Thyroid Cancer Genomics. James A. Fagin MD Memorial Sloan Kettering Cancer Center

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1 Thyroid Cancer Genomics James A. Fagin MD Memorial Sloan Kettering Cancer Center

2 Disclosure Information James Fagin I have the following financial relationships to disclose: Consultant for: LOXO Oncology Grant/Research support from: EISAI - and - I will not discuss off label use and/or investigational use in my presentation. -

3 Pathologic Spectrum of Thyroid Cancers. Fagin JA, Wells SA Jr. N Engl J Med 2016;375:

4 Putting it all together Genomic landscape of papillary thyroid cancer BRAF RAS (N>H>K) Chip Stewart, Broad RTK fusions: RET, NTRK ALK, others.

5 TCGA Network. Cell. 2014

6 Association of Genotype and Differentiated Gene Expression BRAF RAS RTK fusions Iodine metabolism

7 BRAF BRAF tumor cluster retaining differentiation properties Iodine metabolism

8 Functional Consequences of Driver Mutations in Papillary Thyroid Carcinomas. Fagin JA, Wells SA Jr. N Engl J Med 2016;375:

9 TERT promoter mutations in thyroid cancers Papillary thyroid tumors (TCGA) 9% Poorly-differentiated thyroid tumors 40% TERT promoter: C228T (-124) C250T (-146) C228A (-124) CC TT BRAF/RAS: missense Anaplastic thyroid tumors 73% TERT-BRAF/RAS association PTC PDTC+ATC OR p-value

10 Liu R. JAMA Oncol 2017

11 TERT promoter mutations in thyroid cancers TERT promoter mutations are subclonal events in PTCs, but clonal in PDTCs and ATCs key transitional event in tumor microevolution

12 Genomics of Anaplastic and Poorly Differentiated Thyroid Cancers

13 ABL1 AKT1 AKT2 AKT3 ALK ALOX12B AMER1 AR ARAF ARID1A ARID5B ASXL1 ASXL2 ATM ATR ATRX AURKA AURKB AXIN1 AXIN2 AXL B2M BAP1 BARD1 BBC3 BCL2 BCL2L1 BCL2L11 BCL6 BCOR BLM BMPR1A BRAF BRCA1 BRCA2 BRD4 BRIP1 BTK CARD11 CASP8 CBFB CBL CCND1 CCND2 CCND3 CCNE1 CD274 CD276 CD79B CDC73 CDH1 CDK12 CDK4 CDK6 CDK8 CDKN1A CDKN1B CDKN2A CDKN2B CDKN2C CHEK1 CHEK2 CIC CREBBP CRKL CRLF2 CSF1R CTCF CTLA4 CTNNB1 CUL3 DAXX DCUN1D1 DDR2 DIS3 DNMT1 DNMT3B DOT1L E2F3 EED EGFL7 EGFR EIF1AX EP300 EPCAM EPHA3 EPHA5 EPHB1 ERBB2 ERBB3 ERBB4 ERCC2 ERCC3 ERCC4 ERCC5 ERG ESR1 ETV1 ETV6 EZH2 FAM175A FAM46C FANCA FANCC FAT1 FBXW7 FGF19 FGF3 FGF4 FGFR1 FGFR2 FGFR3 FGFR4 FH FLCN FLT1 FLT3 FLT4 FOXA1 FOXL2 FOXP1 FUBP1 GATA1 GATA2 GATA3 G11 GQ GS GREM1 GRIN2A H3F3C HGF HIST1H1C HIST1H2BD HIST1H3B HNF1A HRAS ICOSLG IDH1 IDH2 IFNGR1 IGF1 IGF1R IGF2 IKBKE IKZF1 IL10 IL7R INPP4A INPP4B INSR IRF4 IRS1 IRS2 JAK1 JAK2 JAK3 JUN KDM5A KDM5C KDM6A KDR KEAP1 KIT KLF4 KMT2A KMT2C KMT2D KRAS LATS1 LATS2 LMO1 MAP2K1 MAP2K2 MAP2K4 MAP3K13 MAPK1 MAX MCL1 MDC1 MDM2 MDM4 MED12 MEF2B MEN1 MET MITF MLH1 MPL MRE11A MSH2 MSH6 MTOR MUTYH MYC MYCL1 MYCN MYD88 MYOD1 NBN NCOR1 NF1 NF2 NFE2L2 NKX2-1 NKX3-1 NOTCH1 NOTCH2 NOTCH3 NOTCH4 NPM1 NRAS NSD1 NTRK1 NTRK2 NTRK3 PAK1 PAK7 PALB2 PARK2 PARP1 PAX5 PBRM1 PDCD1 PDGFRA PDGFRB PDPK1 PHOX2B PIK3C2G PIK3C3 PIK3CA PIK3CB PIK3CD PIK3CG PIK3R2 PIK3R3 PIM1 PLK2 PMAIP1 PMS1 PMS2 PNRC1 POLE PPP2R1A PRDM1 PRKAR1A PTCH1 PTPN11 PTPRD PTPRS PTPRT RAC1 RAD50 RAD51 RAD51B RAD51C RAD51D RAD52 RAD54L RAF1 RARA RASA1 RB1 RBM10 RECQL4 REL RET RFWD2 RHOA RICTOR RIT1 RNF43 ROS1 RPS6KA4 RPS6KB2 RUNX1 RYBP SDHA SDHAF2 SDHB SDHC SDHD SF3B1 SH2D1A SHQ1 SMAD2 SMAD3 SMAD4 SMARCA4 SMARCB1 SMARCD1 SMO SOCS1 SOX17 SOX2 SOX9 SPEN SPOP SRC STAG2 STK11 STK40 SUFU SUZ12 SYK TBX3 TERT TET1 TET2 TGFBR1 TGFBR2 TMEM127 TMPRSS2 TNFAIP3 TNFRSF14 TOP1 TP53 TP63 TRAF7 TSC1 TSC2 TSHR U2AF1 VHL VTCN1 WT1 XIAP XPO1 YAP1 YES1 Overview IMPACT genes APC ARID1B ARID2 DICER1 DNMT3A GSK3B MAP3K1 PIK3R1 PTEN RPTOR SETD2 IMPACT targeted sequencing of all exons of 341 actionable genes Point mutations, indels Copy number alterations Fusions on a subset of frequently rearranged genes (w/ introns covered)

