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Cell DOI:10.1016/j.cell.2013.01.019

Evolution and impact of subclonal mutations in chronic lymphocytic leukemia.

Publication TypeJournal Article
Year of Publication2013
AuthorsLandau, DA, Carter, SL, Stojanov, P, McKenna, A, Stevenson, K, Lawrence, MS, Sougnez, C, Stewart, C, Sivachenko, A, Wang, L, Wan, Y, Zhang, W, Shukla, SA, Vartanov, A, Fernandes, SM, Saksena, G, Cibulskis, K, Tesar, B, Gabriel, S, Hacohen, N, Meyerson, M, Lander, ES, Neuberg, D, Brown, JR, Getz, G, Wu, CJ
JournalCell
Volume152
Issue4
Pages714-26
Date Published2013 Feb 14
ISSN1097-4172
KeywordsAlgorithms, Animals, B-Lymphocytes, DNA Copy Number Variations, Genome-Wide Association Study, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Mutation, Ploidies
Abstract

Clonal evolution is a key feature of cancer progression and relapse. We studied intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases by integrating whole-exome sequence and copy number to measure the fraction of cancer cells harboring each somatic mutation. We identified driver mutations as predominantly clonal (e.g., MYD88, trisomy 12, and del(13q)) or subclonal (e.g., SF3B1 and TP53), corresponding to earlier and later events in CLL evolution. We sampled leukemia cells from 18 patients at two time points. Ten of twelve CLL cases treated with chemotherapy (but only one of six without treatment) underwent clonal evolution, predominantly involving subclones with driver mutations (e.g., SF3B1 and TP53) that expanded over time. Furthermore, presence of a subclonal driver mutation was an independent risk factor for rapid disease progression. Our study thus uncovers patterns of clonal evolution in CLL, providing insights into its stepwise transformation, and links the presence of subclones with adverse clinical outcomes.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S0092-8674(13)00071-8
DOI10.1016/j.cell.2013.01.019
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23415222?dopt=Abstract

Alternate JournalCell
PubMed ID23415222
PubMed Central IDPMC3575604
Grant List1R01HL103532-01 / HL / NHLBI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
R01 HL103532 / HL / NHLBI NIH HHS / United States
U54HG003067 / HG / NHGRI NIH HHS / United States
K23 CA115682 / CA / NCI NIH HHS / United States
R01 CA155010 / CA / NCI NIH HHS / United States
1R01CA155010-01A1 / CA / NCI NIH HHS / United States