Next Generation Sequencing: What Will it Mean for the Pathologist?
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1 Next Generation Sequencing: What Will it Mean for the Pathologist? Christopher Corless, MD, PhD Professor of Pathology, Oregon Health & Science University Chief Medical Officer, Knight Diagnostic Laboratories
2 Disclosures Company Ion Torrent/ThermoFisher Ventana/Roche Genentech/Roche Novartis Activity Travel support; reagents Travel support Honoraria & consulting fees Consulting fees I will mention off-label uses of cancer therapeutics
3 Topics Brief introduction to next-gen sequencing (NGS) Critical pre-analytical factors Usefulness of quantitative output from NGS Detecting mutations correlation with specimen Fusion gene detection Copy number assessment Data overload and implications for pathologists
4 Individualized Cancer Medicine - An Example - 42 year old male with glioblastoma treated with surgery, temozolomide and radiation Bone and lymph node mets appeared at 20 months (what is this tumor?) Admitted to OHSU to manage pain, monitor pending cord compression Another round of chemo failed BRAF V600E mutation identified Patient started on dabrafenib Excellent clinical response
5 Garraway, JCO epub April 15, 2013
6 >500 Targeted Therapeutics in Development Receptor tyrosine kinases Trastuzumab Cetuximab Panitumumab METMab Erlotinib Lapatinib Sorafenib Imatinib Sunitinib Afatinib Dovitinib Crizotinib Ceritinib P ALK or ROS1 P P Trametinib Selumetinib Benitinib ERK SHC GRB2 Vemurafenib Dabrafenib LGX818 P MEK SOS BRAF P CDK4/6 NRAS KRAS HRAS P1446A-05 LEE001 PI3K P P P PTEN BEZ235 Buparlisib BGT226 BYL719 Everolimus Temsirolimus P PDK mtor P S6K P AKT P P MK2206 SR13668 P
7
8 DNA Sequencing Traditional Sanger Method Capillary electrophoresis Final Sequence BRAF V600E
9 Next-Generation DNA Sequencing Massively parallel sequencing (many sequencing reactions performed simultaneously) ACTGGTCCTGCTGGTTAG ACTGGTCCTGCTGGTTAG ACTGGTCCTGCTGGTTAG ACTGGTCCTGCTGGTTAG ACTGGTCCTGCTGGTTAG ACTGGTCCAGCTGGTTAG ACTGGTCCAGCTGGTTAG ACTGGTCCAGCTGGTTAG ACTGGTCCAGCTGGTTAG
10 Gastrointestinal Stromal Tumor (GIST) A S P G A C A T C A T G C G T C A T A T G C [Stop] V A L PDGFRA D842V and M844fs*16 Known GIST driver mutation Truncates kinase domain 842 G T C V Frameshift
11 Applications of Next-Gen Sequencing Broad-based approaches Whole genome: all 3.2 billion base pairs Whole transcriptome: all mrnas in a sample Whole exome: ~1.6% of genome that encodes proteins Targeted approaches Panels of genes (10-400) Limited to targets regarded as actionable or prognostic
12 NGS Sequencers in Clinical Labs Ion Torrent PGM Illumina MiSeq (FDA-approved version available) Ion Torrent Proton Illumina NextSeq 500
13 Next-Gen Sequencing Read Out 1. Base-calling: sequencer generates millions of reads (50 to 200 base pair stretches of DNA) 2. Alignment: software matches the reads to the known genome 3. Variant calling: software determines where the sequence differs from a standard reference genome 4. Variant annotation: software programs + manual review to determine whether a variant is a: Benign polymorphism Variant of unknown significance Mutation (single nucleotide change, deletion, etc)
14 Applications How Much Tissue Is Needed? NGS Sequencing Methodology Hybrid-Capture Whole exome; larger panels Amplicon Smaller panels Input DNA 100 ng ng Overnight hybridization Yes No Gene copy number Yes Yes Fusion gene detection Yes Yes (RNA) 5 x 4 μm unstained sections of 1 cm core biopsy is sufficient for amplicon-based method New extraction method may work with just 4 mm 2 from a single section
15 Pre-Analytic Factors Influencing NGS Specimen decalcification Acid is often used to soften the bone for sectioning and this degrades nucleic acids EDTA-based solutions are better DNA deamination is common in older paraffin blocks Result Mimics a C>T mutation Tumor fraction: % of specimen comprised of tumor
16 Impact of Tumor Purity Each cellular nucleus in a specimen contributes DNA % Tumor fraction is based on tumor nuclei, not area The lower limit of sensitivity for most NGS panels is ~2-3% Mutant Allele Ratio in Tumor Cells Percent Tumor in Specimen Mutant Allele Ratio in Sequenced DNA 50% 90% 45% 50% 70% 35% 50% 50% 25% 50% 30% 15% 50% 10% 5%
