Evolution and impact of subclonal mutations in chronic lymphocytic leukemia

By D. Landau, Scott L. Carter, P. Stojanov, A. McKenna, K. Stevenson, M. Lawrence, C. Sougnez, Chip Stewart, A. Sivachenko, Lili Wang and 16 more. Cell, 2013

1,402 citations recorded by the source corpus.

Summary 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, TP53), corresponding to earlier and later events in CLL evolution. We sampled leukemia cells from 18 patients at two timepoints. Ten of 12 CLL cases treated with chemotherapy (but only 1 of 6 without treatment) underwent clonal evolution, predominantly involving subclones with driver mutations (e.g., SF3B1, 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 outcome.

Subfields: Genetics, Molecular Biology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/ad884c581c4591b9a42492252d1b62610fb2f88e

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Citations in the corpus

Lessons from the cancer genome. (2013, positive): “On the other hand, the ability to identify driver or resistance mutations within subclonal populations may allow improved prediction of clinical outcomes (Landau et al., 2013).”
Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy (2014, positive): “Systemic treatment with chemotherapy may affect the fitness of some subclones more than others, and thus may alter the tumor composition by promoting particular subclones (Landau et al., 2013b).”
Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. (2015, positive): “Because leukaemic clones may evolve, FISH and TP53 mutation analyses should be repeated before relapse treatment is administered [III, B] [13].”
Prospective derivation of a Living Organoid Biobank of colorectal cancer patients (2015, background): “Our CCF analysis of clonal structure determined that almost all of the biopsies were polyclonal at the time of resection, and this is reflected to varying extent in the corresponding organoid culture.”
Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets (2015, methodology): “S1, S3, Supplementary file 3) using a 2D version of the Bayesian clustering algorithm described above.(19) In most patients, we observed some mutations with CCFmet = 1 that were not detected in the primary.”
Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade (2016, methodology): “, 2015) whereas clonal and subclonal origins of the neoantigens were estimated as previously described (Landau et al., 2013).”
Nanomedicine therapeutic approaches to overcome cancer drug resistance (2013, background): “For the treated patients that did exhibit subclonal evolution, the somatic driver mutations that expanded were detectable at the first time point and thus could potentially be anticipated in association with treatment [34].”