5 th July 2016 ACGS Dr Michelle Wood Laboratory Genetics, Cardiff

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1 5 th July 2016 ACGS Dr Michelle Wood Laboratory Genetics, Cardiff

2 National molecular screening of patients with lung cancer for a national trial of multiple novel agents NSCLC patients/year (late stage met disease) 18 CHs (ECMCs = Experimental Cancer Medicine Centre) 3 THs Molecular analysis for recruitment to the National Lung Matrix Trial being run by the Birmingham Cancer Research Clinical Trials Unit (CR-TU) SMP2 sample collection started in September 2014

3 CR-UK SMP2: Sample/ info data flow Cancer Patients Research Database (ECRiC) Genetic and clinical Data Bha m Leed s Genetic Results Clinical Hubs (ECMC network) Cardiff Man Edin Glas Cam b Birming ham Anonymised Data ICR Genetic Technology Hubs Samples Researchers Partners NHS Car d RM H MATRIX TRIAL

4 A national phase II trial open at all ECMCs (Experimental Cancer Medicine Centres). Run by the Birmingham Cancer Research Clinical Trials Unit (CR-CTU) This trial allows NSCLC patients to be stratified into a specific trial arm according to their tumour molecular profile. There are multi-arms to this trial allowing multiple novel therapies to be tested under a single clinical trial protocol. This will give patients access to a wider portfolio of treatments delivered through the ECMC Network. Each novel drug arm will contain up to 30 patients Genes for analysis can be revised accordingly. Biopsy will be taken (where possible) post therapy to compare molecular characterisation pre and post therapy. Repeat biopsy will be offered to patients at relapse.

5 Drug arms involving CNVs and translocations highlighted

6 CR-UK NGS Panel 2 Illumina Nextera hybridisation 28 genes For detection of: SNVs small insertions and deletions larger structural variants including translocations and CNVs. The use of matched blood sample eliminates germline variants. Developed and validated in partnership with Illumina A technology transfer to the TH ensures consistency between the laboratories Panel linked to Matrix Trial FFPE and matched blood DNA AKT1 ALK BRAF CCND1 CCND2 CCND3 CCNE1 CDK2 CDK4 CDKN2A EGFR FGFR2 FGFR3 Her2 HRAS KRAS MET NF1 NRAS NTRK1 PIK3CA PTEN RB1 RET ROS1 STK11 TSC1 TSC2

7 Patient DNA is processed to generate a sequencing library collection of DNA fragments derived from the patient Transposons simultaneously fragment and tag the DNA with primers Indexes are added to each sample so they can be separated DNA fragments are flanked by adaptor sequences Allow fragments to stick to the flow cell surface

8 Sequencing libraries are hybridised to Biotin labelled probes complementary to regions of interest Positively enrich for library fragments covering regions of interest Uses an enrichment or capture approach positively select fragments of interest from your sequencing library

9 Detected somatic variants are compared to a list of variants that have scientific evidence of acting as effective biomarkers and predictors of drug response. Variants are tiered (Tier 1-3) based on the level of scientific evidence, where Tier 1 and 2 are eligible for NLMT. Tier 1 well characterised aberrations with demonstrated clinical evidence Tier 2 aberrations likely to have clinical significance e.g. in known activation hotspot Tier 3 aberrations that do not fall into Tier 1 or 2 A report containing the genes and variants plus any clinical interpretation is generated and sent to treating oncologists via an XML message. Confidence levels are given for wild type genes.

10 CRUK panel can detect small CNVs encompassing regions sequenced whole gene or multiple exons. NGS panel contains probes for control regions as well as genes of interest. Called manually - plot mean coverage of the target regions Normalise to blood sample coverage.