17 Selecting Tumor-Rich Material for DNA Extraction Coring a block Scraping slides
18 Metastatic Melanoma in Lung Tumor purity: ~90%
19 Metastatic Colorectal Adenocarcinoma in Mesentery Tumor purity: ~10-20%
20 Transbronchial Biopsy Adenocarcinoma of the Lung Please, get another sample!
21 Metastatic Colorectal Adenocarcinoma NRAS p.q61r (27% mutant allele) TP53 p.r282w (26% mutant allele) Tumor fraction: 52-54% Estimated Tumor Fraction Microscope: 60%
22 Quantitating Tumor Nuclei Using CellProfiler Semi-automated using machine learning algorithm Tumor nuclei Normal nuclei
23 Molecular Subtypes of NSCLC Before 2000 KRAS Unknown FGFR1 EGFR FGFR2 FGFR3 ARAF PTEN RET HRAS NTRK3 BRAF ERBB2 PIK3CA MAPK1 ALK DDR2 ROS1 MET NTRK1
24 Molecular Subtypes of NSCLC in 2003 KRAS Unknown FGFR1 EGFR FGFR2 FGFR3 ARAF PTEN DDR2 RET HRAS ROS1 MET NTRK3 ERBB2 MAPK1 NTRK1 BRAF PIK3CA ALK
25 Molecular Subtypes of NSCLC in 2015 KRAS Unknown FGFR1 EGFR FGFR2 FGFR3 ARAF PTEN DDR2 RET HRAS ROS1 MET NTRK3 ALK BRAF ERBB2 PIK3CA MAPK1 NTRK1 FDA approved drugs FDA approved drugs in other cancers In clinical trials
26 NSCLC Case Example /12/new_oregon_health_science_univ_1.html 47 y/o woman with treatment refractory bronchioalveolar carcinoma Genotyping: BRAF V600E mutation Phase I study combining BRAF + MEK inhibitors: 6 month response Disease controlled for 7 months; she died about 1 year later Baseline 2 months
27 Interim results of phase II study BRF of dabrafenib in BRAF V600E mutation positive non-small cell lung cancer (NSCLC) patients. J Clin Oncol 31, 2013 (suppl; abstr 8009)
28 Molecular Subtypes of Lung Cancer 2015 KRAS Unknown FGFR1 EGFR FGFR2 FGFR3 ARAF PTEN RET HRAS NTRK3 BRAF ERBB2 PIK3CA MAPK1 ALK GENE FUSIONS DDR2 ROS1 MET NTRK1
29 ROS1 fusions in lung adenocarcinoma Discovery published in Jan Trial published Nov FDA-approved tx in Apr nd Line drug published in Oct. 2014
30 Detecting Actionable Gene Fusions In NSCLC Kinase Fusion FISH IHC RNAseq ALK Yes Yes Yes AXL Yes?? Yes BRAF Yes No Yes FGFR1 Yes No Yes FGFR2 Yes No Yes FGFR3 Yes No Yes MET Yes No Yes NTRK1 Yes?? Yes NTRK3 Yes?? Yes PGDFRA Yes No Yes RET Yes?? Yes ROS1 Yes Yes Yes
31 Kohno et al. Trans Lung Cancer Res. Vol 4, No 2 (April 2015)
32 Target Genes (169 potential fusions / 94 partners) ALK BRAF FGFR1 FGFR2 FGFR3 MET NTRK1 NTRK2 NTRK3 PDGFRA PDGFRB RAF1 RET ROS1 TMPRSS2 EGFR EGFRvIII ERBB4 NRG1 AKT3 Gene Expression ALK ROS1 RET EGFR NTRK1 NTRK2 Also useful for: Cholangioca Bladder ca HNSQCC NTRK3 BRAF Housekeeping genes (5) Beadling et al., submitted
33 Detecting Copy Number Alterations by NGS Breast Carcinoma With FGFR1 and HER2 Amplification FGFR1 ERRB2/HER2 Validation Samples Normal (2 Copies) Known FISH status Microarray results Grasso et al. J Mol Diag 17:53-63; 2015
34 FFPE Ductal Carcinoma of the Breast EGFR