14 Number of mutations in 341 genes Sample Type Met site Growth PDTC defin. Genetic alteration missense truncating Poorly-differentiated thyroid cancers (PDTC) Mutation burden and clinicopathological features in PDTC PDTC = 78 Below Median Above p median (26) (24) median(28) value BRAF (y) 47±15 58±15 64±15 <0.001 NRAS Tumor size HRAS 4 64% 57% 29% KRAS >4 36% 43% 71% NF1 Pathology staging TSHR STK11 EIF1AX PIK3CA PTEN T1/T2 17% 15% 4% T3/T4 83% 85% 96% Nx/N0 54% 45% 52% N1a/N1b 46% 55% 48% RET/PTC M0 73% 54% 32% PAX8-PPARɣM1 8% 29% 57% ALK Mx 19% 17% 11% NUT-BRD4 Overall survival 19% 25% 46% 0.07 TERT (died) TP53 Overall survival time 2242± ± ± ATM (days±sd) RB1 analysis: HR: NF2 HR (95%CI) ( ) MEN1 Log rank PI3K/AKT SWI/SNF HMTS MMR Fusion inframe fusion CCDC6-RET NCOA4-RET STRN-ALK EML4-ALK CCDC149-ALK PIK3CA Sample Type Met site % of tumors mutated Anaplastic (ATC) Log-rank p= TERT promoter E542K/E545K (helical) H1047R (kinase) E81K K111E C228T (-124) C250T (-146) Sample type primary metastasis recurrence male female Met-site no met lung bone lung+bone other alive deceased <50% 50-70% >70% papillary follicular tall-cell variant Hurthle mixed/other Growth solid papillary mixed/other PDTC definition Turin proposal MSKCC CC TT Pathway altered

15 Number of mutations in 341 genes Sample Type Met site Growth PDTC defin. BRAF NRAS HRAS KRAS NF1 TSHR STK11 EIF1AX PIK3CA PTEN RET/PTC PAX8-PPARɣ ALK NUT-BRD4 TERT TP53 ATM RB1 NF2 MEN1 PI3K/AKT SWI/SNF HMTS MMR Genetic alteration missense truncating Poorly-differentiated thyroid cancers (PDTC) BRAF and RAS dictate distinct tropisms for metastasis in PDTCs M1 Fusion 45% 14% inframe fusion CCDC6-RET NCOA4-RET STRN-ALK EML4-ALK CCDC149-ALK Sample Type Met site % of tumors mutated Anaplastic (ATC) BRAF and 81% RAS of were BRAFthe main drivers; 92% RAS of RAS more frequent than in PTC PDTC definition Total PDTC = 84 MSKCC high mitotic rate and necrosis irrespective of growth pattern BRAF wt (56) BRAF + (28) vs. p value Tumor size 4 40% 70% >4 60% 30% 0.01 Pathology staging T1/T2 11% 15% T3/T4 89% 85% Nx/N0 61% 37% N1a/N1b 39% 63% M0 38% 79% Mx 17% 7% Turin proposal solid growth plus high grade features (mitosis and necrosis) Total PDTC = 84 RAS wt RAS + p (60) (24) value Tumor size % 19% >4 37% 81% Pathology staging T1/T2 16% 5% T3/T4 84% 95% Nx/N0 37% 86% N1a/N1b 63% 14% <0.001 M0 62% 25% PIK3CA M1 22% TERT promoter67% E542K/E545K (helical) H1047R (kinase) E81K K111E C228T (-124) C250T (-146) Mx 16% Sample type primary metastasis recurrence male female Met-site no met lung bone lung+bone other alive deceased Hiltzik D, et al. Cancer 2006 Volante M, et al. Am J Surg Pathol 2007 <50% 50-70% >70% papillary follicular tall-cell variant Hurthle mixed/other Growth solid papillary mixed/other PDTC definition Turin proposal MSKCC CC TT Pathway altered

