mutational impact on diagnostic and prognostic evaluation ... · mutational impact on diagnostic...
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![Page 1: Mutational Impact on Diagnostic and Prognostic Evaluation ... · Mutational Impact on Diagnostic and Prognostic Evaluation of MDS Elsa Bernard, PhD Papaemmanuil Lab, Computational](https://reader035.vdocuments.site/reader035/viewer/2022062602/5edea43fad6a402d6669f8a3/html5/thumbnails/1.jpg)
Mutational Impact on Diagnostic and Prognostic Evaluation of MDSElsa Bernard, PhDPapaemmanuil Lab, Computational Oncology, MSKCC MDS Foundation ASH 2018 Symposium
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Disclosure
Research funds provided by MDS Foundation and Celgene
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QuestionThe good prognosis associated with SF3B1 is shifted with co-mutators in which of the following genes?
a. TET2b. DNMT3Ac. RUNX1d. All of the above
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Clinical, Morphology and Cytogenetics Molecular
Figure from:Patel et al Clinical Lymphoma Myeloma and Leukemia 2017
Clinical management of MDS
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Evolution of MDS stratification Diagnosis
Prognosis
Cytopenias Dysplasia
FAB WHO WHO
IPPS IPPS-R1982 2008 2016
1997 2012
Cytogenetics
Gene mutationsArber et al Blood 2016Greenberg et al Blood 2012Vardiman et al Blood 2008Bennett Semin Oncol 2005Greenberg et al Blood 1997
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Integration of recent molecular discoveries
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MDS mutations across pathways
Kennedy and Ebert JCO 2017Sperling et al Nature Rev 2017Saez et al Blood 2017Haferlach at al Leukemia 2014Yoshida et al Nature 2011Papaemmanuil et al NEJM 2011 Figure from Kennedy and Ebert JCO 2017
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Splicing factor deregulation central to MDS biology
Figure from Kennedy and Ebert JCO 2017
Kennedy and Ebert JCO 2017Sperling et al Nature Rev 2017Saez et al Blood 2017Haferlach at al Leukemia 2014Yoshida et al Nature 2011Papammanuil et al NEJM 2011
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PatientNumber
Authors Year Prognostic genes in multivariate model
439 Bejar et al. 2011 ASXL1, ETV6, EZH2, RUNX1, TP53
738 Papaemmanuil et al. 2013 EZH2, DNMT3A, SF3B1, SRSF2, RUNX1, TET2, TP53
944 Haferlach et al. 2014 ASXL1, KRAS, LAMB4, NPM1, PRPF8, RUNX1, TP53
508 Nazha et al. 2017 CBL, NRAS, TP53
685 Tefferi et al. 2018 ASXL1, SF3B1, RUNX1
Genomic population studies identify molecular prognostic markers
➔ Need to develop a robust consensus prognostic model
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1. Incorporate gene mutations into formal classification i.e.
WHO classification for MDS?
2. Improve prognostic accuracy and treatment decisions by
consideration of gene mutations in formal prognostic i.e.
IPSS molecular model?
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International Working Group for the prognosis of MDS13 countries | 25 centers
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International Working Group for the prognosis of MDS Retrospective cohorts Prospective sequencing study
N=1,682Bejar et al 2011Haferlach et al 2014Papaemmanuil et al 2013
N=4,270
MSKCC IWG-PM Cohort13 countries 25 centers
N to be determined
ClevelandMD Anderson
Validation
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International Working Group for the prognosis of MDS Retrospective cohorts Prospective sequencing study
N=4,270
MSKCC IWG-PM Cohort13 countries 25 centers
N to be determined
ClevelandMD Anderson
Validation
N=1,682Bejar et al 2011Haferlach et al 2014Papaemmanuil et al 2013
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International Working Group for the prognosis of MDS Retrospective cohorts Prospective sequencing study
N=4,270
MSKCC IWG-PM Cohort13 countries 25 centers
N to be determined
ClevelandMD Anderson
Validation
Study Entry Criteria:
Diagnostic, pre-treatment samplesComplete clinical annotation Diagnostic Morphology | CBC TreatmentLong-term follow-up data
N=1,682Bejar et al 2011Haferlach et al 2014Papaemmanuil et al 2013
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International Working Group for the prognosis of MDS Retrospective cohorts Prospective sequencing study
N=4,270
MSKCC IWG-PM Cohort13 countries 25 centers
N to be determined
ClevelandMD Anderson
Validation
Sequencing:
155 myeloid genes Genome-wide copy number probesFocal regions of LOHPanel information available on requestUnmatched settingCoverage 600-800x
N=1,682Bejar et al 2011Haferlach et al 2014Papaemmanuil et al 2013
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Demographics age,sex
Clinical Parameters blood counts, blasts%
Karyotype cytogenetics
Treatment hma, transplant
AML transformation transformation in 20% of patients
Overall survival median follow-up 3.5 years
Molecular
Integration of clinical and molecular data
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Outline
Splicing factorsDisease defining
Mutual exclusivityCo-mutations effect
Cohort overviewClinical
MolecularCorrelative analysis
