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Dynamics Of Genetic And Epigenetic Information In Inheritance And Cancer Maxwell Lee

Dynamics Of Genetic And Epigenetic Information In Inheritance And Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics February 12 th , 2009. Epigenetics. Genetic and epigenetic information. DNA. RNA. protein. phenotype. genome.

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Dynamics Of Genetic And Epigenetic Information In Inheritance And Cancer Maxwell Lee

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  1. Dynamics Of Genetic And Epigenetic Information In Inheritance And Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics February 12th, 2009

  2. Epigenetics Genetic and epigenetic information DNA RNA protein phenotype genome transcriptome proteome

  3. Gene expression variation between individuals and allelic gene expression variation within an individual gene expression variation between individuals allelic variation within an individual genomic DNA cDNA A B AA AB BB

  4. High throughput allelic-specific gene expression analyses using SNP arrays RNA cDNA Affymetrix HuSNP array Lo et al. Genome Res. 2003

  5. Allele-specific CHIP-on-chip experiments 1347 1362 DNA total intensity: X = A + B control input Pol II H3Ac allelic fraction: X = A/(A + B) active H3K4 H3K9 inactive K27di K27tri 0 0.5 1 Kadota et al. PLoS Genet. 2007

  6. Genetic influence on the global DNA methylation total intensity (A+B) allelic fraction A /(A+B)

  7. Inheritance analysis of allelic histone H3 acetylation state

  8. Breast cancer progression model HRAS MCF10A (M1) MCF10AT (M2) MCF10CA1h (M3) MCF10CA1a (M4)

  9. Summary of experiments done using 500K SNP arrays genomic analysis DNA methylation--MeIP M1-M4 cell lines chromatin--H3Ac gene expression--SNP array and gene array From Lalage Wakefield mutation analysis--on selected genes genomic analysis--161 tumors 250 breast tumors DNA methylation--66 tumors mutation analysis--on selected genes (A + B) analyses allelic analysis---A/(A+B), A, B

  10. Genetic and epigenetic characterization of the cell lines gDNA cDNA H3Ac MeIP MeUB M1 M2 M3 M4 M1 M2 M3 M4 M1 M2 M3 M4 M1 M2 M3 M4 M1 M2 M3 M4

  11. DNA copy number changes and mutations in the cell lines HRAS M1 M2 M3 M4 1q, 2p LRP1B LRP1B 3p14-qter 3p14-qter PIK3CA PIK3CA CHL1, CNTN6 CHL1, CNTN6 CHL1, CNTN6, FHIT CHL1, CNTN6 5q23-qter 5q23-qter 5q23-qter 5q23-qter MYC MYC MYC MYC CDKN2A CDKN2A CDKN2A CDKN2A Chr9 Chr9 chr9 10q22 10q22 10q22 10q22 13q32 13q32 13q32 13q32 13q21 14q12-q24 17p11 17p11 17p11 17p11 17q21-qter 19q13-qter 19q13-qter 19q13-qter chr20 20q11 21q11 21q11 21q11 21q11 RUNX1

  12. MYC amplification in the cell lines

  13. CDKN2A and CDKN2B deletion in the cell lines

  14. PIK3CA mutation in M3 and M4 M1 M2 M3 M4 H1047R

  15. High level gene expression in copy number gain region L: bottom 10% CN value H: top 10% CN value M: middle 80% CN value

  16. Correlation between gene expression and epigenetic markers

  17. Correlation between gene expression and epigenetic markers in promoter vs. gene body promoter CGI gene body

  18. Distribution of epigenetic signals around transcription start site in M1 H3Ac cDNA Methyl (high CpG) Methyl Distance to TSS

  19. DNA hypomethylation in promoter regions in the cell lines

  20. DNA copy number analysis of primary breast tumors 20q13 8q 1q

  21. Chromosome 17 DNA copy number analysis of primary breast tumors 78 Mb 64 Mb 48 Mb ERBB2 31 Mb 14 Mb

  22. Focal gene amplification in breast tumors

  23. Focal amplification of IRX2 in breast tumors

  24. Focal amplification of TBL1XR1 in breast tumors

  25. IHC studies of IRX2 and TBL1XR1 in normal mammary gland

  26. Increased expression of IRX2 and TBL1XR1 in the nuclei of M4 M1 M4

  27. Frequent over-expression of IRX2 in breast tumors

  28. Simultaneous presence of amplification and activating mutation of PIK3CA in breast tumors

  29. Acknowledgements NCI/CCR/LPG Mitsutaka Kadota Howard Yang Natacha Diaz-Meyer Beverly Duncan Sheryl Gere Shuen Lo NCI/CCR/LCBG Misako Sato Lalage Wakefield Kent Hunter Japan/Toyama University Shun-Ichiro Kageyama Junya Fukuoka

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