Emerging landscape of oncogenic signatures across human cancers
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Raunak ShresthaPhD Student (Bioinformatics)
Dr. Colin Collin’s Lab31st October 2013
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The Cancer Genome Atlas Pan-Cancer analysis project
Ashworth & Hudson. Nature 502, 306–307 (17 October 2013)
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Two fundamental observations across various cancer types
• tumors originating in the same organ or tissue vary substantially in genomic alterations
• similar patterns of genomic alteration are observed in tumors from different tissues of origin
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In brief• Analyzed >3000 tumors across 12 different cancer types• integrated multiple types of alterations (genomic & epigenomic)• Used hierarchical stratification approach to obtain clusters of
tumors• Observed two major clusters of tumors
– Cluster I: primarily with somatic mutation (M class)– Cluster II: primarily with copy number alterations (C class)
• Observed a striking inverse relationship between # of copy number alterations & # of somatic mutations (when averaged over 12 cancer types)
• Oncogenic signatures were used to derive the oncogenic pathways
• Nominated therapeutically actionable targets across tumor types
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3299 tumors from 12 cancer types 3299 tumors
Recurrentevents
Selected Functional
Events (SFE)
116 Gains151 Losses199 Mutations13 Meth
Somatic Mutations
Copy Number Alterations
DNA Methylation events
Geneexpression
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Hierarchical ClassificationM Class (primarily with mutations)
C Class (primarily with copy number alterations)
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Cancer Genome Hyperbola
inverse relationship between # of copy number alterations & # of somatic mutations (when averaged over 12 cancer types)
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Cancer Genome Hyperbola
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ARID1A is a member of the chromatin-remodeling complex SWI/SNF and, although truncating mutations in this gene have been reported in several tumor types, no recurrent hotspot had previously been identified.
CTCF encodes a chromatin-binding factor that acts as both a repressor and an activator of multiple genes, including known oncogenes and tumor suppressor genes (MYC, PLK, PIM1, CDKN2A and IGF2)
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From Oncogenesis to Therapy
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From Oncogenesis to Therapy
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Summary
• Tissue-independent classification of tumors on the basis of genetic and epigenetic alterations;– Thousands of molecular alterations to a few hundred plausibly
functional events.– Stratify tumors on the basis of distinct patterns of those
selected alteration events.
• Hierarchical classification identified M class and C class of tumors, and their subclasses
• Provide insight into the mechanisms of oncogenesis and therapeutically actionable alterations
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