EHA Library - The official digital education library of European Hematology Association (EHA)

CLINICAL IMPACT OF THE SUBCLONAL ARCHITECTURE AND MUTATIONAL COMPLEXITY IN CHRONIC LYMPHOCYTIC LEUKEMIA
Author(s): ,
Ferran Nadeu
Affiliations:
IDIBAPS,Barcelona,Spain;CIBERONC,Madrid,Spain
,
Guillem Clot
Affiliations:
IDIBAPS,Barcelona,Spain;CIBERONC,Madrid,Spain
,
Julio Delgado
Affiliations:
IDIBAPS,Barcelona,Spain;Hospital Clínic de Barcelona,Barcelona,Spain;CIBERONC,Madrid,Spain
,
David Martín-García
Affiliations:
IDIBAPS,Barcelona,Spain;CIBERONC,Madrid,Spain
,
Tycho Baumann
Affiliations:
Hospital Clínic de Barcelona,Barcelona,Spain
,
Itziar Salaverria
Affiliations:
IDIBAPS,Barcelona,Spain;CIBERONC,Madrid,Spain
,
Sílvia Beà
Affiliations:
IDIBAPS,Barcelona,Spain;CIBERONC,Madrid,Spain
,
Magda Pinyol
Affiliations:
Unitat de Genòmica,IDIBAPS,Barcelona,Spain;CIBERONC,Madrid,Spain
,
Pedro Jares
Affiliations:
IDIBAPS,Barcelona,Spain;Hospital Clínic de Barcelona,Barcelona,Spain;CIBERONC,Madrid,Spain
,
Alba Navarro
Affiliations:
IDIBAPS,Barcelona,Spain;CIBERONC,Madrid,Spain
,
Helena Suárez-Cisneros
Affiliations:
Unitat de Genòmica,IDIBAPS,Barcelona,Spain
,
Marta Aymerich
Affiliations:
IDIBAPS,Barcelona,Spain;Hospital Clínic de Barcelona,Barcelona,Spain;CIBERONC,Madrid,Spain
,
Maria Rozman
Affiliations:
IDIBAPS,Barcelona,Spain;Hospital Clínic de Barcelona,Barcelona,Spain;CIBERONC,Madrid,Spain
,
Neus Villamor
Affiliations:
IDIBAPS,Barcelona,Spain;Hospital Clínic de Barcelona,Barcelona,Spain;CIBERONC,Madrid,Spain
,
Dolors Colomer
Affiliations:
IDIBAPS,Barcelona,Spain;Hospital Clínic de Barcelona,Barcelona,Spain;CIBERONC,Madrid,Spain
,
Marcos González
Affiliations:
Hospital Universitario,Salamanca,Spain;CIBERONC,Madrid,Spain
,
Miguel Alcoceba
Affiliations:
Hospital Universitario,Salamanca,Spain;CIBERONC,Madrid,Spain
,
Maria José Terol
Affiliations:
Hospital Clínico Universitario,Valencia,Spain
,
Blanca Navarro
Affiliations:
Hospital Clínico Universitario,Valencia,Spain
,
Enrique Colado
Affiliations:
Hospital Universitario Central de Asturias,Oviedo,Spain
,
Xose S Puente
Affiliations:
Instituto Universitario de Oncología, Universidad de Oviedo,Oviedo,Spain;CIBERONC,Madrid,Spain
,
Carlos López-Otín
Affiliations:
Instituto Universitario de Oncología, Universidad de Oviedo,Oviedo,Spain;CIBERONC,Madrid,Spain
,
Armando López-Guillermo
Affiliations:
IDIBAPS,Barcelona,Spain;Hospital Clínic de Barcelona,Barcelona,Spain;Universitat de Barcelona,Barcelona,Spain;CIBERONC,Madrid,Spain
,
Anna Enjuanes
Affiliations:
Unitat de Genòmica,IDIBAPS,Barcelona,Spain;CIBERONC,Madrid,Spain
Elías Campo
Affiliations:
IDIBAPS,Barcelona,Spain;Hospital Clínic de Barcelona,Barcelona,Spain;Universitat de Barcelona,Barcelona,Spain;CIBERONC,Madrid,Spain
(Abstract release date: 05/18/17) EHA Library. Nadeu F. 06/23/17; 181402; S115
Ferran Nadeu
Ferran Nadeu
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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