title: Evolution and impact of subclonal mutations in chronic lymphocytic leukemia.
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.
authors: Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Dan A
authors: DA
authors: Landau
authors: Scott L
authors: SL
authors: Carter
authors: Petar
authors: P
authors: Stojanov
authors: Aaron
authors: A
authors: McKenna
authors: Kristen
authors: K
authors: Stevenson
authors: Michael S
authors: MS
authors: Lawrence
authors: Carrie
authors: C
authors: Sougnez
authors: Chip
authors: C
authors: Stewart
authors: Andrey
authors: A
authors: Sivachenko
authors: Lili
authors: L
authors: Wang
authors: Youzhong
authors: Y
authors: Wan
authors: Wandi
authors: W
authors: Zhang
authors: Sachet A
authors: SA
authors: Shukla
authors: Alexander
authors: A
authors: Vartanov
authors: Stacey M
authors: SM
authors: Fernandes
authors: Gordon
authors: G
authors: Saksena
authors: Kristian
authors: K
authors: Cibulskis
authors: Bethany
authors: B
authors: Tesar
authors: Stacey
authors: S
authors: Gabriel
authors: Nir
authors: N
authors: Hacohen
authors: Matthew
authors: M
authors: Meyerson
authors: Eric S
authors: ES
authors: Lander
authors: Donna
authors: D
authors: Neuberg
authors: Jennifer R
authors: JR
authors: Brown
authors: Gad
authors: G
authors: Getz
authors: Catherine J
authors: CJ
authors: Wu
mesh_terms: D000465:Algorithms; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D056915:DNA Copy Number Variations; D055106:Genome-Wide Association Study; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation; D011003:Ploidies