Molecular classesAb-initio clustering Diagnostic valuePrognostic value
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Outline
Splicing factorsDisease defining
Mutual exclusivityCo-mutations effect
Cohort overviewClinical
MolecularCorrelative analysis
Molecular classesAb-initio clustering Diagnostic valuePrognostic value
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IWG-MDS MSKCC cohort
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Clinical cohort characteristics
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Genomic analysis backbone1) Comprehensive annotation of putative oncogenic mutations
Mutation distribution among patientsGene-level annotationHotspot-level annotationPatterns of co-mutationsAssociations with clinical presentation and outcome
2) Integration of cytogenetics data and NGS copy-number eventsCytogenetics score and complex karyotypeFocal LOH
3) Unmatched sequencing dataControl for germline infiltration
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Molecular cohort characteristics5,002,459
raw calls
82,773filtered
13,063oncogenic
2,322new
data-driven cutoffs
statistical recurrencemanual curation
Combination of 4 variant callersSequencing metrics
Population based metricsSomatic | Germline
Background mutation rateStatistical recurrence
Identification of new putative driversCorrelative analysis
Mutation signature analysis
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Most mutations are not recurrent5,002,459
raw calls
82,773filtered
13,063oncogenic
2,322new
data-driven cutoffs
statistical recurrencemanual curation
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Annotation of new likely oncogenic variantsRUNX1 example
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Annotation of new likely oncogenic variantsRUNX1 example
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95% of patients with driver alteration(s)
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Median of 4 oncogenic events per patient
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Clinical features trend with number of drivers
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Disease subtypes with number of drivers
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Risk groups with number of drivers
IPSS Good MDS
Substratify by number of oncogenic events
Evaluate prognostic significance
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Risk groups with number of drivers
Substratify by number of oncogenic events
Evaluate prognostic significance
IPSS Good MDS
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Detailed map of co-mutations
Haferlach at al Leukemia 2014Papammanuil et al Blood 2013
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Detailed map of co-mutations
Molecular classification
Disease modelling
Drug developpement
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Main points1. Sequencing analysis of 4,270 MDS patients with molecular and clinical annotation
2. Developed methodology to characterize rare non-recurrent variants
3. >13,000 oncogenic events, characterize at least 1 mutation in 95% of MDS
4. Mutation negative cases, not satisfying standard diagnostic criteria
5. Number of mutations, associated with severity of clinical presentation and outcome
6. Strong and novel patterns of co-mutation: framework for genotype-clinical studies
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Outline
Splicing factorsDisease defining
Mutual exclusivityCo-mutations effect
Cohort overviewClinical
MolecularCorrelative analysis
Molecular classesAb-initio clustering Diagnostic valuePrognostic value
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Splicing factors mutations
Splicing factors as candidate biomarkers 55% of MDS patients have
mutations in splicing factor genes
Disease defining | Associate with diagnostic MDS features | Mutually Exclusive | Early clonal events
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Splicing factors as candidate biomarkers
Saez et al Blood 2017Yoshida et al Nature 2011Papaemmanuil et al Blood 201Haferlach at al Leukemia 2014
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Incorporation of SF3B1 status in WHO 2016WHO 2016 MDS-RS:
more than 15% ringed sideroblasts or
more than 5% of ringed sideroblasts and SF3B1 mutation
Malcovati et al Blood 2011Papaemmanuil et al NEJM 2011
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Detailed map of co-mutations: SF3B1 K700 other
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Mutation hotspots with SF3B1
p<0.001
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SF3B1 cases have a median of 2 other alterations
From 0 to many other alterations with median of 28% of SF3B1 isolated cases
Co-occurrence occurs with various genes or copy-number events
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SF3B1 cases have a median of 2 other alterations
From 0 to many other alterations with median of 28% of SF3B1 isolated cases
Co-occurrence occurs with various genes or copy-number events
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SF3B1 cases have a median of 2 other alterations
Effect of co-mutators on the SF3B1 phenotype and outcome?Is it clinically relevant?
