The document summarizes the findings of The Cancer Genome Atlas Pan-Cancer analysis project, which analyzed over 3,000 tumors across 12 cancer types. The analysis integrated genomic and epigenomic alterations and identified two major clusters of tumors - Cluster I (M class) with primarily somatic mutations, and Cluster II (C class) with primarily copy number alterations. It also observed an inverse relationship between the number of copy number alterations and somatic mutations across cancer types. Several therapeutically actionable targets were nominated across tumor types based on oncogenic signatures and pathways. The analysis provides tissue-independent classification of tumors and insight into mechanisms of oncogenesis and potential therapeutic targets.

1. Raunak Shrestha
PhD Student (Bioinformatics)
Dr. Colin Collin’s Lab
31st October 2013

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

4. 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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5. 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

6. 3299 tumors from 12 cancer types
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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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8. Hierarchical Classification
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M Class (primarily with mutations)
C Class (primarily with copy number alterations)

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

10. 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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16. 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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