emerging landscape of oncogenic signatures across human cancers

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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