Presenter : CR 周益聖 Supervisor: VS 曾主任
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Transcript of Presenter : CR 周益聖 Supervisor: VS 曾主任
Presenter : CR 周益聖Supervisor: VS 曾主任
Cell 152, 714–726, February 14, 2013
Chronic lymphocytic leukemia
• CLL– Mature B lymphocyte 5000/uL in the peripheral ≧
blood• Monoclonal B-lymphocytosis– Mature B lymphocyte < 5000/uL– No lymphadenopathy, organomegaly, cytopenia or
symptoms
Blood. 2008;111:5446-5456ASH image bank
Staging
NCCN Guideline V 1.2013
Treatment indications• Not indicated for Rai stage 0 or Binet stage A• Absolute lymphocyte count alone is not an indication for treatment
unless above 200-300 x 10 /L or symptoms related leuastasis• Binet stage C or Rai stage III or Rai stage IV• progressive marrow failure / worsening of anemia and/or
thrombocytopenia• progressive or symptomatic splenomegaly• progressive or symptomatic lymphadenopathy• Progressive lymphocytosis
– an increase of more than 50% over a 2-month period – lymphocyte doubling time (LDT) of less than 6 months
• Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids NCCN Guideline V 1.2013
Blood. 2008;111:5446-5456
17p with poor prognosis
N Engl J Med 343:1910-1916, 2000
Unmutated IGHV as poor prgnositic factor of OS in CLL
Blood. 1999 Sep 15;94(6):1848-54.
Un vs mut:117 vs 293 months, P=0.001
Whole exome sequencing
• Affordable, rapid, and comprehensive for detecting somatic coding mutations
• High sequencing depth (typically 100X–150X)• Coding mutations likely encompass many of the
important driver events that provide fitness advantage for specific clones
• Low cost of WES permits studies of large cohort to assess the impact of clonal heterogeneity on disease outcome
What are the Mutations In CLL?
Fig 1
Will Age or IGHV status affect clonal or subclonal mutations?
Fig 2
posterior probability distribution over CCF c : Consider a somatic mutation observed in a of N sequencing reads on a locus of absolute somaticcopy number q in a sample of purity α. The expected allele-fraction f of amuta-tion present in one copy in a fraction c of cancer cells
Clonal mutation
Subclonal mutations
Comparison of mutational spectrum between subclonal and clonal sSNVs
Mutation spectrum are similar in clonal and subclonal sSNVs
When did clonal or subclonal mutations occur?
Fig 3
9/12(MYD88) and 12/14(Tri12) had at least one other mutations
Will clonal or subclonal evolution occur in chemotheray treated patient?
Fig 4
C/T Untreated
C/T Treated
Genetic Evolution and Clonal Heterogeneity Result inAltered Clinical Outcome
Presence of Subclonal Drivers Mutations Adversely Impacts Clinical Outcome
Multivariate Cox regression models
All patients
62 patients who had at least one driver
Proposed model of CLL clonal evolution
Fig7
Discussion
Why CLL?
• Slow growing B cell malignancy– extended window for observing the process of clonal
evolution• Highly variable disease course• Diverse combinations of somatic mutations
Presence, diversity, and evolutionary dynamics of subclonal mutations in CLL contribute to the variations observed in disease tempo and response to therapy
Different periods of clonal evolution• First period prior to transformation– Passenger events accumulate in the cell that will eventually be
the founder of the leukemia• in proportion to the age of the patient
• Second period– the founding CLL mutation appears in a single cell and leads to
transformation– Recurrent clonal mutations across patients
• del(13q), MYD88, and trisomy 12
• Third period– subclonal mutations expand over time as a function of their
fitness-integrating intrinsic factors (proliferation and apoptosis) and extrinsic pressures (interclonal competition and therapy)• ATM, TP53,or RAS mutation
How does treatment affects evolution?
• Clonal equilibrium– Untreated patients– relative sizes of each subclone were maintained– some subclones emerge as dominant – more time is needed for a new fit clone to take over the
population in the presence of existing dominant clones • Emergence of fitter clones
– treated patients– cytotoxic therapy typically removes the incumbent clones– shifts the evolutionary landscape in favor of one or more
aggressive subclones– highly fit subclones likely benefit from treatment and exhibit
rapid outgrowth
Therapeutic implications• Presence of pretreatment subclonal driver mutations
anticipated the dominant genetic composition of the relapsing tumor– therapies to prevent the expansion of highly fit subclones
• Potential hastening of the evolutionary process with treatment provides a mechanistic justification for the empirical practice of ‘‘watch and wait’’ as the CLL treatment paradigm
• Detection of driver mutations in subclones (a testimony toan active evolutionary process) may thus provide a prognostic approach in CLL
Conclusion
• WES to study tumor heterogeneity and clonal evolution – readily adopted for clinical applications
• Importance of evolutionary development as the engine driving cancer relapse
• Develop therapeutic paradigms that not only target specific drivers (i.e., ‘‘targeted therapy’’) but also the evolutionary landscape of these drivers