 ALL patients entered Results of Interphase FISH Screening Programme Harrison et al 2005 Br J Haematol 129:
14 ALL97 Triple Test Inadequate material 16% positive 23% negative 61% n=1936 cases
15 Cytogenetics vs FISH (21%) BCR-ABL1 MLL ETV6-RUNX1
16 BCR-ABL +ve cases (n=37) Cytogenetics No. Cases t(9;22) 28 Normal 4 Failed 5
17 Cryptic BCR-ABL1 rearrangement
18 MLL +ve cases (n=37) Cytogenetics No. Cases t(4;11) 15 t(11;19) 7 t(9;11) 5 t(11;v) 3 Fail 4 add(11)(q23) 2 del(11)(q23) 1
19 MLL ve cases with an 11q23 abnormality Abnormality No. Cases del(11)(q23) 19 add(11)(q23) 2 t(11;v)(q23;v) 3 Total 24
20 ALL97 Failed and Normal Cytogenetics Centromeric probes to look for hidden numerical abnormalities
21 Moorman AV, Clark R, Farrell DM, Hawkins JM, Martineau M, Secker-Walker, LM Probes for hidden hyperdiploidy in acute lymphoblastic leukaemia. Genes Chromosomes Cancer 1996,16: / /21 X
22 ALL97 Failed and Normal Cytogenetics Total cases tested 130 Hidden high hyperdiploidy Failed 39/65 (60%) Normal 25/65 (38%)
23 Advantages of interphase FISH in ALL97 Result With FISH Without FISH Abnormal 1,538 (89%) 1,325 (83%) Normal 189 (11%) 275 (17%) Failed 174 (9%) 301 (16%) 127 failed > abnormal 86 normal >abnormal
24 Interphase FISH Screening was integrated as routine practice
25 Reza Jalali
26
27 Case study of monozygotic twin girls Zoe Broadfield Broadfield et al 2004 Br J Haemat.126: ETV6-RUNX1 probe
28 46,XX,der(5)t(5;11)(q12;?),der(9)t(12;21;9;18),der(11)t(5;11)(q31.3;?)der(12)t(12;21;9;18), der(18)invins(18;5)(q31.1;q12)t(12;21;9;18),der(21)t(12;21;9;18),dup(21)
29 Reza Jalali Mary Martineau
30 Interphase FISH screening led to identification of new genetic subgroups Amplification of ABL1 Intrachromosomal amplification of chromosome 21 (iamp21)
31 Amplification of ABL1 Kerry Barber BCR-ABL1 Barber et al 2004 Leukemia 18: ABL1 acgh
32 Fusion of NUP214 to ABL1 on episome Graux et al 2004 Nature Genetics 36:
33 NUP214-ABL1 fusion
34
35 Complexity of chromosome 21 (185K Agilent arrays) Jon Strefford
36
37 Chromosome 21 from iamp21 patient SNP6.0 Sarra Ryan Next generation Complex rearrangements involving deletions, tandem duplications and inversions Peter Campbell Phil Stephens Wellcome Trust Sanger Centre Read depth
38 Helen Parker Vikki Rand
39 Oncogenomics In vivo functional model to determine the driver genes within regions of deletion and amplification. Paul Sinclair
40 iamp21 While the search continues for the initiating mechanism FISH with probes directed to RUNX1 remain the only reliable detection method
41 translocations in lymphoid malignancies Xp22/Yp11 CRLF2 22q11 - IGL Identified in BCP-ALL 1p34 LAPTM5 Mature leukaemia/lymphoma 20q13 - CEBPB 1p22 - BCL10 20q11 - MAFB 1q21 ITRA1 19p13 - EPOR 1q21 - BCL9 19q13 - BCL3 1q21- FCGR2B 19q13 - CEBPG 1q21- MUC1 19q13 - CEBPA 1q24 - LHX4 18q21 - MALT1 2p13 - BCL11A 18q21 - BCL2 17q21 IGF2BP1 16q23 - MAF 15q12 - BCL8 14q11 - TCRA 14q11 - CEBPE 12p13 BCL1 12q23 - CHST11 IGH@ Translocations 11q24 mir-125b 11q23 - PAFHA1B2 11q23 - PCSK7 11q13 - UK 11q23 - DDX6 11q13 - CCND1 10q24 - NFKB2 9p13 - PAX5 3p14 - FOXP1 3q27 - BCL6 4p16 - FGFR3 4p16 - WHSC1 4p13 - RHOH 5q31 IL3 6p25 - IRF4 6p22 ID4 6p21 - CCND3 7p14 TRG@ 7q21 - CDK6 7q21 - ERVWE1 8q11 - CEBPD 8q24 MYC Lisa Russell
42 XX-87136C11 XX-82904A1 RP4-674K6 RP13-309C18 CRLF2 CSF2RA IL3RA ASMTL P2RY8 Pseudoautosomal region (PAR1) SLC25A6
43 Yp11.32 PAR1 Xp22.33 CRLF2 CSF2RA IL3RA SLC25A6 ASMTL P2RY8 Russell et al Blood 2009 Mullighan et al Nature Genetics 2009
