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Emerging landscape of oncogenic signatures across human cancers

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Information about Emerging landscape of oncogenic signatures across human cancers
Health & Medicine

Published on March 14, 2014

Author: raunakms1

Source: slideshare.net

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Emerging landscape of oncogenic signatures across human cancers
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Raunak Shrestha PhD Student (Bioinformatics) Dr. Colin Collin’s Lab 31st October 2013

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The Cancer Genome Atlas Pan-Cancer analysis project 3 Ashworth & Hudson. Nature 502, 306–307 (17 October 2013)

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 4

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 5

3299 tumors from 12 cancer types 6 3299 tumors Recurrent events Selected Functional Events (SFE) 116 Gains 151 Losses 199 Mutations 13 Meth Somatic Mutations Copy Number Alterations DNA Methylation events Gene expression

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Hierarchical Classification 8 M Class (primarily with mutations) C Class (primarily with copy number alterations)

Cancer Genome Hyperbola 9 inverse relationship between # of copy number alterations & # of somatic mutations (when averaged over 12 cancer types)

Cancer Genome Hyperbola 10

11 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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13 From Oncogenesis to Therapy

14 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 16

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