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Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia

Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia
Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia
The identification of new genetic lesions in chronic lymphocytic leukemia (CLL) prompts a comprehensive and dynamic prognostic algorithm including gene mutations and chromosomal abnormalities and their changes during clonal evolution. By integrating mutational and cytogenetic analysis in 1274 CLL samples and using both a training-validation and a time-dependent design, 4 CLL subgroups were hierarchically classified: (1) high-risk, harboring TP53 and/or BIRC3 abnormalities (10-year survival: 29%); (2) intermediate-risk, harboring NOTCH1 and/or SF3B1 mutations and/or del11q22-q23 (10-year survival: 37%); (3) low-risk, harboring +12 or a normal genetics (10-year survival: 57%); and (4) very low-risk, harboring del13q14 only, whose 10-year survival (69.3%) did not significantly differ from a matched general population. This integrated mutational and cytogenetic model independently predicted survival, improved CLL prognostication accuracy compared with FISH karyotype (P < .0001), and was externally validated in an independent CLL cohort. Clonal evolution from lower to higher risk implicated the emergence of NOTCH1, SF3B1, and BIRC3 abnormalities in addition to TP53 and 11q22-q23 lesions. By taking into account clonal evolution through time-dependent analysis, the genetic model maintained its prognostic relevance at any time from diagnosis. These findings may have relevant implications for the design of clinical trials aimed at assessing the use of mutational profiling to inform therapeutic decisions.
0006-4971
1403-1412
Rossi, Davide
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Rasi, Silvia
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Spina, Valeria
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Bruscaggin, Alessio
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Monti, Sara
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Ciardullo, Carmela
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Deambrogi, Clara
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Khiabanian, Hossein
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Serra, Roberto
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Bertoni, Francesco
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Forconi, Francesco
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Laurenti, Luca
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Marasca, Roberto
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Dal-Bo, Michele
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Rossi, Francesca Maria
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Bulian, Pietro
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Nomdedeu, Josep
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Del Poeta, Giovanni
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Gattei, Valter
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Pasqualucci, Laura
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Rabadan, Raul
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Foà, Robin
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Dalla-Favera, Riccardo
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Gaidano, Gianluca
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Rossi, Davide
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Rasi, Silvia
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Spina, Valeria
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Bruscaggin, Alessio
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Monti, Sara
b8d4905b-c63d-47bf-a30a-993be44e0799
Ciardullo, Carmela
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Deambrogi, Clara
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Khiabanian, Hossein
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Serra, Roberto
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Bertoni, Francesco
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Forconi, Francesco
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Laurenti, Luca
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Marasca, Roberto
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Dal-Bo, Michele
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Rossi, Francesca Maria
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Bulian, Pietro
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Nomdedeu, Josep
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Del Poeta, Giovanni
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Gattei, Valter
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Pasqualucci, Laura
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Rabadan, Raul
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Foà, Robin
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Dalla-Favera, Riccardo
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Gaidano, Gianluca
1a6a7107-107b-4891-82e0-5fedadd2f65a

Rossi, Davide, Rasi, Silvia, Spina, Valeria, Bruscaggin, Alessio, Monti, Sara, Ciardullo, Carmela, Deambrogi, Clara, Khiabanian, Hossein, Serra, Roberto, Bertoni, Francesco, Forconi, Francesco, Laurenti, Luca, Marasca, Roberto, Dal-Bo, Michele, Rossi, Francesca Maria, Bulian, Pietro, Nomdedeu, Josep, Del Poeta, Giovanni, Gattei, Valter, Pasqualucci, Laura, Rabadan, Raul, Foà, Robin, Dalla-Favera, Riccardo and Gaidano, Gianluca (2013) Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood, 121 (8), 1403-1412. (doi:10.1182/blood-2012-09-458265). (PMID:23243274)

Record type: Article

Abstract

The identification of new genetic lesions in chronic lymphocytic leukemia (CLL) prompts a comprehensive and dynamic prognostic algorithm including gene mutations and chromosomal abnormalities and their changes during clonal evolution. By integrating mutational and cytogenetic analysis in 1274 CLL samples and using both a training-validation and a time-dependent design, 4 CLL subgroups were hierarchically classified: (1) high-risk, harboring TP53 and/or BIRC3 abnormalities (10-year survival: 29%); (2) intermediate-risk, harboring NOTCH1 and/or SF3B1 mutations and/or del11q22-q23 (10-year survival: 37%); (3) low-risk, harboring +12 or a normal genetics (10-year survival: 57%); and (4) very low-risk, harboring del13q14 only, whose 10-year survival (69.3%) did not significantly differ from a matched general population. This integrated mutational and cytogenetic model independently predicted survival, improved CLL prognostication accuracy compared with FISH karyotype (P < .0001), and was externally validated in an independent CLL cohort. Clonal evolution from lower to higher risk implicated the emergence of NOTCH1, SF3B1, and BIRC3 abnormalities in addition to TP53 and 11q22-q23 lesions. By taking into account clonal evolution through time-dependent analysis, the genetic model maintained its prognostic relevance at any time from diagnosis. These findings may have relevant implications for the design of clinical trials aimed at assessing the use of mutational profiling to inform therapeutic decisions.

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More information

e-pub ahead of print date: 13 December 2012
Published date: 21 February 2013
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 358104
URI: http://eprints.soton.ac.uk/id/eprint/358104
ISSN: 0006-4971
PURE UUID: 02f673e5-e55e-496e-b3e4-0b02bba530f9
ORCID for Francesco Forconi: ORCID iD orcid.org/0000-0002-2211-1831

Catalogue record

Date deposited: 04 Oct 2013 09:53
Last modified: 15 Mar 2024 03:40

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Contributors

Author: Davide Rossi
Author: Silvia Rasi
Author: Valeria Spina
Author: Alessio Bruscaggin
Author: Sara Monti
Author: Carmela Ciardullo
Author: Clara Deambrogi
Author: Hossein Khiabanian
Author: Roberto Serra
Author: Francesco Bertoni
Author: Luca Laurenti
Author: Roberto Marasca
Author: Michele Dal-Bo
Author: Francesca Maria Rossi
Author: Pietro Bulian
Author: Josep Nomdedeu
Author: Giovanni Del Poeta
Author: Valter Gattei
Author: Laura Pasqualucci
Author: Raul Rabadan
Author: Robin Foà
Author: Riccardo Dalla-Favera
Author: Gianluca Gaidano

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