35 EGFR Amplification in Breast Carcinoma 68 year old F Tumor metastatic to the liver HER2-negative [6% of breast carcinomas have EGFR amplif] Bhargava et al. Mod Pathol Aug;18(8):
36 Example of Variant List For a 37-Gene Panel Head & Neck Squamous Cell Carcinoma Chrom Position_Start Position_End Ref Variant Type Consequence Zygosity Var_Freq Gene p_aa_change chr T G SNP nonsynonymous Het KDR p.k747n chr C A SNP nonsynonymous Het CDKN2A p.e88* chr * CGCCCA C DEL stop gain Het TP53 p.g245g chr * A C SNP stop gain Het TP53 p.c242g chr * G C SNP stop gain Het TP53 p.s241s chr G A SNP nonsynonymous Het EGFR p.r521k chr G C SNP nonsynonymous Het TP53 p.p72r chr C G SNP nonsynonymous Het 60 ERBB2 p.p1170a chr A G SNP nonsynonymous Het ERBB2 p.i655v chr G C SNP nonsynonymous Het ALK p.d1529e chr T C SNP nonsynonymous Hom ALK p.i1461v chr A G SNP synonymous Het 7.37 NOTCH1 p.n104n Amino acid chr A G SNP synonymous Het 8.61 ALK p.g845g chr T A SNP synonymous Het EGFR p.t629t chr Gene G A Change SNP synonymous Het NF1 p.l234l chr G C SNP synonymous Het KIT p.l862l chr KDR G A K747N SNP synonymous Het NF1 p.p678p chr A G SNP synonymous Het KRAS p.d173d chr CDKN2A G A E88*(stop) SNP synonymous Het 80 MET p.p1382p chr C T SNP synonymous Het MET p.d1304d chr TP53 G A G245G SNP synonymous Het MET p.a1357a chr G A SNP synonymous Het ALK p.t1446t chr TP53 G T C242G SNP synonymous Het ALK p.g1125g chr G C SNP synonymous Hom 97.3 ALK p.l9l chr C T SNP synonymous Hom EGFR p.n158n chr T C SNP synonymous Hom 99.5 EGFR p.t903t chr C T SNP synonymous Hom KRAS p.r161r KDR encodes VEGFR2 chr A T SNP synonymous Hom ALK p.p234p chr T C SNP synonymous Hom ALK p.q500q chr G A SNP synonymous Hom EGFR p.q787q chr G A SNP synonymous Hom 100 FGFR3 p.t651t
37 Head & Neck SQCC Before Treatment Treatment Day 15 TKI With VEGFR2 Activity
38 We need to provide knowledge, not just data Dr. Kojo Elenitoba-Johnson, Nov year old male with thymic carcinoma and no good treatment options Tumor sequenced by a commercial laboratory (large gene panel) No actionable mutations reported Variants of unknown significance at very bottom of report included KIT Y646D
39 KIT-Mutant Thymic Carcinoma Patient Exon Mutation Treatment Response Reference 54 yr M KIT 11 Deletion V560D Imatinib 46 yr M KIT 17 D820E Sorafenib 47 yr F KIT 11 Deletion Sorafenib 48 yr M KIT 11 Y553N Imatinib 55 yr F KIT 11 Deletion V560D Imatinib 58 yr M KIT 13 K642E Sorafenib Mixed 6 mo PR 15+ mo PR 6+ mo PR 9+ mo SD 12+ mo PR 6 mo N Engl J Med Jun 17;350(25): J Thorac Oncol Jun;4(6):773-5 Lung Cancer Jan;71(1): J Clin Oncol Nov 20;29(33):e803-5 J Thorac Oncol Feb;9(2):e12-6 Onco Targets Ther. 2014, 7: KIT Mutations occur in ~10% of thymic carcinomas Y646D is a non-conservative substitution located near K642E Recommendation to oncologist: try a KIT inhibitor
40 Sorafenib x 12 days Patient remains on treatment and is doing well at 15 months
