Published on March 14, 2014
Raunak Shrestha PhD Student (Bioinformatics) Dr. Colin Collin’s Lab 31st October 2013
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
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)
13 From Oncogenesis to Therapy
14 From Oncogenesis to Therapy
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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