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Emerging landscape of oncogenic signatures across human cancers.

Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, Schultz N, Sander C - Nat. Genet. (2013)

Bottom Line: Cancer therapy is challenged by the diversity of molecular implementations of oncogenic processes and by the resulting variation in therapeutic responses.The top classes are dominated by either mutations (M class) or copy number changes (C class).This distinction is clearest at the extremes of genomic instability, indicating the presence of different oncogenic processes.

View Article: PubMed Central - PubMed

Affiliation: Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

ABSTRACT
Cancer therapy is challenged by the diversity of molecular implementations of oncogenic processes and by the resulting variation in therapeutic responses. Projects such as The Cancer Genome Atlas (TCGA) provide molecular tumor maps in unprecedented detail. The interpretation of these maps remains a major challenge. Here we distilled thousands of genetic and epigenetic features altered in cancers to ∼500 selected functional events (SFEs). Using this simplified description, we derived a hierarchical classification of 3,299 TCGA tumors from 12 cancer types. The top classes are dominated by either mutations (M class) or copy number changes (C class). This distinction is clearest at the extremes of genomic instability, indicating the presence of different oncogenic processes. The full hierarchy shows functional event patterns characteristic of multiple cross-tissue groups of tumors, termed oncogenic signature classes. Targetable functional events in a tumor class are suggestive of class-specific combination therapy. These results may assist in the definition of clinical trials to match actionable oncogenic signatures with personalized therapies.

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Related in: MedlinePlus

Map of functional and actionable alterations across 12 tumor types. Genes (rows) encoding components of four major oncogenic pathways (RTK-RAS-RAF, PI3K-AKT-mTOR, cell cycle and p53–DNA repair; shown schematically in the pathway column) are affected by selected functional events (percent of samples altered and types of alteration are represented by colored squares) across tissue-specific tumor types (columns). Alterations to at least one of these pathways are observed in almost all samples of almost all tumor types (stacked green bar plots at bottom), except in KIRC and LAML. A sizable fraction of these alterations are directly or indirectly therapeutically actionable given the current availability of anticancer drugs (the column with drug family information shows the targets of specific inhibitors). Tumor types abbreviated as in Table 1.
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Figure 4: Map of functional and actionable alterations across 12 tumor types. Genes (rows) encoding components of four major oncogenic pathways (RTK-RAS-RAF, PI3K-AKT-mTOR, cell cycle and p53–DNA repair; shown schematically in the pathway column) are affected by selected functional events (percent of samples altered and types of alteration are represented by colored squares) across tissue-specific tumor types (columns). Alterations to at least one of these pathways are observed in almost all samples of almost all tumor types (stacked green bar plots at bottom), except in KIRC and LAML. A sizable fraction of these alterations are directly or indirectly therapeutically actionable given the current availability of anticancer drugs (the column with drug family information shows the targets of specific inhibitors). Tumor types abbreviated as in Table 1.

Mentions: To explore the relationship between functional alterations and therapeutic interventions in more detail, we first assessed the distribution of potentially actionable alterations in different tissue-specific tumor types, focusing on a subset of the ~500 SFEs with well-characterized roles in pathways (Fig. 4). As is well known, such alterations are typically not exclusive to one tumor type, nor are they, with few exceptions, present in 100% of samples in a particular tumor type.


Emerging landscape of oncogenic signatures across human cancers.

Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, Schultz N, Sander C - Nat. Genet. (2013)

Map of functional and actionable alterations across 12 tumor types. Genes (rows) encoding components of four major oncogenic pathways (RTK-RAS-RAF, PI3K-AKT-mTOR, cell cycle and p53–DNA repair; shown schematically in the pathway column) are affected by selected functional events (percent of samples altered and types of alteration are represented by colored squares) across tissue-specific tumor types (columns). Alterations to at least one of these pathways are observed in almost all samples of almost all tumor types (stacked green bar plots at bottom), except in KIRC and LAML. A sizable fraction of these alterations are directly or indirectly therapeutically actionable given the current availability of anticancer drugs (the column with drug family information shows the targets of specific inhibitors). Tumor types abbreviated as in Table 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4320046&req=5

Figure 4: Map of functional and actionable alterations across 12 tumor types. Genes (rows) encoding components of four major oncogenic pathways (RTK-RAS-RAF, PI3K-AKT-mTOR, cell cycle and p53–DNA repair; shown schematically in the pathway column) are affected by selected functional events (percent of samples altered and types of alteration are represented by colored squares) across tissue-specific tumor types (columns). Alterations to at least one of these pathways are observed in almost all samples of almost all tumor types (stacked green bar plots at bottom), except in KIRC and LAML. A sizable fraction of these alterations are directly or indirectly therapeutically actionable given the current availability of anticancer drugs (the column with drug family information shows the targets of specific inhibitors). Tumor types abbreviated as in Table 1.
Mentions: To explore the relationship between functional alterations and therapeutic interventions in more detail, we first assessed the distribution of potentially actionable alterations in different tissue-specific tumor types, focusing on a subset of the ~500 SFEs with well-characterized roles in pathways (Fig. 4). As is well known, such alterations are typically not exclusive to one tumor type, nor are they, with few exceptions, present in 100% of samples in a particular tumor type.

Bottom Line: Cancer therapy is challenged by the diversity of molecular implementations of oncogenic processes and by the resulting variation in therapeutic responses.The top classes are dominated by either mutations (M class) or copy number changes (C class).This distinction is clearest at the extremes of genomic instability, indicating the presence of different oncogenic processes.

View Article: PubMed Central - PubMed

Affiliation: Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

ABSTRACT
Cancer therapy is challenged by the diversity of molecular implementations of oncogenic processes and by the resulting variation in therapeutic responses. Projects such as The Cancer Genome Atlas (TCGA) provide molecular tumor maps in unprecedented detail. The interpretation of these maps remains a major challenge. Here we distilled thousands of genetic and epigenetic features altered in cancers to ∼500 selected functional events (SFEs). Using this simplified description, we derived a hierarchical classification of 3,299 TCGA tumors from 12 cancer types. The top classes are dominated by either mutations (M class) or copy number changes (C class). This distinction is clearest at the extremes of genomic instability, indicating the presence of different oncogenic processes. The full hierarchy shows functional event patterns characteristic of multiple cross-tissue groups of tumors, termed oncogenic signature classes. Targetable functional events in a tumor class are suggestive of class-specific combination therapy. These results may assist in the definition of clinical trials to match actionable oncogenic signatures with personalized therapies.

Show MeSH
Related in: MedlinePlus