16 Number of mutations in genes Sample Type Met site Growth PDTC defin. BRAF NRAS HRAS KRAS NF1 TSHR STK11 EIF1AX PIK3CA PTEN RET/PTC PAX8-PPARɣ ALK NUT-BRD4 TERT TP53 ATM RB1 NF2 Pathways MEN1 PI3K/AKT SWI/SNF HMTS MMR Poorly-differentiated thyroid cancers (PDTC) 0 Sample Type Met site % of tumors mutated Anaplastic (ATC) Sample type primary metastasis recurrence male female Met-site no met lung bone lung+bone other alive deceased <50% 50-70% >70% papillary follicular tall-cell variant Hurthle mixed/other Growth solid papillary mixed/other PDTC definition Turin proposal MSKCC Genetic alteration missense truncating Fusion inframe fusion CCDC6-RET NCOA4-RET STRN-ALK EML4-ALK CCDC149-ALK PIK3CA TERT promoter E542K/E545K (helical) H1047R (kinase) E81K K111E C228T (-124) C250T (-146) CC TT Pathway altered

17 Number of mutations in 341 genes Sample Type Met site Growth PDTC defin. BRAF NRAS HRAS KRAS NF1 TSHR STK11 EIF1AX PIK3CA PTEN RET/PTC PAX8-PPARɣ ALK NUT-BRD4 TERT TP53 ATM RB1 NF2 MEN1 PI3K/AKT SWI/SNF HMTS MMR Genetic alteration missense truncating Poorly-differentiated thyroid cancers (PDTC) Fusion inframe fusion CCDC6-RET NCOA4-RET STRN-ALK EML4-ALK CCDC149-ALK PIK3CA Sample Type Met site % of tumors mutated Anaplastic (ATC) Rearrangements involving RET, PAX8/PPARG and ALK exclusive of PDTCs; NF1 mutations in ATC PIK3CA and PTEN are frequent events in ATC, specific patterns: PIK3CA-BRAF PTEN-NF1 TERT promoter E542K/E545K (helical) H1047R (kinase) E81K K111E C228T (-124) C250T (-146) Sample type primary metastasis recurrence male female Met-site no met lung bone lung+bone other alive deceased <50% 50-70% >70% papillary follicular tall-cell variant Hurthle mixed/other Growth solid papillary mixed/other PDTC definition Turin proposal MSKCC CC TT Pathway altered

18 Pozdeyev N. CCR ATCs: MSK-IMPACT Foundation Medicine Cluster 1 BRAF/PIK3CA, BRAF/AKT1 BRAF/ARID2 Cluster 2 Cluster 3 CDKN2A/CDKN2B NRAS/CCNE1 Gene alterations and associations from clusters 1,3,4 and 5 Cluster 4 NRAS, HRAS KDR/KIT/PDGFRA CD274/JAK2 Cluster 5 PTEN/NF1/RB1 Mutation-High ATC Type 1 Mixed, types 1-3 ATC Type 2 ATC Type 3

