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Cell 152, 714–726, February 14, 2013 Presenter : CR 周益聖 Supervisor: VS 曾主任 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;111:5446-5456 ASH 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 Un vs mut: 117 vs 293 months, P=0.001 Blood. 1999 Sep 15;94(6):1848-54. 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 Fig 1 What are the Mutations In CLL? Fig 2 Will Age or IGHV status affect clonal or subclonal mutations? posterior probability distribution over CCF c : Consider a somatic mutation observed in a of N sequencing reads on a locus of absolute somatic copy number q in a sample of purity α. The expected allele-fraction f of amutation 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 Fig 3 When did clonal or subclonal mutations occur? 9/12(MYD88) and 12/14(Tri12) had at least one other mutations Fig 4 Will clonal or subclonal evolution occur in chemotheray treated patient? C/T Untreated C/T Treated Genetic Evolution and Clonal Heterogeneity Result in Altered 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 Fig7 Proposed model of CLL clonal evolution 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