ID
45784
Descripción
Principal Investigator: Catherine Wu, MD, Dana Farber Cancer Institute, Boston, MA, USA MeSH: Leukemia, Lymphocytic, Chronic, B-Cell https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001091 We analyzed clonal evolution in serial samples from five CLL patients who became resistant to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, using whole-exome and deep targeted sequencing. We observe a BTK-C481S mutation in one of five patients, and multiple PLCG2 mutations in a second patient. The other patients had an expansion of clones harboring del(8p) carrying additional driver mutations (EP300, MLL2, EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. We calculated the growth kinetics of ibrutinib-resistant subclones and estimated the size of the resistant clones at treatment initiation, which we validated by droplet-microfluidic technology. Haplo-insufficiency of TRAIL-R, a consequence of del(8p), led to TRAIL insensitivity which may contribute to development of ibrutinib resistance. These findings demonstrate that ibrutinib therapy has the potential to lead to clonal selection and expansion of rare cell populations already present at the time of treatment initiation. They also provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance, previously attributed solely to mutations in BTK and related pathway molecules.
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Versiones (1)
- 21/6/23 21/6/23 - Chiara Middel
Titular de derechos de autor
Catherine Wu, MD, Dana Farber Cancer Institute, Boston, MA, USA
Subido en
21 de junio de 2023
DOI
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Licencia
Creative Commons BY 4.0
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dbGaP phs001091 Clonal Evolution in Patients with Chronic Lymphocytic Leukemia
The subject consent file includes subject IDs and consent information.
- StudyEvent: SEV1
- The subject consent file includes subject IDs and consent information.
- This data table contains a mapping of study subject IDs to sample IDs. Samples are the final preps submitted for genotyping, sequencing, and/or expression data. For example, if one patient (subject ID) gave one sample, and that sample was processed differently to generate 2 sequencing runs, there would be two rows, both using the same subject ID, but having 2 unique sample IDs. The data table also includes sample use.
- This subject phenotype table contains subject IDs, gender, age, primary disease, mutational status of the IgHV genes, and chromosomal alterations as identified by FISH.
- This sample attributes table contains sample IDs, sample type, tumor type, and analyte type.
Similar models
The subject consent file includes subject IDs and consent information.
- StudyEvent: SEV1
- The subject consent file includes subject IDs and consent information.
- This data table contains a mapping of study subject IDs to sample IDs. Samples are the final preps submitted for genotyping, sequencing, and/or expression data. For example, if one patient (subject ID) gave one sample, and that sample was processed differently to generate 2 sequencing runs, there would be two rows, both using the same subject ID, but having 2 unique sample IDs. The data table also includes sample use.
- This subject phenotype table contains subject IDs, gender, age, primary disease, mutational status of the IgHV genes, and chromosomal alterations as identified by FISH.
- This sample attributes table contains sample IDs, sample type, tumor type, and analyte type.
C0441833 (UMLS CUI [1,2])
C0242481 (UMLS CUI [1,2])