19 Number of mutations in 341 genes Sample Type Met site Growth PDTC defin. BRAF NRAS HRAS KRAS NF1 TSHR STK11 EIF1AX PIK3CA PTEN RET/PTC PAX8-PPARɣ ALK NUT-BRD4 TERT TP53 ATM RB1 NF2 MEN1 PI3K/AKT SWI/SNF HMTS MMR Genetic alteration missense truncating Poorly-differentiated thyroid cancers (PDTC) Fusion inframe fusion CCDC6-RET NCOA4-RET STRN-ALK EML4-ALK CCDC149-ALK PIK3CA Sample Type Met site % of tumors mutated Anaplastic (ATC) TERT promoter mutations track with virulence in advanced thyroid tumors TP53 mutations are key distinguishing events between PDTCs (8%) and ATCs (73%) TERT promoter E542K/E545K (helical) H1047R (kinase) E81K K111E C228T (-124) C250T (-146) Sample type primary metastasis recurrence male female Met-site no met lung bone lung+bone other alive deceased <50% 50-70% >70% papillary follicular tall-cell variant Hurthle mixed/other Growth solid papillary mixed/other PDTC definition Turin proposal MSKCC CC TT Pathway altered

20 The EIF1AX-RAS association Papillary thyroid tumors (TCGA) 10% Poorly-differentiated thyroid tumors (MSKCC) 1% Anaplastic thyroid tumors (n=55) [(MSKCC, n=33) + (Kunstman et al, 2015, n=22)] EIF1AX-RAS association 14/15 PDTCs+ATCs 3/3 Cell lines 3/3 ATCs from Kunstman et al Log-rank p= OR= 58.3 p <

21 Mechanism of EIF1AX/RAS co-operation and nodes for targeting EIF1AX A113splice RAS mut MAPK PI3K/ MTORC2 GADD34 ATF4 C-MYC stability MEK inhibition c-myc inhibition MTOR kinase inhibition EIF2α P-EIF2α AA transporters MTORC1 TC/PIC Global protein synthesis thyroid tumorigenesis/ disease progression Mechanisms of mutant EIF1AX co-operation with RAS in thyroid tumorigenesis. EIF1AX-c spl activates ATF4 expression, inducing a GADD34 mediated negative feedback on EIF2α, leading to TC loading and an increase in global protein synthesis. RAS in turn stabilizes cmyc, an effect augmented by EIF1AX-c spl. ATF4 and cmyc induce expression of AA transporters, and cooperate to activate mtorc1. RAS further activates mtor kinase signaling via PI3K. The potential targetable nodes that disrupt the oncogenic drive of EIF1AX + RAS are indicated. Gnana Krishnamoorthy

22 PI3K/AKT/mTOR pathway SWI/SNF chromatin remodelling complex Histone methyltransferases Anaplastic thyroid cancers Poorly differentiated thyroid cancers PDTC ATC Poorly-differentiated Anaplastic PI3K SWI/SNF HMTs MMR 39% 36% 24% 12% 11% 6% 7% 2% Poorly-diff. Anaplastic Poorly-diff. Anaplastic Mismatch excision repair Genetic alteration missense truncating inframe epigenetic deregulation in advanced thyroid tumors

23 Clinical Responses to Pembrolizumab Treatment. Le DT et al. N Engl J Med 2015;372:

24 PI3K/AKT/mTOR pathway SWI/SNF chromatin remodelling complex Histone methyltransferases Anaplastic thyroid cancers Poorly differentiated thyroid cancers PDTC ATC Poorly-differentiated Anaplastic PI3K SWI/SNF HMTs MMR 39% 36% 24% 12% 11% 6% 7% 2% Poorly-diff. Anaplastic Poorly-diff. Anaplastic Mismatch excision repair Genetic alteration missense truncating inframe epigenetic deregulation in advanced thyroid tumors

25 Genomic Hallmarks of Thyroid Cancer along the Spectrum of Disease Progression Landa et al. J Clin Invest. 2016

26 Jeff Knauf Maria Elena Rodriguez Garcia Rendueles Inigo Landa Gnana Krishnamoorthy Javier Leandro Garcia Mahesh Saqcena Vanessa Dos Anjos Anthony Glover Katie Luckett Prassana Tamaratapu Vera Tiedje Brian Untch Janet Li Recent former lab members: James Nagarajah Jennifer Cracchiolo Xu Chen Julio Ricarte-Filho Debyani Chakravarty Cristina Montero-Conde Sergio Ruiz-Llorente Jose M Dominguez Gisele Oler Aime Franco Mina Le Francesca Voza MSKCC Collaborators Ronald Ghossein Laura Boucai Steve Larson Ian Ganly Tihana Ibrahimpasic Mike Berger Mike Tuttle Clinical Trials Alan Ho Lara Dunn Eric Sherman David Pfister Mike Tuttle Steve Larson Ravi Grewal Desiree D Andreis Keith Pentlow Pat Zanzonico Ronald Ghossein Ronglai Shen Sofia Haque Somali Gavane Molecular Diagnostics Lab SKI Institutional Cores Support NIH P50-CA72012 RO1-CA72597 RO1-CA50706 Byrne Fund MSK patients.