41 Turning Data Into Knowledge LIS Ion Torrent PGM Clinical Genomics Database Clinical Reports Illumina NextSeq500 Exacloud Computing Cluster Public Databases COSMIC dbsnp, Clinvar PCT (MD Anderson) My Cancer Genome CIViC
42 Whole Exome Sequencing (Sequencing All Protein-Coding Regions Across 20,000 Genes)
43 OHSU/Intel Collaboration Clinical Sequence Data Exacloud Computing Center Variant Annotation Research Genomic Data Sequence alignment Variant calling Clinical Genomics Database Data Reporting 7,000 Processors for data crunching 220 Terabytes of storage for clinical datasets 1200 Terabytes of storage for research samples
44 Liquid Biopsies DNA in Plasma and Urine Small fragments of DNA are present in normal plasma and urine Increased levels occur in patients with advanced cancer New, high sensitivity tests based on next-gen sequencing can be used to detect mutations in such samples May be useful in monitoring treatment responses Commercial Labs
45 Summary Advances in DNA sequencing technology are supporting the new era of precision cancer care NGS supports: o o o Determination of exact allele frequency Detection of gene fusion events Assessment of gene copy number The pathologist plays a critical role in selecting material appropriate for testing NGS panels are becoming very routine and can be integrated into practice as another tool alongside IHC, FISH, etc.
46 Acknowledgements Carol Beadling, PhD Richard Press, MD, PhD Tanaya Neff, MA Fei Yang, MD Rebecca O Gara Marina Pukay Andrea Warrick Cara Poage Amy Schilling Catie Grasso, PhD With Assistance From: Knight Cancer Institute Ion Torrent/ThermoFisher Intel GIST Cancer Research Fund LifeRaft Group
47
48 Cutaneous Melanoma Cases (n=140) No Mutation 34% AKT1 1% BRAF 44% BRAF V600E(K) Vemurafenib Dabrafenib Trametinib TP53 1% PIK3CA 1% NRAS 16% MAP2K1 1% KIT 1% CTNNB1 2% GNAQ 1% Updated from Beadling et al. J Molec Diag, 2011 Sep;13(5):504-13
49 Best Response to Vemurafenib in Metastatic BRAF V600E Melanoma Flaherty, et al. N Engl J Med Aug 26;363(9):809-19
50 KRAS p.a146t
51 Metastatic BRAF V600E Papillary Thyroid Carcinoma Treated With Vemurafenib
52 Cutaneous Melanoma Cases (n=140) No Mutation 34% AKT1 1% BRAF 44% TP53 1% PIK3CA 1% NRAS 16% MAP2K1 1% KIT 1% CTNNB1 2% GNAQ 1% Would imatinib work in melanoma? Updated from Beadling et al. J Molec Diag, 2011 Sep;13(5):504-13
53 KIT-Mutant Mucosal Melanoma Response to Imatinib Hodi et al. J Clin Onc 2008 Apr 20;26(12):
54 Targeting KIT-Mutant Melanoma Phase II Clinical Trials Drug # Pts Clinical Benefit Rate Carvajal et al. JAMA 2011;305(22): Guo et al. JCO 2011;29(21): Minor et al. Clin Cancer Res 2012; 18(5): Hodi et al. JCO (epub Jul 8, 2013) Imatinib 25 72% Imatinib 43 53% Sunitinib 4 75% Imatinib 13 77%
55 72 Year Old Female Smoker Left Lower Lobe Left Upper Lobe KRAS G12V KRAS G12C
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