Evolution and impact of subclonal mutations in chronic lymphocytic leukemia
Open accessAbstract
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.
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Several recent studies have shown a similar spectrum of genetic alterations to those observed here during the somatic evolution of cancers in patients undergoing chemotherapy or treated with specific inhibitors.
“Indeed, several recent studies have shown a similar spectrum of genetic alterations to those observed here during the somatic evolution of cancers in patients undergoing chemotherapy (Podlaha et al., 2012; Landau et al., 2013) or treated with specific inhibitors (Ding et al., 2012) to those observed here.”
From The evolution of drug resistance in clinical isolates of Candida albicans. (2015) · cites this paper as Landau et al., 2013
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Self-citation
- Authors
- Landau, D. A., Carter, S. L., Stojanov, P., McKenna, A., Stevenson, K., Lawrence, M. S., Sougnez, C., Stewart, C., Sivachenko, A., Wang, L., Wan, Y., Zhang, W., Shukla, S. A., Vartanov, A., Fernandes, S. M., Saksena, G., Cibulskis, K., Tesar, B., Gabriel, S., Hacohen, N., Meyerson, M., Lander, E. S., Neuberg, D., Brown, J. R., Getz, G., & Wu, C. J.
- Affiliations
- Broad Institute (US)
- Dana-Farber Cancer Institute (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Getz, Gad
- Wu, Catherine J.
- ORCID
- Landau, Dan A.
- Carter, Scott L.
- McKenna, Aaron
- Stevenson, Kristen
- Lawrence, Michael S.
- Stewart, Chip
- Sivachenko, Andrey
- Wang, Lili
- Wan, Youzhong
- Zhang, Wandi
- Shukla, Sachet A.
- Vartanov, Alexander
- Fernandes, Stacey M.
- Saksena, Gordon
- Cibulskis, Kristian
- Tesar, Bethany
- Gabriel, Stacey
- Hacohen, Nir
- Meyerson, Matthew
- Lander, Eric S.
- Neuberg, Donna
- Brown, Jennifer R.
- Getz, Gad
- Wu, Catherine J.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-02
- Volume
- 152
- Issue
- 4
- Pages
- 714-726
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3575604
- OpenAlex
- W2088580309
- Cited by
- 1,379
- References
- 77
- Citations by year
- 2026: 29 · 2025: 38 · 2024: 47 · 2023: 70 · 2022: 94 · 2021: 110 · 2020: 86 · 2019: 103 · 2018: 134 · 2017: 133 · 2016: 156 · 2015: 144 · 2014: 147 · 2013: 85 · 2012: 1
- FWCI
- 87.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Heart, Lung, and Blood Institute (R01HL103532)
- National Human Genome Research Institute (U54HG003067)
- National Cancer Institute (K23CA115682, R01CA155010)
- Topics
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- chronic lymphocytic leukemia, clonal evolution, subclonal mutations, intratumoral heterogeneity, driver mutations, SF3B1, TP53, MyD88, trisomy 12, del(13q), copy number alterations, disease progression, chemotherapy, clonal expansion
- MeSH terms
- Algorithms, Animals, B-Lymphocytes, Humans, Mutation, Ploidies, Leukemia, Lymphocytic, Chronic, B-Cell, Genome-Wide Association Study, DNA Copy Number Variations
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