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Allele-Specific Copy Number in Tumors

Allele-Specific Copy Number in Tumors. Itsik Pe’er Department of Computer Science Center for Computational Biology & Bioinformatics Columbia University. C 2 B 2. 1981. 2000. 2001. 2002. 2003. 2004. 2005. 2006. 2007. Breakthrough of the Year: Whole-Genome Association.

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Allele-Specific Copy Number in Tumors

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  1. Allele-Specific Copy Number in Tumors Itsik Pe’er Department of Computer Science Center for Computational Biology & Bioinformatics Columbia University C2 B2

  2. 1981 2000 2001 2002 2003 2004 2005 2006 2007 Breakthrough of the Year:Whole-Genome Association Age-related Macular Degeneration QT Interval Multiple Sclerosis Systemic Lupus Erythematosis ORMDL3 MEIS1 BTBD8 MAP2K5 ABCG8 6q25 2q36 9p21 CF3 IL7R IL2R IRGM ATG16L1 IL23R NKX2-3 5p13 PTPN2 HLA region 12q24 KIAA0350 PTPN2 INS IL-2 IL21 LOXL1 SMAD7 6q23#1 6q23#2 6p21 1p13 TRAF1-C5 DPP6 8q24#1 8q24#2 8q24#3 8q24#4 8q24#5 8q24#6 TCF2 17p PAX5 FTO CDKAL1 TCF2 CDKN2B/A IGF2BP2 HHEX WF81 SLC30A8 MTHFD1L 9p21 FGFR2 TNCR9 MAP3K1 LSP 16q12 16p12 4q25 [Science] Restless Leg Syndrome Amyotrophic Lateral Sclerosis Acute Lymphoblastic Leukemia Obesity Myocardial Infarction Breast Cancer Biopolar Disorder Rheumatoid Arthritis Celiac Disease Coronary Artery Disease Glaucoma Atrial Fibrillation Asthma Gallstone Disease Prostate Cancer Colorectal Cancer Cholesterol Type II Diabetes Crohn’s Disease Type I Diabetes Venous Thromboembolism TCF7L2 NOS1AP IRF5 CFH HLA-DRB1 IFIH1 IL2RA NOD2 F5 F2 PPARγ SH2B3 KCNJ11 CTLA4 ApoE PTPN22

  3. A C T C T G A G T C T G A C A G A C T G Single Nucleotide Polymorphisms (SNPs) A A G A A G A G G G

  4. Association & Haplotypes A A C A T C Cases G T G A A G A T C G T G A A C Controls G A G G A C G T G

  5. Association & Haplotypes A A C A T C Cases G T G A A G A T C G T G A A C Controls G A G G A C G T G

  6. Copy Number Variation Amplicons: Regions whose copy number varies between homologs

  7. Copy Number Variation Amplicons: Regions whose copy number varies between homologs Rare event May impact Mbps

  8. Tumor Selects for Amplification

  9. Recurrent SomaticAmplification in Cancer Independent tumors show similar amplifications May point to genesselected for in tumor Problem:Segments are too long!

  10. Amplification Across the Genome 20% Inferred copy number > 2Inferred copy number > 3 10% Chr_1 Chr_2 Chr_3 4 5 6 7 8 9 10 11 12 13 14 15 16 1718 19 20 21 22

  11. Two Hit Hypothesis Knudson, 1971

  12. Two Hit Hypothesis Knudson, 1971

  13. Hypothesis: Allele Specific Selection for Amplicons

  14. Amplification Distortion Test A A A A A A G G G A A A A A A A A A G G G G G G • Null: #Amplified A’s ~ Binomial(p=1/2) • Alternative: Amplification distortion

  15. Inspiration:Transmission Disequilibrium Test AG GG AG GG AG GG AG GA … AG

  16. Unique Dataset Genomewide SNPs (240,000) Lung tumors (700) … AAG Data: Matthew Meyerson (Broad) Copy Number Calls: PLASQ (LaFramboise, 2006)

  17. Genomewide Results LOD6- 3- 0- SNPs How can we interpret theoretical significance?

  18. Evaluating Significance 1 2 n … Marker 1 No Flip Null expectation: One SNP exceeds Pval=10-4 Marker 2 No Flip … No Flip Marker M Number of Iterations per Test: 1, 10, 100, 1000 A A A A G G G A A A A G G G A A A A G G G A A A A G G G T T T C C C C C T T T C C C C C T T T C C C C C T T T C C C C C

  19. Genomewide Results LOD6- 3- 0- SNPs 9- 6- 3- 0- Haplotypes • Genomic control/fitting -priors for uniform p-values

  20. AG? AGG? Quality Control AAG • Accuracy of genotype: • - 432 Matched normals • Accuracy of copy number: • - Called over megabases • Accuracy of amplified allele: • - Filtered vs. computational phasing AAA? Experimental validationof top candidates

  21. Kudos Data: Meyerson Lab NLM Training MAGNet NIH NCI Matthew Freedman Ninad Dewal Tom LaFramboise

  22. Posters by our group A A G A A • Ninad Dewal: Allele-Specific Amplification in Tumors • Sasha Gusev: Rapid Identification of Identity-by-Descent • Eimear Kenny: Genetics-Genomics of Parkinson’s Disease in Ashkenazis • Snehit Prabhu: Overlapping Pools for 2nd-Generation Resequencing

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