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SF3B1 phenotype and outcome shift with co-mutatorsSF3B1 isolated or with TET2 | DNMT3A No shift
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SF3B1 phenotype and outcome shift with co-mutatorsSF3B1 isolated or with TET2 | DNMT3A No shift
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SF3B1 phenotype and outcome shift with co-mutatorsSF3B1 isolated or with TET2 | DNMT3A No shift
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SF3B1 phenotype and outcome shift with co-mutatorsSF3B1 with ASXL1 or RUNX1 or TP53 Shift
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SF3B1 phenotype and outcome shift with co-mutatorsSF3B1 with ASXL1 or RUNX1 or TP53 Shift
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SF3B1 phenotype and outcome shift with co-mutatorsSF3B1 with ASXL1 or RUNX1 or TP53 Shift
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The genetic context in which mutations occur shape clinical trajectories
Formalize approach across MDS genes in cohort
Global analysis of MDS landscape
Genotype- Clinical
Genotype- Outcome
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Integrative genotype-clinical analyses
Many mutations Integration of molecular and morphological features
Clinical
Molecular
Clinical relevance
SF3B1
DNMT3A
ASXL1
BCOR
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Outline
Splicing factorsDisease defining
Mutual exclusivityCo-mutations effect
Cohort overviewClinical
MolecularCorrelative analysis
Molecular classesAb-initio clustering Diagnostic valuePrognostic value
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Freq
uent
gen
e m
utat
ions
Patients
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Comprehensively evaluate patterns of co-mutations and mutual exclusivity
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Comprehensively evaluate patterns of co-mutations and mutual exclusivity
Identify non-overlapping molecular subgroups
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Molecular clustering identifies patient classesMinimum class numbers
explained by dataPatient
molecular profiles
n=192 recurrent genetic alterations
n=12,970 patient alterations
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Molecular clustering identifies patient classes
Ab-initioProbabilistic | Bayesian
Consider only molecular featuresEach gene can be present in more than one classEach class can be defined by more than one geneEach patient is assigned probability to each class
Minimum class numbers explained by data
Patient molecular profiles
n=192 recurrent genetic alterations
n=12,970 patient alterations
Class assignment of each individual
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Comprehensively evaluate patterns of co-mutations and mutual exclusivity
Identify non-overlapping molecular subgroups
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Comprehensively evaluate patterns of co-mutations and mutual exclusivity
Identify non-overlapping molecular subgroups
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Comprehensively evaluate patterns of co-mutations and mutual exclusivity
Identify non-overlapping molecular subgroups
Test for specific associations between clinical presentation & outcomes
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Molecular groups are associated with clinical featuresPlatelets
Platelet variations across molecular subgroups
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Molecular groups are associated with clinical featuresBM
Blasts %
Bone marrow blast% variations across molecular subgroups
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Molecular groups are associated with demographics
Male | Female occurrence variations across molecular subgroups
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Molecular groups are associated with outcome
Rate of AML transformation vary across molecular subgroups
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Morphology subtypes are split across molecular groups
Different molecular profile groups lead to a given phenotypeComplementary approaches
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Prognostic significance of molecular subgroups
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Molecular subgroups hold independent prognostic valueIPSS-R across molecular subgroups
IPSS-R good patients from one molecular subgroup (n=122)
behave as IPSS-R int
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Take home messagesDeliver molecular blueprint of MDS
95% of patients with at least one driver alteration
SF3B1 phenotype and good prognosis can shift with specific co-players
Molecular clustering identifies classes of patients that are associated with demographics, clinical features and outcome
Findings from this study will inform future clinical decision support in MDS
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Molecular sub-classification | IPSS-molecular
1997
2012
2019+
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Next Steps
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Thank youIWG collaborators Clinical Data Curation Papaemmanuil Lab | MSKCC
Maria Creignou - Lindberg LabLuca MalcovatiKelly Bolton
WHO Classification Robert Hasserjian
IPSS-R Heinz Tuechler
Administration Project ManagementCytogenetics Minal Patel, Yessenia Werner, Chris Famulare, Erin McGovernDetlef HasseRaf Bejar Biostatistics Sean Devlin, Pierre Guilmin
Method Development Juan Medina, Juan Arango Ossa, Joe Zhou, Max Levine, Gunes Gundem, Teja Yellapantula, Teng Gao, Noushin Farnoud, Matthieu Cornet, Dominik Glodzik
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See you in Copenhagen
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QuestionThe good prognosis associated with SF3B1 is shifted with co-mutators in which of the following genes?
a. TET2b. DNMT3Ac. RUNX1d. All of the above
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