Association of gene mutations with time-to-first treatment in 384 treatment-naive chronic lymphocytic leukaemia patients
Boyu Hu
Division of Hematology/Hematologic Malignancies, Huntsman Cancer Institute, Salt Lake City, UT, USA
Search for more papers by this authorKeyur P. Patel
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorHsiang-Chun Chen
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorXuemei Wang
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorRajyalakshmi Luthra
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorMark J. Routbort
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorRashmi Kanagal-Shamanna
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorL. Jeffrey Medeiros
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorC. Cameron Yin
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorZhuang Zuo
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorChi Y. Ok
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorSanam Loghavi
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorGuilin Tang
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorFrancesco P. Tambaro
S.S.D. TMO - AORN Santobono-Pausilipon, Napoli, Italy
Search for more papers by this authorPhilip Thompson
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorJan Burger
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorNitin Jain
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorAlessandra Ferrajoli
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorPrithviraj Bose
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorZeev Estrov
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorMichael Keating
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorCorresponding Author
William G. Wierda
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Correspondence: William G. Wierda, Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit #428, Houston, TX 77030, USA.
E-mail: [email protected]
Search for more papers by this authorBoyu Hu
Division of Hematology/Hematologic Malignancies, Huntsman Cancer Institute, Salt Lake City, UT, USA
Search for more papers by this authorKeyur P. Patel
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorHsiang-Chun Chen
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorXuemei Wang
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorRajyalakshmi Luthra
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorMark J. Routbort
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorRashmi Kanagal-Shamanna
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorL. Jeffrey Medeiros
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorC. Cameron Yin
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorZhuang Zuo
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorChi Y. Ok
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorSanam Loghavi
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorGuilin Tang
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorFrancesco P. Tambaro
S.S.D. TMO - AORN Santobono-Pausilipon, Napoli, Italy
Search for more papers by this authorPhilip Thompson
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorJan Burger
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorNitin Jain
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorAlessandra Ferrajoli
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorPrithviraj Bose
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorZeev Estrov
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorMichael Keating
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorCorresponding Author
William G. Wierda
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Correspondence: William G. Wierda, Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit #428, Houston, TX 77030, USA.
E-mail: [email protected]
Search for more papers by this authorSummary
This study correlated somatic mutation results and known prognostic factors with time-to-first treatment (TTFT) in 384 treatment-naïve (TN) chronic lymphocytic leukaemia (CLL) patients to help determine disease-specific drivers of early untreated CLL. CLL DNA from either peripheral blood or bone marrow underwent next generation targeted sequencing with a 29-gene panel. Gene mutation data and concurrent clinical characteristics, such as Rai/Binet stage, fluorescence in situ hybridisation (FISH), ZAP70/CD38, karyotype and IGHV mutation, status were analysed in univariable and multivariable analyses to identify associations with TTFT. TTFT was defined as time from diagnosis to initial treatment. In univariable analyses, mutated ATM (P < 0·001), NOTCH1 (P < 0·001) and SF3B1 (P = 0·002) as well as unmutated IGHV (P < 0·001), del(11q) (P < 0·001) and trisomy 12 (P < 0·001) by hierarchal FISH and advanced Rai (P = 0·05) and Binet (P < 0·001) stages were associated with shorter TTFT. Importantly, del(17p), mutated TP53 and complex karyotype were not associated with shorter TTFT. In a reduced multivariable analysis, mutated ATM (P < 0·001) and unmutated IGHV status (P < 0·001) remained significant, showing their importance in early leukaemogenesis. High-risk prognostic markers such as del(17p), mutated TP53 and complex karyotype, were not correlated with TTFT, suggesting that these abnormalities have limited roles in early disease progression but are more important in relapsed CLL.
Conflicts of Interest
All authors have no conflicts to disclose.
Supporting Information
| Filename | Description |
|---|---|
| bjh16042-sup-0001-Supinfo.docxapplication/docx, 56.9 KB |
Table S1. Exons sequenced of the 29 genes within the END CLL Assay V1 panel. Table S2. Median time to first treatment of selected mutations that were not statistically significant in a univariate analysis. Table S3. Modified reduced model of the multivariate analysis with addition of the del(11q)/ATM mutation co-occurrence, which included 234 patients. Table S4. Modified reduced model of the multivariate analysis with addition of the del(11q)/SF3B1 mutation co-occurrence, which included 234 patients. Table S5. Modified reduced model of the multivariate analysis with addition of the trisomy 12/NOTCH1 mutation co-occurrence, which included 198 patients. Table S6. Comparison of the location of mutations in certain genes and its effects on median time to first treatment. Fig S1. Scatter plot of tumor purity graphed against the variant allele frequency (VAF) detected in each sample according to mutation. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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