1. Copyright, ©, 2002, John Wiley & Sons, Inc.,Karp/CELL & MOLECULAR BIOLOGY 3E Molecular Portraits of Cancer Microarrays and Cell Biology

2. Copyright, ©, 2002, John Wiley & Sons, Inc.,Karp/CELL & MOLECULAR BIOLOGY 3E Microarrays and Clustering Microarrays –provides a matrix of information –correlated gene expression –group GENES by similarity of expression pattern –group CELLS by similarity of expression pattern –usually reorder rows and columns for presenting –Both genes, cells grouped by Cluster Analysis –Lots of different programs/methods for clustering

3. Copyright, ©, 2002, John Wiley & Sons, Inc.,Karp/CELL & MOLECULAR BIOLOGY 3E Microarrays and Clustering Supervised clustering Uses external information to guide clustering Frequently used to “train” neural network algorithms Sometimes “known” tumors used to “learn” pattern/portrait Unsupervised clustering Groups tumors based on similarity of gene expression Usually some “vector analogy” applies Both methods can be used to define and predict tumor types

4. Copyright, ©, 2002, John Wiley & Sons, Inc.,Karp/CELL & MOLECULAR BIOLOGY 3E Molecular Definition of Tumors Tumors are individuals –Each tumor has its own unique gene expression pattern –Can be referred to as a “Molecular Portrait” –Even highly related tumors (same clone?) can show differences –sub-clonal diversity

5. Copyright, ©, 2002, John Wiley & Sons, Inc.,Karp/CELL & MOLECULAR BIOLOGY 3E Tumor Portraits Arrays contain info about cell type of origin –Example: CNS tumors (Fig2) Clear distinctions between CNS tumors Medulogliomas likely derived from non-neural oligodendrocytes Meduloblastomas (MD’s) from cerebellar granule cells 50 gene set used to diagnose CNS tumor type Improvement over predictions based on histology PCA:“strongest” linear combination of genes

6. Copyright, ©, 2002, John Wiley & Sons, Inc.,Karp/CELL & MOLECULAR BIOLOGY 3E Principle Components Analysis (3D) Full Gene Set Best 50 Genes

7. Copyright, ©, 2002, John Wiley & Sons, Inc.,Karp/CELL & MOLECULAR BIOLOGY 3E Best 50 Genes

8. Copyright, ©, 2002, John Wiley & Sons, Inc.,Karp/CELL & MOLECULAR BIOLOGY 3E Tumor Portraits Arrays contain info about developmental stage –Stage of development affects clinical behavior –DLBCL (diffuse, large B-cell lymphomas) Germinal center B-cell-like (GCBL) Activated B-cell-like (ABL) Third type lacking pattern of other two –ALL subtypes found Pro-T-cell Early cortical thymocyte Late cortical thymocyte

9. Copyright, ©, 2002, John Wiley & Sons, Inc.,Karp/CELL & MOLECULAR BIOLOGY 3E Tumor Portraits Arrays contain info about prognosis –Meduloblastomas (MD’s) with or without metastasis –Metastasis was correlated with PDGF, ras, MAPK –Treatment can potentially be informed by primary tumor gene expression patterns –Predicting the future phenotype of the tumor

10. Copyright, ©, 2002, John Wiley & Sons, Inc.,Karp/CELL & MOLECULAR BIOLOGY 3E Tumor Portraits Arrays reveal a common (cancer) imprint –Interferon gene set (3c) –Proliferation gene set (3g) –Basal epithelial gene set (3e)

11. Copyright, ©, 2002, John Wiley & Sons, Inc.,Karp/CELL & MOLECULAR BIOLOGY 3E