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  1. 1. Yuri E. Nikiforov Department of Pathology University of Cincinnati Genetic Alterations Involved in the Transition from Well Differentiated to Poorly Differentiated and Anaplastic Thyroid Carcinomas Endocrine Pathology Companion Meeting
  2. 2. Outline <ul><li>Genetic events in thyroid WDC, PDC, and AC </li></ul><ul><li>Molecular evidence for progression </li></ul><ul><li>• BRAF and RAS mutations </li></ul><ul><li>• RET/PTC and PAX8-PPAR  </li></ul><ul><li>rearrangements </li></ul><ul><li>• p53 and β-catenin mutations </li></ul><ul><li>Evidence from LOH studies </li></ul><ul><li>Molecular pathways in progression of thyroid CA: Summary </li></ul>
  3. 3. Thyroid follicular cell Papillary Carcinoma AC PDC PAX8-PPAR γ BRAF RET/PTC RAS P53 β-catenin RAS Molecular Alterations in Thyroid Tumors Hurthle Cell Carcinoma Follicular Carcinoma
  4. 4. BRAF
  5. 5. SOS B-RAF RAS GRB2 SOS Signaling Pathways Activated by BRAF in Thyroid Tumors Y1015 Y1062 Y1096 MEK ERK c-Jun, Fos , c- Myc , Elk-1 PLC γ Enigma SHC FRS2 P P P RET P P P
  6. 6. Kinase domain Spectrum of BRAF Point Mutations in Various Tumors Phe Gly Leu Val 594 595 598 601 596 599 Val Glu Leu 585 Gly 465 Gly 465 Gly 463 RBD C Ala The Lys Ser P P
  7. 7. Prevalence of BRAF Mutations in Thyroid Tumors Nikiforova et al. 2003 Cohen et al., 2003 Xu et al., 2003 Namba et al., 2003 Fukashima et al., 2003 Trovisco et al., 2004
  8. 8. BRAF Mutations Present in Both Well Differentiated and Poorly Differentiated Carcinoma Areas Nikiforova et al. (2003) DNA DNA BRAF + BRAF + PC,WD PDC
  9. 9. BRAF Mutations in Poorly Differentiated and Anaplastic Carcinomas Nikiforova et al. (2003)
  10. 10. BRAF Mutations: Summary <ul><li>PC with BRAF are prone to dedifferentiation and transformation to PDC and AC </li></ul><ul><li>Other genetic mutations are required to direct this process </li></ul>BRAF PC Additional mutations N PDC AC
  11. 11. RAS
  12. 12. <ul><li>Point mutations found in many human cancers and in most types of thyroid tumors </li></ul><ul><li>K-RAS , H-RAS , N-RAS genes may be involved </li></ul><ul><li>Hot spots - codons 12, 13 and 61 </li></ul><ul><li>N-RAS codon 61 mutations most common in thyroid tumors </li></ul>RAS Mutations
  13. 13. Mechanism of RAS Activation by Point Mutation GAPs SOS GDSs CDC25 C3G Downstream Effectors Mutations codons 12/13 or 61 RAS RAS GTP GDP H 2 O Pi GTP GDP
  14. 14. Molecular Pathways Activated by RAS B-RAF BAD Apoptosis Y1062 RAS GRB2 SOS PLC Ral /Cdc42 DAG PKC AKT Rho Rac MEK ERK PI3K JNK P70S6K MEKK1 BCL c-Jun, Fos , c- Myc , Elk-1 SHC FRS2 RET P P P P
  15. 15. Prevalence of RAS Mutations in Thyroid Tumors
  16. 16. RAS in Progression of Thyroid Tumors: Case report of AC with areas of FC AC RAS codon 61 CAA CGA + + p53 codon 189 GCC GTC - + Asakawa & Kobayashi (2002) Mutations found: FC
  17. 17. <ul><li>Development of nodules, adenomas, and carcinomas in transgenic mice </li></ul><ul><li>Increased cell proliferation but insufficient for complete transformation of cultured cells </li></ul><ul><li>Increased chromosome instability, i.e. micronuclei, centrosome amplification, chromosome misalignment during mitosis </li></ul>Consequences of RAS Activation in Thyroid Cells
  18. 18. RAS Mutations: Summary <ul><li>Predispose FC and PC to dedifferentiation, likely by increasing genomic instability </li></ul><ul><li>Require additional mutations for dedifferentiation </li></ul>RAS PC Additional mutations N PDC AC FC
  19. 19. RET/PTC Rearrangement
  20. 20. RET / PTC Rearrangements
  21. 21. SOS GRB2 Y1015 Y1062 RET/PTC Molecular Pathways Activated by RET/PTC PLC γ Enigma SHC FRS2 RAF RAS MEK ERK P P P P c-Jun, Fos , c- Myc , Elk-1
  22. 22. Prevalence of RET/PTC in Thyroid Tumors
  23. 23. RET/PTC Rearrangements: Summary <ul><li>No RET/PTC in anaplastic carcinomas </li></ul><ul><li>Data on PDC not entirely conclusive </li></ul><ul><li>Likely - PC with RET/PTC have low potential for dedifferentiation/progression </li></ul>RET/PTC PC N
  24. 24. Molecular Pathways in Thyroid Papillary Carcinogenesis RET-PTC 15% 40% BRAF RAS 20% PC PC PC N PDC AC
  25. 25. PAX8-PPAR γ Rearrangement
  26. 26. Structure of PAX8-PPAR  Fusion Protein Kroll et al. (2000)
  27. 27. <ul><li>Results from fusion of PAX8 (2q13) and PPAR γ (3p25) genes </li></ul><ul><li>PAX8-PPAR γ chimeric protein h as dominant negative effect on wild-type PPAR γ </li></ul><ul><li>Wild-type PPAR γ may inhibit thyroid cell growth (tumor suppressor gene) </li></ul>PAX8-PPAR γ Rearrangement
  28. 28. Prevalence of PAX8-PPAR  in Thyroid Tumors
  29. 29. PAX8-PPAR  Rearrangements: Summary <ul><li>No RET/PTC in PDC and AC </li></ul><ul><li>Likely - FC with PAX8-PPAR γ lack potential for dedifferentiation/ </li></ul><ul><li>progression </li></ul>PAX8-PPAR γ N FC
  30. 30. Molecular Pathways in Thyroid Follicular Carcinogenesis PAX8-PPAR γ 35% FA RAS 45% FC FC PDC AC N
  31. 31. Mutations Directing Progression/ Dedifferentiation of Thyroid Tumors: p53
  32. 32. Mutations Directing Progression/ Dedifferentiation of Thyroid Tumors: β-catenin
  33. 33. Specific Genetic Events in Thyroid Tumors: Summary
  34. 34. Molecular Evidence for Progression/Dedifferentiation: LOH Studies <ul><li>In the same tumor, WDC and AC components have similar patterns of allelic loss </li></ul><ul><li>Increased LOH rate in AC component </li></ul>J. Hunt et al. (2003)
  35. 35. Molecular Pathways in Progression of Thyroid Carcinomas: Summary <ul><li>Studies of gene mutations and LOH supports the following progression: </li></ul><ul><li>WDC PDC AC </li></ul><ul><li>WD tumors with BRAF and RAS mutations are prone for dedifferntiation, but require additional mutations </li></ul><ul><li>p53 and possibly β- catenin directly guide progression </li></ul>
  36. 36. Nikiforov Lab Marina Nikiforova Zhaowen Zhu Raffaele Ciampi Christy Caudill Manoj Gandhi Acknowledgements James Fagin University of Cincinnati Todd Kroll Emory University Giovanni Tallini