11 Limit of detection for this panel is approx 3x with a good quality sample CNVs are more easily detectable in samples with high tumour % and if the CNV is large. Confirmation of trial-eligible dels/amps by FISH MET amplification

12 Nextera analysis TH contacts CH FISH confrimations on... Technical Hub receives report Detection of CNV by Nextera Clinical Hub sends additional section (2x4uM) for FISH MET CCND1 PTEN PIK3CA CDKN2A CDK4 FISH report received by TH

13 No CNV 3-5x CCND1 AMP 15-20x EGFR AMP

14 Detection of CNVs using NGS CNV detection is challenging in poor quality samples

15 Much more difficult to detect Requires good quality sequence coverage 40% tumour content 90% tumour content Homozygous dels not detectable in samples with <60% of neoplastic nuclei any contamination with normal tissue will affect the reading from the panel

16 Homozygous deletion in CDKN2A confirmed with FISH ~ 90% tumour

17 Day 1: Blood and FFPE (6x10uM) received from Newcastle CH Day 2: Tumour region assessed as 60% containing neoplastic cells (Histo) Day 3: DNA extracted from blood and tumour Day 4*: Nextera set-up and MiSeq *dependent on NGS service workflow

18 Day 10: Nextera data analysis: 2x CCND1 amplification

19 Day 11: Request FISH slides from CH for confirmation of CNV Day X: 2x4uM FISH slides received FISH: Vysis single colour CCND1 (11q13) plus centromeric control probe CEP11

20 Patient eligible for NLMT: CCND1 amplification AND Rb1 wild-type

21 Confirmed with FISH Not confirmed with FISH PIK3C A CCND CCNE

22 Translocations are called by Manta software; calls structural variants (SVs) and indels from mapped paired-end sequencing reads - can be viewed in IGV Poor quality samples that yield low coverage of the target regions make identification of translocations difficult. Confirmation of trial-eligible translocations (ROS1) by FISH Chr4: (SLC34A2 int4)-chr6: (ROS1 int31) ROS1 SLC34A2

23 Sample received as DNA extracted from FFPE tissue from Glasgow Tumour region assessed as 50% containing neoplastic cells (Histo)

24 No SNVs or CNVs detected in this sample Manta called a translocation between CD74 and ROS1

25 Case study: Translocation detection

26 Case study: Translocation detection Patient eligible for NLMT: ROS1 gene fusion Crizotinib Anaplastic lymphoma kinase (ALK) inhibitor D1: MET amplified D2: ROS1 gene fusions D3: MET exon 14 skipping, including splice variants and deletions

27 ROS1 translocation Translocation between ZCCHC8 and ROS1

28 EML4-ALK translocation EML4 ALK

29 Clear CNV on NGS reported immediately Low or unclear CNV on NGS FISH confirmation The TH will never say no translocation or no copy number variation currently no confidence value for this,

30 NLMT CNV As the limits of detection of CNVs are not fully known and these variants are required for trial opening, the programme has decided to confirm some potential amplifications and homozygous deletions with FISH analysis. Confirmations on: MET, CCND1, PTEN, PIK3CA, CDKN2A, CDK4

31 Number of aberrations Tier 1 and 2 NLMT gene aberrations translocation whole gene deletion amplification indel Types of Tier 1 and 2 aberrations detected by NGS in biopsies from patients with advanced NSCLC. Jan 2015 to April 2016.

32 Eligibility for Matrix trial RB1 wildtype STK11 loss + KRAS mut CCND1 Amp CDK4 Amp CDKN2A loss ROS1 fusion PIK3CA amp & PTEN loss PTEN Loss MET Amp PIK3CA amp

33 CRUK SMP2 Technology Hubs Birmingham- Mike Griffiths, Jennie Bell, Fiona MacDonald, Pauline Rehal, Alessandro Rettino, Sam Clokie Cardiff- Rachel Butler, Ian Williams, Michelle Wood, Helen Roberts RMH- David Gonzalez de Castro, Lisa Thompson, Keeda Dover, Brian Walker, Lisa Grady Illumina David McBride Mark Ross THANK YOU

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