Nikiforov

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Published on January 5, 2008

Author: Oceane

Source: authorstream.com

Slide1:  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 Outline:  Outline Genetic events in thyroid WDC, PDC, and AC Molecular evidence for progression • BRAF and RAS mutations • RET/PTC and PAX8-PPAR rearrangements • p53 and β-catenin mutations Evidence from LOH studies Molecular pathways in progression of thyroid CA: Summary Slide3:  Thyroid follicular cell Papillary Carcinoma AC PDC PAX8-PPARγ BRAF RET/PTC RAS P53 β-catenin RAS Molecular Alterations in Thyroid Tumors Hurthle Cell Carcinoma Follicular Carcinoma Slide4:  BRAF Slide5:  SOS B-RAF RAS GRB2 SOS Signaling Pathways Activated by BRAF in Thyroid Tumors Y1015 Y1062 Y1096 Slide6:  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 Slide7:  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 Slide8:  BRAF Mutations Present in Both Well Differentiated and Poorly Differentiated Carcinoma Areas Nikiforova et al. (2003) DNA DNA BRAF + BRAF + PC,WD PDC Slide9:  BRAF Mutations in Poorly Differentiated and Anaplastic Carcinomas Nikiforova et al. (2003) BRAF Mutations: Summary:  BRAF Mutations: Summary PC with BRAF are prone to dedifferentiation and transformation to PDC and AC Other genetic mutations are required to direct this process BRAF PC Additional mutations Slide11:  RAS Slide12:  Point mutations found in many human cancers and in most types of thyroid tumors K-RAS, H-RAS, N-RAS genes may be involved Hot spots - codons 12, 13 and 61 N-RAS codon 61 mutations most common in thyroid tumors RAS Mutations Slide13:  Mechanism of RAS Activation by Point Mutation GAPs SOS GDSs CDC25 C3G Downstream Effectors Mutations codons 12/13 or 61 Slide14:  Molecular Pathways Activated by RAS B-RAF BAD Apoptosis Y1062 Slide15:  Prevalence of RAS Mutations in Thyroid Tumors Slide16:  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: Slide17:  Development of nodules, adenomas, and carcinomas in transgenic mice Increased cell proliferation but insufficient for complete transformation of cultured cells Increased chromosome instability, i.e. micronuclei, centrosome amplification, chromosome misalignment during mitosis Consequences of RAS Activation in Thyroid Cells RAS Mutations: Summary:  RAS Mutations: Summary Predispose FC and PC to dedifferentiation, likely by increasing genomic instability Require additional mutations for dedifferentiation RAS PC Additional mutations Slide19:  RET/PTC Rearrangement Slide20:  RET/PTC Rearrangements Slide21:  SOS GRB2 Y1015 Y1062 RET/PTC Molecular Pathways Activated by RET/PTC Slide22:  Prevalence of RET/PTC in Thyroid Tumors RET/PTC Rearrangements: Summary:  RET/PTC Rearrangements: Summary No RET/PTC in anaplastic carcinomas Data on PDC not entirely conclusive Likely - PC with RET/PTC have low potential for dedifferentiation/progression RET/PTC PC Slide24:  Molecular Pathways in Thyroid Papillary Carcinogenesis RET-PTC 15% 40% BRAF RAS 20% PC PC PC Slide25:  PAX8-PPARγ Rearrangement Slide26:  Structure of PAX8-PPAR Fusion Protein Kroll et al. (2000) Slide27:  Results from fusion of PAX8 (2q13) and PPARγ (3p25) genes PAX8-PPARγ chimeric protein has dominant negative effect on wild-type PPARγ Wild-type PPARγ may inhibit thyroid cell growth (tumor suppressor gene) PAX8-PPARγ Rearrangement Slide28:  Prevalence of PAX8-PPAR in Thyroid Tumors PAX8-PPAR Rearrangements: Summary:  PAX8-PPAR Rearrangements: Summary No RET/PTC in PDC and AC Likely - FC with PAX8-PPARγ lack potential for dedifferentiation/ progression PAX8-PPARγ Molecular Pathways in Thyroid Follicular Carcinogenesis:  Molecular Pathways in Thyroid Follicular Carcinogenesis PAX8-PPARγ 35% FA RAS 45% FC Slide31:  Mutations Directing Progression/ Dedifferentiation of Thyroid Tumors: p53 Slide32:  Mutations Directing Progression/ Dedifferentiation of Thyroid Tumors: β-catenin Slide33:  Specific Genetic Events in Thyroid Tumors: Summary Slide34:  Molecular Evidence for Progression/Dedifferentiation: LOH Studies In the same tumor, WDC and AC components have similar patterns of allelic loss Increased LOH rate in AC component J. Hunt et al. (2003) Slide35:  Molecular Pathways in Progression of Thyroid Carcinomas: Summary Studies of gene mutations and LOH supports the following progression: WDC PDC AC WD tumors with BRAF and RAS mutations are prone for dedifferntiation, but require additional mutations p53 and possibly β-catenin directly guide progression Slide36:  Nikiforov Lab Marina Nikiforova Zhaowen Zhu Raffaele Ciampi Christy Caudill Manoj Gandhi Acknowledgements James Fagin University of Cincinnati Todd Kroll Emory University Giovanni Tallini

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