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Stan Hamilton, MD Head, Pathology and Laboratory Medicine

Division Faculty Meeting March 29, 2011 Initial Findings in The Cancer Genome Atlas (TCGA) for Colorectal Cancer. Stan Hamilton, MD Head, Pathology and Laboratory Medicine The University of Texas M. D. Anderson Cancer Center. AACR Meeting Raju Kucherlapati Harvard Medical School.

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Stan Hamilton, MD Head, Pathology and Laboratory Medicine

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  1. Division Faculty MeetingMarch 29, 2011Initial Findings in The Cancer Genome Atlas (TCGA) for Colorectal Cancer Stan Hamilton, MD Head, Pathology and Laboratory Medicine The University of Texas M. D. Anderson Cancer Center

  2. AACR MeetingRaju KucherlapatiHarvard Medical School April 5, 2011 (With additions and modifications)

  3. Molecular characteristics of colorectal cancer • Chromosomal instability type • Microsatellite instability type • DNA methylation type • Heterogeneity

  4. TCGA for Colorectal Cancer Tumor/Normal pairs from colonic and rectal tumors (80% from Germany) Low pass whole genome sequencing for copy number variation and chromosomal aberrations (Harvard) – 90 pairs SNP arrays for copy number variation (Dana Farber CI/Broad) – 160 pairs Array and RNA-Seq for expression profiling (U No Carolina) -250 pairs Infinium arrays for methylation studies (U So Cal/Johns Hopkins) – 250 pairs Sequence based methods for miRNA (British Columbia CC) – 250 pairs Whole exome sequencing of all samples and whole genome sequencing on a subset (Baylor Houston and Washington U St. Louis) – 139 pairs Microsatellite instablity status (MD Anderson CC) – 202 pairs Analysis (Broad, Memorial Sloan-Kettering CC, UCSC, Institute for Systems Biology, MD Anderson CC)

  5. Microsatellite instability status • Seven marker panel of four mononucs (BAT25, BAT26, BAT40, TGFbRII) and three dinucs (D2S123, D5S346, D17S250) from NCI Consensus Conference on MSI • 0 markers altered = MS-Stable • 1 to 3 altered = MSI-Low and add 6 dinucs on 18q (no changes in classification) • 5 to 7 altered = MSI-High • 71.8% MSS • 14.9% MSI-L (30% mononucs only, 50% dinucs only, 20% both) • 13.4% MSI-H

  6. CNV profiles from 3-5X coverage WGS Sequencing (3000 base fixed window)

  7. Copy number profiles 8q gain 13 gain 18q loss 20q gain Colon Rectal No differences between colonic and rectal tumors

  8. Focal amplifications IGF2/Insulin ASCL2

  9. ERBB2 amplifications ERBB2

  10. Chromosomal translocations Confirmed by RNA Seq PRSS3-TMEM45B t (9;11)(p11;q24.3) PTPN14-AP3S1 t (1;5)(q32.2;q22) TGFb-signaling “Low” “High”

  11. Loss of Chr 18, Chr 5 Loss of Chr 22, Chr 11 Gain of Chr 20 (20q) Expression profiles by RNA Seq Inter mediate CIN CIMP

  12. Mutation in miRNA maturation regulatory genes (RNASEN, DICER Complexes)

  13. Multiple aberrations in miRNA biogenesis • Ago1/2/3/4, MOV10, TNRC6A and TNRC6B mutation  miR-17-92  miR-1247    • DICER1*, TRBP1 and TRBP2 mutation • DGCR8, RNASEN and DDX17 mutation

  14. Somatic mutation frequencies in tumors colon rectum

  15. Mutations in genes of the Wnt signaling pathway Moon et al. Nat Rev Genet. 2004 5: 689-699. 113 patients

  16. Mutations in the ERBB and MAPK pathway genes 91 patients

  17. ErbB family of genes including amplications of ErbB2

  18. PI3Kinase pathway mutations including PTEN deletions 47% 38% 2% 1% 1% 6% 4% • PI3K and Ras mutations include all the family members • PIK3CA only from Illumina patients (13 mut in 55 pts) Annu Rev Pathol. Mech. Dis. 2009. 4:127-50

  19. TGF-B signaling pathway mutations

  20. Location of SMAD mutations MH2 domain: protein interaction, homo- and heterooligomerization MH1: DNA binding domain

  21. IDH mutations

  22. Conclusions TCGA is generating comprehensive genetic/genomic data from analysis of colorectal tumor/normal pairs. The data are deposited at DbGap and TCGA’s DCC. http://www.ncbi.nlm.nih.gov/gap and http://cancergenome.nih.gov/. CNV, expression profiling, and miRNA analysis reveal no significant differences between colon and rectal tumors. 15% of the tumors have high somatic mutation rates resulting from mutations in DNA mismatch repair genes, most with MSI-H. MicroRNA biogenesis might be altered in colorectal tumors.

  23. Conclusions Translocations involving TTC28 gene (chr 22) Four methylation clusters: CIMP-High, CIMP-Low, Non-CIMP with two different patterns Mutation rate groups with >40/Mb, 10 to 40/Mb, and <10/Mb >40/Mb and 10 to 40/Mb usually MSI-H and CIMP-H, but occasional hypermutated cancers without MSI-H Occasional cancers with methylation of MLH1 lack MSI-H and hypermutation MSI-H with five pathway markers: Myc/Max, HIF1a/ARNT, FOXA1, Myb, and Delta-notch Beta-catenin pathway marker in MSS cancers

  24. Conclusions Key pathways that are critical for the initiation and progression of colorectal cancer are modified in diverse ways. Extensive genomic analysis of individual tumors will help stratify patients for targeted therapies. Integrative analyses are in progress.

  25. Acknowledgements Broad/DFCI ISB MDA MSKCC UCSC BCCA Broad Harvard UNC USC/JHU BCM Broad Wash U Project Team DCC Tissue Source sites Disease working group Analysis working group IGC and NCH

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