44 Yp11.32 PAR1 Xp22.33 CRLF2 CSF2RA IL3RA SLC25A6 ASMTL P2RY8 Russell et al Blood 2009 Mullighan et al Nature Genetics 2009
45 CRLF2 mrna expression Translocation patients 1200 Fold change CRLF ALL control cohort Fold change Deletion patients 20 Russell et al Blood ALL control cohort
46 Rearrangements of CRLF2 in paediatric ALL CRLF2 (cytokine receptor like factor 2) (TSLPR- thymic stromalderived lymphopoietin receptor ) IGH@-CRLF2 t(x;14)(p22;q32) or t(y;14)(p11;q32) P2RY8-CRLF2 Interstitial deletion: del(x)(p22.33p22.33) or del(y)(p11.32p11.32) Activating mutations CRLF2 F232C 6% childhood and adult BCP-ALL High incidence in Down syndrome ALL (50%) High incidence in iamp21 All rearrangements lead to up regulation of CRLF2 Association with JAK mutations Activation of JAK-STAT pathway Potential molecular target for therapy Interest in the prognostic significance Russell et al (2009) Blood Mullighan et al (2009) Nature Genetics Hertzberg et al (2009) Blood Chapiro et al (2010) Leukemia Harvey et al (2010) Blood Cario et al (2010) Blood
47 Submicroscopic deletions identified by SNP arrays
48 Transcription factors controlling normal B cell development Mullighan et al Nature 2007 Copyright 2006 American Society of Hematology. Copyright restrictions may apply.
49 Deletions of B-cell differentiation genes and cell cycle progression in BCP-ALL by SNP arrays Jon Strefford FOXO3A 12% FBXW7 3% CREG1 3% EBF1 3% PAX5 24% RB1 9% PAX5 mut 6% CDKN2A 21% IKZF1 7% Other 9% BLNK 1% TCF3 <1% LEF1 1% IKZF3 1% Mullighan et al 2007 Nature Kuiper et al 2007 Leukemia Strefford et al 2007 Oncogene
50 BCP-ALL MLPA Kit (SALSA MLPA kit P335-A1 ALL IKZF1) Probes for genes most frequently deleted in BCP-ALL IKZF1 (8) Early B-cell differentiation gene (deleted in 29% high risk ALL) CDKN2A/B (3) Cell cycle G1 control -CDK inhibitor and p53 stabilizer (deleted in 20% BCP-ALL) PAX5 (6) B-cell differentiation gene (deleted in 32% of BCP-ALL) EBF1 (4) - Early B-cell differentiation gene activating PAX5 ETV6 (6) Transcription factor required for haematopoiesis (involved in translocations in ALL and deleted in 5%) BTG1 (4) Negative regulator of cell cycle RB1 (5) - Negative regulator of cell cycle (deleted in 5-11% B-ALL) CRLF2/CSF2RA/IL3RA (1 each) Deregulated in 6% BCP-ALL Claire Schwab
51 Mutations in the RAS Signaling, B-Cell Development, TP53/RB1, and JAK Signaling Pathways Are Common in High Risk BCP-ALL. Zhang et al (2011) Blood 118: CREBBP JAK1 2% TBL1XR1 2% 2% ETV6 JAK2 4% 9% Others/Unknown 9% NRAS 17% KRAS 16% CDKN2A 1% RB1 1% TP53 4% IKZF1 3% PAX5 15% NF1 3% FLT3 7% PTPN11 5% Coding region and UTR of 125 genes sequenced in 187 high risk childhood BCP-ALL in COG P9906
52 How do these genomic abnormalities all fit together? t(1;19) t(9;22) 1% Normal 4% 2% 11% Other 11% 3% CRLF2 5% iamp21 2% JAK1 2% Hypo (<40) 1% HeH 30% Cytogenetic abnormalities Others? 22% t(12;21) 25% 11q23 2% t(17;19) 1% RB1 9% t(4;11) 2% CDKN2A 21% NRAS 16% KRAS 15% FOXO3A 12% FBXW7 3% Other 9% Mutations CREG1 3% BLNK 1% EBF1 3% TCF3 <1% LEF1 1% Deletions PAX5 24% PAX5 mut 6% IKZF1 7% IKZF3 1% JAK2 9% CDKN2A 2% RB1 2% TP53 5% IKZF1 4% PAX5 11% NF1 3% PTPN11 5% FLT3 4% Gene Expression Epigenetics MicroRNA MRD
53
54 Outcome by karyotype complexity Harrison, Hills, Moorman, Grimwade et al (2010) JCO, 28:2674 Lucy Chilton
55 Thanks to Leukaemia Research Cytogenetics Group past and present
56 Thanks to our sponsors
57
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