Aliccia Bollig-Fischer, PhD Department of Oncology, Wayne State University Associate Director Genomics Core Molecular Therapeutics Program Karmanos

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1 Aliccia Bollig-Fischer, PhD Department of Oncology, Wayne State University Associate Director Genomics Core Molecular Therapeutics Program Karmanos Cancer Institute

2 Development of a multiplexed assay to detect ROS1 and RET fusion genes identified in NSCLC specimens using MassArray technology by Sequenom (targeted amplification, targeted extension primer reaction plus mass spectrometry analysis). An extension of the Lung Cancer Mutation panel. Goal: Research Tool & Advance Genomic Diagnostics

3 Estimation of the Molecular Heterogeneity in NSCLC RET 1% 2% 3% Pao, William, and Katherine E. Hutchinson. "Chipping away at the lung cancer genome." Nature medicine 18.3 (2012):

4 Sequenom LungCarta Panel Mutation panel provides the capability to measure 214 well-documented mutations in 26 oncogene and tumor suppressor genes in fresh/flash frozen and formalin-fixed paraffin-embedded lung cancer specimens using the Sequenom MassARRAY System Matrix-Assisted Laser Desorption/Ionization and Time of Flight (MALDI-TOF) mass spectrometer

5 Result for an individual MET N375S (asparagine serine) assay is highlighted in the frame. Based on input DNA sequence, a multiplexed reaction adds a single base to an extension primer, the nature of the base pair added to a primer affects its mass and time-offlight through a vacuum. The red line indicates a depleted extension primer peak. The masses of two possible extension results are determined: guanine (G, mutation) and adenine (A, wild-type).

6 Methods for discovery of gene rearrangements or fusion transcript junctions Whole transcriptome sequencing RACE PCR Whole-genome sequencing for discovery of genomic break points or discordant paired-end reads (end-sequences are aligned to each of the fusion partner genes) Methods for detection of gene rearrangements or fusion transcript junctions Break apart FISH PCR/sanger sequencing Mass spectrometry of multiplexed extension reactions Multiplexing is recommended due to scarcity of tumor material

7 Summary of Rearrangement Anatomy: RET Reference Ju et al, 2012 Kohno et al, 2012 Takeuchi et al, 2012 Lipson et al, 2012 KIF5B-RET Fusion K16R12 K15R12 K23R12 K15R12 K16R12 K23R12 K24R8 K15R12 K16R12 K22R12 K23R22 K24R11 K15R12 K16R12 K22R12 K15R11 Chromosome 10 inversion CCDC6 Ex 1 Ex 2 Ex 1 Ex 1 RET Ex 11 Ex 12 Ex 12 Ex 12 CCDC6-RET

8 Activated RET is a target for kinase inhibitors, e.g., Cabozantinib, Vandetanib, Ponatinib, Sorafinib, Overview presented in: Takeuchi, Kengo, et al. "RET, ROS1 and ALK fusions in lung cancer." Nature medicine 18.3 (2012):

9 Fusion Chromosomal Rearrangement Tumor type 1st ROS1 exon Partner Exon Reference CD74-ROS1 t(5;6)(q32;q22) NSCLC 35 6 Rikova et al., 2007 Lung adenocarcinoma 34 6 Li et al., 2011 Lung adenocarcinoma Takeuchi et al., 2012 NSCLC 34 6 Davies, 2012 EZR-ROS1 inv(6)(q22q25.3) Lung adenocarcinoma Takeuchi et al., 2012 LRIG3-ROS1 t(6;12)(q22;q14.1) Lung adenocarcinoma Takeuchi et al., 2012 SLC34A2-ROS1 t(4;6)(p15.2;q22) NSCLC Rikova et al., 2007 Lung adenocarcinoma Takeuchi et al., 2012 NSCLC Davies, 2012 SDC4-ROS1 t(6;20)(q22;q12) Lung adenocarcinoma 32 2 Takeuchi et al., 2012 NSCLC Davies, 2012 TPM3-ROS1 t(1;6)(q21.2;q22) Lung adenocarcinoma 35 8 Takeuchi et al., 2012 t(5;6)=translocation between chromosome 5 and 6 of

10 Activated ROS1 is a target for kinase inhibitor Crizotinib Overview presented in: Takeuchi, Kengo, et al. "RET, ROS1 and ALK fusions in lung cancer." Nature medicine 18.3 (2012):

11 Number of Fusion Genes Assayed for = 15 Number of ROS1 Fusion Genes = 9 Number of RET Fusion Genes = 6 Reactions per Fusion Gene = 4 Total number of primers = 150 (45 amplicon pairs + 60 extension primers) Degree of multiplexing = 5 reactions per well 12 wells per assay

12 1. TPM3-ROS1 2. SDC4-ROS1 S2; R32 3. SDC4-ROS1 S4; R34 4. SLC34A2-ROS1 SL4; R32 5. SLC34A2-ROS1 SL13; R32 6. CD74-ROS1 C6; R32 7. CD74-ROS1 C6; R34 8. EZR-ROS1 E10; R34 9. LRIG3-ROS1 10. KIF5B-RET K15;R KIF5B-RET K16; R KIF5B-RET K22; R KIF5B-RET K23; R KIF5B-RET K24; R CCDC6-RET 9 ROS1 fusions (with 6 other genes, 3 variants) 6 RET fusions (2 genes, 6 KIF5B variants) In variants, the exon number involved in the fusion has been indicated, e.g., R32 = exon 32 of ROS1

13 Schematic of the designed test: reactions per fusion junction 5 Upstream exon junction Amplicon Engineered plasmids made up first validation target sequence Downstream exon junction Normal lung cdna background was first validation control template PCR F F F R R R Ext Primers F F R F

14 1) Engineered plasmids and normal lung cdna internal controls Major Milestone 2) Lung cancer-derived cell lines with endogenous fusions 3) RNA from NSCLC specimens Select samples downstream of mutation analysis, based on evidence that mutations are often mutually exclusive Select samples based on patient history of smoking Select samples based on breakpoint evidence from acgh analysis Sample ID 384 candidate (showing amplification in ROS1 gene by acgh)

15 Priyanga Wijesingha, PhD (poster #21) Mike Hagen, PhD Gerold Bepler, MD, PhD William Block, MD, Clinical Genomics Lab Medical Director Sue Land, PhD, Director Applied Genomics Technology Center Others from the Lung Cancer Working Group at KCI Shirsh Gadgeel, MD Ann Schwartz, PhD Michele Cote, PhD

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