CLINICAL IMPACT OF THE SUBCLONAL ARCHITECTURE AND MUTATIONAL COMPLEXITY IN CHRONIC LYMPHOCYTIC LEUKEMIA
(Abstract release date: 05/18/17)
EHA Library. Nadeu F. 06/23/17; 181402; S115
Ferran Nadeu
Contributions
Contributions
Abstract
Abstract: S115
Type: Oral Presentation
Presentation during EHA22: On Friday, June 23, 2017 from 11:30 - 11:45
Location: Hall D
Background
Recent studies have revealed the presence and prognostic impact of small mutated subclones in chronic lymphocytic leukemia (CLL) (Rossi et al 2014, Nadeu et al 2016, Rasi et al 2016). Although these studies focused only on a small subset of 5 genes, their results opened a new perspective where the proportion of cells carrying each specific driver mutation may be relevant to the evolution of this disease. Moreover, the subclonal and mutational complexity estimated by the presence of subclonal driver alterations (Landau et al 2013, Landau et al 2015) or the accumulation of driver alterations (Puente et al 2015) have been proposed as promising indicators of clinical behavior.
Aims
The goal of this study was to determine the relevance of the quantitative subclonal architecture and mutational complexity in the evolution of CLL integrating the deep sequencing analysis of a large panel of driver genes and DNA copy number alterations (CNA).
Methods
The mutational status of 28 driver genes was investigated in 406 previously untreated CLL patients by targeted-deep next-generation sequencing (NGS). Mutations present in less than 1% of tumor cells were identified. All low frequency mutations were verified by allele-specific PCR or a second round of NGS. CNA were analyzed by SNP-arrays. Alterations were classified as clonal if their CCF was ≥85%, and subclonal otherwise. All patients gave informed consent.
Results
Using a highly sensitive NGS strategy we observed that small subclonal mutations were the sole alteration in 22% of the mutated cases, and were frequently detected in nearly all investigated genes. We identified three gene-specific patterns that linked the magnitude of the mutated clones (or mutated cancer cell fraction, CCF) with the prognosis of the patients: i) CCF-independent pattern: mutations at any CCF had prognostic value, ii) CCF-gradual pattern: the poor prognostic impact was a continuous variable directly related to the size of the clone, and iii) CCF-clonal pattern: only mutations with a CCF above a certain threshold impacted the outcome of the patients.
Combining mutations and driver CNA, 86% of the patients carried at least one driver alteration, which was clonal in 66%. On the other hand, subclonal driver alterations were present in 60% of the patients. The mutational complexity (accumulation of 1 to ≥4 driver alterations), but not the presence of subclonal driver populations, gradually shortened the time to first treatment independently of the IGHV mutational status and Binet stage. Conversely, the subclonal complexity, defined as the accumulation of driver alterations with the presence of at least one driver subclone, predicted for a worse overall survival independently of the IGHV and Binet stage. Patients with a pure clonal population (presence of one or more driver alterations in all tumor cells) had a similar overall survival than patients without any alteration.
Conclusion
Our study shows that the prognostic impact of different driver mutations is related to the size of the mutated population. Therefore, the clinical evaluation of gene mutations should consider the quantitative representation of the mutations and not only their presence or absence. In addition, the mutational complexity predicts for shorter time to first treatment independently of the IGHV and Binet stage, whereas the subclonal complexity confers an independent adverse impact for overall survival. Altogether, the integration of the subclonal architecture and mutational complexity in prognostic indexes may improve the stratification of CLL patients.
Session topic: 5. Chronic lymphocytic leukemia and related disorders - Biology
Keyword(s): prognosis, mutation analysis, Chronic Lymphocytic Leukemia
Abstract: S115
Type: Oral Presentation
Presentation during EHA22: On Friday, June 23, 2017 from 11:30 - 11:45
Location: Hall D
Background
Recent studies have revealed the presence and prognostic impact of small mutated subclones in chronic lymphocytic leukemia (CLL) (Rossi et al 2014, Nadeu et al 2016, Rasi et al 2016). Although these studies focused only on a small subset of 5 genes, their results opened a new perspective where the proportion of cells carrying each specific driver mutation may be relevant to the evolution of this disease. Moreover, the subclonal and mutational complexity estimated by the presence of subclonal driver alterations (Landau et al 2013, Landau et al 2015) or the accumulation of driver alterations (Puente et al 2015) have been proposed as promising indicators of clinical behavior.
Aims
The goal of this study was to determine the relevance of the quantitative subclonal architecture and mutational complexity in the evolution of CLL integrating the deep sequencing analysis of a large panel of driver genes and DNA copy number alterations (CNA).
Methods
The mutational status of 28 driver genes was investigated in 406 previously untreated CLL patients by targeted-deep next-generation sequencing (NGS). Mutations present in less than 1% of tumor cells were identified. All low frequency mutations were verified by allele-specific PCR or a second round of NGS. CNA were analyzed by SNP-arrays. Alterations were classified as clonal if their CCF was ≥85%, and subclonal otherwise. All patients gave informed consent.
Results
Using a highly sensitive NGS strategy we observed that small subclonal mutations were the sole alteration in 22% of the mutated cases, and were frequently detected in nearly all investigated genes. We identified three gene-specific patterns that linked the magnitude of the mutated clones (or mutated cancer cell fraction, CCF) with the prognosis of the patients: i) CCF-independent pattern: mutations at any CCF had prognostic value, ii) CCF-gradual pattern: the poor prognostic impact was a continuous variable directly related to the size of the clone, and iii) CCF-clonal pattern: only mutations with a CCF above a certain threshold impacted the outcome of the patients.
Combining mutations and driver CNA, 86% of the patients carried at least one driver alteration, which was clonal in 66%. On the other hand, subclonal driver alterations were present in 60% of the patients. The mutational complexity (accumulation of 1 to ≥4 driver alterations), but not the presence of subclonal driver populations, gradually shortened the time to first treatment independently of the IGHV mutational status and Binet stage. Conversely, the subclonal complexity, defined as the accumulation of driver alterations with the presence of at least one driver subclone, predicted for a worse overall survival independently of the IGHV and Binet stage. Patients with a pure clonal population (presence of one or more driver alterations in all tumor cells) had a similar overall survival than patients without any alteration.
Conclusion
Our study shows that the prognostic impact of different driver mutations is related to the size of the mutated population. Therefore, the clinical evaluation of gene mutations should consider the quantitative representation of the mutations and not only their presence or absence. In addition, the mutational complexity predicts for shorter time to first treatment independently of the IGHV and Binet stage, whereas the subclonal complexity confers an independent adverse impact for overall survival. Altogether, the integration of the subclonal architecture and mutational complexity in prognostic indexes may improve the stratification of CLL patients.
Session topic: 5. Chronic lymphocytic leukemia and related disorders - Biology
Keyword(s): prognosis, mutation analysis, Chronic Lymphocytic Leukemia
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