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Data Integration for Cancer Genomics

Data Integration for Cancer Genomics . Personalized Medicine Tumor Board Question : given all we know about a patient, what is the “optimal” treatment? . The Cancer Genome Atlas Project (TCGA). SNP Structural variations DNA methylation Gene expression microRNA expression

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Data Integration for Cancer Genomics

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  1. Data Integration for Cancer Genomics

  2. Personalized Medicine Tumor Board Question: given all we know about a patient, what is the “optimal” treatment?

  3. The Cancer Genome Atlas Project(TCGA) SNP Structural variations DNA methylation Gene expression microRNA expression Paired samples/unpaired samples

  4. Data Processing Challenges Contamination Subclones

  5. Biological questions • Changes in genes between cancer and normals • Disease heterogeneity, subtypes • Joint modeling, mechanisms

  6. Integrative approach Meta-analytical approach

  7. PARADIGM: PAthway Recognition Algorithm using Data Integration on Genomic Models

  8. Xpxn = Wpx(k-1) Z(k-1)xn + epxn cov(e) = diag(ψ1, ψ2,…,ψp)

  9. Non-negative matrix factorization XMxN = WMxK x HKxN All matrix entries are nonnegative Minimize

  10. X1: an M x N1 matrix X2: an M x N2matrix X3: an M x N3matrix X1 = W x H1 X2= W x H2 X3= W x H3

  11. TCGA and GWAS, and ENCODE

  12. Cancer Treatment

  13. Examples http://discover.nci.nih.gov/cellminer/ Gene expression data: HG-U133A chip, mapped to 12980 genes across 59 cell lines (expression data of the cell line “LC:NCI_H23” was unavailable). Use genes included in two lists: (1) 766 cancer-related genes (Chen, et al., 2008); (2) 8919 genes from the Integrated Druggable Genome Database (IDGD) Project (Hopkins and Groom, 2002; Russ and Lampel, 2005). After this filtering, 6958 genes retained. Drug response data: 101 drugs annotated in the CancerResource database (Ahmed, et al., 2011). –log(GI50) Pathway association information: Retrieved from the KEGG MEDICUS database (Kanehisa, et al., 2010). 58 pathways which are either known to be related to cancer or have drug targets. Among the 6958 genes selected in step (1), 1863 genes are covered by these 58 pathways and constitute the final list of genes in our real data analysis.

  14. GI50 values

  15. Cancer Types

  16. Connectivity Map Data • CMap Build 02 (http://www.broadinstitute.org/cmap/) provides public download of genome-wide transcriptional profiles of five human cancer cell lines (MCF7: human breast cancer; HL60: human promyelocytic leukemia; ssMCF7: MCF7 grown in a different vehicle; PC3: human epitelial prostate cancer; SKMEL5: human skin melanoma) both before and after the treatments of 1309 distinct bioactive small molecules. • Used the data from the HT_HG-U133A array platform, which consists of 4466 expression response profiles, representing 1084 different compounds.

  17. Integration within the same cancer type • Integration across different cancer types

  18. One individual with 188 fold coverage

  19. Ideal Pipeline • Patient diagnosis and sample collection • Various types of genomics profiling • Driver mutations, disease subtypes • Targeted treatments, monitoring, and additional treatments

  20. Topics of Interest • Data processing • Relationships among different data types • Tumor heterogeneity • Single cell analysis • Modeling • Targeted treatment • Integration over different tumor types • TCGA, ENCODE, GWAS, 1000 Genomes, and others

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