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Arthur Edwards Broad Summer Research Program in Genomics Cancer Program 08/06/07

Genome-wide miRNA Expression Analysis in Lymphoma. miRNAs. Lymphoma. Arthur Edwards Broad Summer Research Program in Genomics Cancer Program 08/06/07. Why Lymphoma?. Cases. Lymphoma. Men 38,670. Women 32,610. Non-Hodgkin’s lymphoma. Hodgkin’s lymphoma. 56,390 patients (est. 2007).

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Arthur Edwards Broad Summer Research Program in Genomics Cancer Program 08/06/07

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  1. Genome-wide miRNA Expression Analysis in Lymphoma miRNAs Lymphoma Arthur Edwards Broad Summer Research Program in Genomics Cancer Program 08/06/07

  2. Why Lymphoma? Cases Lymphoma Men38,670 Women32,610 Non-Hodgkin’s lymphoma Hodgkin’s lymphoma 56,390 patients (est. 2007) 7,350 patients (est. 2007) Deaths 09/01/06 – Stays at MGH 07/23/07 – Plays at Fenway About 50% not so happy ending Men10,370 Women9,360 Adapted from J.L Peck, SI 2007 Source: American Cancer Society, 2006. Adapted from J.L Peck, SI 2007

  3. Diffuse Large B-Cell Lymphoma (DLBCL) Naive B-cells Antigen Memory B-cells Centroblasts Centrocytes Plasma cells • DLBCL is a result of abnormal B-cell development. • Mediastinal Large B-Cell Lymphoma (MLBCL) – Subtype of DLBCL with worse prognosis than DLBCL. • Significant clinical and genetic heterogeneity.

  4. Challenges to the Lymphoma Field • Lack of understanding of its molecular mechanisms • Lack of diagnostic / prognostic tools • Lack of effective therapeutic drugs

  5. miRNAs as regulators of gene expression and biology Cell Death Cell proliferation Differentiation The start of something new: lin-4 and let-7 found in C.Elegans miRNAs Physiological Responses Some miRNAs play functional roles in tumorgenesis particularly in lymphoma Expression Profiles Contain Diagnostic Information “miR-17 cluster cooperates with c-myc in lymphomagenesis” Lu et. al. (2005) – Nature He et. al. (2005) – Nature Lee et. al. (1993) – Cell Reinhart et. al. (2000) - Nature

  6. Approach: genome-wide miRNA expression analysis Diagnosis n = Lymphoma Cell Line 34 Paired DLBCL 18 Primary MLBCL 39 Primary DLBCL 139 Normal B-Cell 12 242 Controls n = Cell Line (HeLa) 9 Cell Line (MCF-7) 9 Cell Line (MOLT-4) 6 Blank Controls 22 Lymphoma Samples 242 288

  7. Overview of miRNA Profiling

  8. Quality Control of Technical Procedure Code Category Molt4 MCF-7 HeLa Plate 1 Plate 2 Plate 3 Fig 1a. Plot of cell line controls and their relative expression values. Fig 1b. Cell line controls cluster.

  9. miRNA Expression Profiles Differentiate B-Cell Development 1 2 1 Code Category Naïve Centroblast Centrocyte Memory Fig 2. Clustering of Normal B-Cell Samples

  10. miRNA Expression Differentiates Primary Lymphoma Samples Code Category Primary DLBCL Primary MLBCL Normal B-Cell Naïve Centroblast Memory Centrocyte miR-150 miR-17 cluster Fig 3. Primary Lymphoma Samples Clustered

  11. Non-Random Association of Patient Outcome 1 2 Code Category MLBCL DLBCL Failure Cure No Data p=0.018 Fisher’s Exact Test Fig 4b. Correlation between Cure and Failure Fig 4a. DLBCL vs. MLBCL

  12. Lymphoma Cell Line Comparison Hodgkin’s Lymphoma DLBCL Mantle Cell Lymphoma MLBCL miR-155 Fig 5. Lymphoma Cell Lines Clustered

  13. Conclusions Classifying Primary Lymphoma Samples. CB / CC – like lymphoma. Naïve / memory - like lymphoma Another class B-Cell Development Two distinct patterns of miRNA expression. CB / CC vs. Naïve / Memory miRNAs and prognosis. miRNAs may give clues on molecular signatures in prognosis of lymphoma patients. Lymphoma Cell Lines Hodgkin’s Lymphoma have a different miRNA expression pattern

  14. Future Studies • Unraveling the functional aspect of miRNAs in B-Cell development and in lymphomagenesis. • More comprehensive data analysis with additional clinical information. • Integrative data analysis (Affy data, miRNA data, SNP data and sequence data)

  15. Broad Members Jun Lu Hao Zhang Stefano Monti Alper Uzun Yuliya Kodysh Arthur Liberzon Xiaohui Xie Jill Mesirov Todd Golub Broad Summer Research Program in Genomics Shawna Young Bruce Birren Maura Silverstein Scott Breiding DFCI / Harvard Medical Kunihiko Takeyama Margaret Shipp MIR WAY Acknowledgements

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