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Mutations driving CLL and their evolution in progression and relapse.

Landau DA, Tausch E, Taylor-Weiner AN, Stewart C, Reiter JG, Bahlo J, Kluth S, Bozic I, Lawrence M, Böttcher S, Carter SL, Cibulskis K, Mertens D, Sougnez CL, Rosenberg M, Hess JM, Edelmann J, Kless S, Kneba M, Ritgen M, Fink A, Fischer K, Gabriel S, Lander ES, Nowak MA, Döhner H, Hallek M, Neuberg D, Getz G, Stilgenbauer S, Wu CJ - Nature (2015)

Bottom Line: Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology.Direct comparison between matched pre-treatment and relapse samples from 59 patients demonstrated highly frequent clonal evolution.Thus, large sequencing data sets of clinically informative samples enable the discovery of novel genes associated with cancer, the network of relationships between the driver events, and their impact on disease relapse and clinical outcome.

View Article: PubMed Central - PubMed

Affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.

ABSTRACT
Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. Here we identify 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 chronic lymphocytic leukaemia (CLL) and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These include previously unrecognized putative cancer drivers (RPS15, IKZF3), and collectively identify RNA processing and export, MYC activity, and MAPK signalling as central pathways involved in CLL. Clonality analysis of this large data set further enabled reconstruction of temporal relationships between driver events. Direct comparison between matched pre-treatment and relapse samples from 59 patients demonstrated highly frequent clonal evolution. Thus, large sequencing data sets of clinically informative samples enable the discovery of novel genes associated with cancer, the network of relationships between the driver events, and their impact on disease relapse and clinical outcome.

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Cellular networks and processes affected by putative CLL driversPutative CLL cancer genes cluster in pathways that are central to CLL biology such as Notch signaling, inflammatory response and B cell receptor signaling. In addition, proteins that participate in central cellular processes such as DNA damage repair, chromatin modification and mRNA processing, export and translation are also recurrently affected. Boxed in yellow—new CLL subpathways highlighted by the current driver discovery effort. Red circles- putative driver genes previously identified3 ; purple circles- newly identified in the current study.
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Figure 7: Cellular networks and processes affected by putative CLL driversPutative CLL cancer genes cluster in pathways that are central to CLL biology such as Notch signaling, inflammatory response and B cell receptor signaling. In addition, proteins that participate in central cellular processes such as DNA damage repair, chromatin modification and mRNA processing, export and translation are also recurrently affected. Boxed in yellow—new CLL subpathways highlighted by the current driver discovery effort. Red circles- putative driver genes previously identified3 ; purple circles- newly identified in the current study.

Mentions: We detected 44 putative CLL driver genes, including 18 CLL mutated drivers that we previously identified3, as well as 26 additional putative CLL genes (Fig. 1-2, Extended Data Fig. 1-2). In total, 33.5% of CLLs harbored mutation in at least one of these 26 additional genes. Targeted DNA sequencing as well as variant allele expression by RNAseq demonstrated high rates of orthogonal validation (Extended Data Fig. 3).


Mutations driving CLL and their evolution in progression and relapse.

Landau DA, Tausch E, Taylor-Weiner AN, Stewart C, Reiter JG, Bahlo J, Kluth S, Bozic I, Lawrence M, Böttcher S, Carter SL, Cibulskis K, Mertens D, Sougnez CL, Rosenberg M, Hess JM, Edelmann J, Kless S, Kneba M, Ritgen M, Fink A, Fischer K, Gabriel S, Lander ES, Nowak MA, Döhner H, Hallek M, Neuberg D, Getz G, Stilgenbauer S, Wu CJ - Nature (2015)

Cellular networks and processes affected by putative CLL driversPutative CLL cancer genes cluster in pathways that are central to CLL biology such as Notch signaling, inflammatory response and B cell receptor signaling. In addition, proteins that participate in central cellular processes such as DNA damage repair, chromatin modification and mRNA processing, export and translation are also recurrently affected. Boxed in yellow—new CLL subpathways highlighted by the current driver discovery effort. Red circles- putative driver genes previously identified3 ; purple circles- newly identified in the current study.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4815041&req=5

Figure 7: Cellular networks and processes affected by putative CLL driversPutative CLL cancer genes cluster in pathways that are central to CLL biology such as Notch signaling, inflammatory response and B cell receptor signaling. In addition, proteins that participate in central cellular processes such as DNA damage repair, chromatin modification and mRNA processing, export and translation are also recurrently affected. Boxed in yellow—new CLL subpathways highlighted by the current driver discovery effort. Red circles- putative driver genes previously identified3 ; purple circles- newly identified in the current study.
Mentions: We detected 44 putative CLL driver genes, including 18 CLL mutated drivers that we previously identified3, as well as 26 additional putative CLL genes (Fig. 1-2, Extended Data Fig. 1-2). In total, 33.5% of CLLs harbored mutation in at least one of these 26 additional genes. Targeted DNA sequencing as well as variant allele expression by RNAseq demonstrated high rates of orthogonal validation (Extended Data Fig. 3).

Bottom Line: Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology.Direct comparison between matched pre-treatment and relapse samples from 59 patients demonstrated highly frequent clonal evolution.Thus, large sequencing data sets of clinically informative samples enable the discovery of novel genes associated with cancer, the network of relationships between the driver events, and their impact on disease relapse and clinical outcome.

View Article: PubMed Central - PubMed

Affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.

ABSTRACT
Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. Here we identify 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 chronic lymphocytic leukaemia (CLL) and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These include previously unrecognized putative cancer drivers (RPS15, IKZF3), and collectively identify RNA processing and export, MYC activity, and MAPK signalling as central pathways involved in CLL. Clonality analysis of this large data set further enabled reconstruction of temporal relationships between driver events. Direct comparison between matched pre-treatment and relapse samples from 59 patients demonstrated highly frequent clonal evolution. Thus, large sequencing data sets of clinically informative samples enable the discovery of novel genes associated with cancer, the network of relationships between the driver events, and their impact on disease relapse and clinical outcome.

Show MeSH
Related in: MedlinePlus