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Download Sequencing Circulating Tumour DNA to Monitor
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Circula(ng tumour DNA as a tool for non invasive cancer analysis Tim Forshew – Transla(onal Cancer Gene(cs Detecting and tracking circulating tumor DNA (ctDNA)! 2 Cell-free DNA for pre natal diagnosis! Detecting and tracking ctDNA! A>T Genetic changes -Mutation/rearrangement -Copy number change Epigenetic changes (methylation) 4 Tumour burden/ circula*ng tumour DNA The different potential roles of ctDNA as a biomarker! Tumour ini*a*on Treatment response Molecular stra*fica*on Early detec*on Time First treatment Differing treatment response Tumour evolu*on Residual disease Second treatment 5 Detecting and tracking individual mutations! Mutation-specific assay 6 ctDNA to assess colorectal cancer dynamics! Diehl et al, Nat Med. Sep 2008 7 Analysis of ctDNA to monitor metastatic breast cancer! 8 Analysis of ctDNA to monitor metastatic breast cancer! Dawson et al, N Engl J Med. 2013 Mar 9 ctDNA in advanced malignancies! 10 Bettegowda et al. Sci Transl Med 19 February 2014: Vol. 6, Issue 224, p. 224ra24 Bettegowda et al, Sci Transl Med. Feb 2014 ctDNA in localized and nonlocalized malignancies! Bettegowda et al, Sci Transl Med. Feb 2014 11 Sequencing ctDNA! Mutation-specific assay 12 De novo mutation detection by targeted ctDNA sequencing! PE1-‐CS1 CS1-‐TS-‐F Target Sequence CS2-‐TS-‐R PE2-‐BC-‐CS2 Forshew et al, Sci Transl Med. May 2012 13 ctDNA levels can be high! Exome Exome Dawson et al, N Engl J Med. 2013 Mar 14 Why exome sequence ctDNA? – Tumour evolution! 15 Allele fraction Allele fraction Allele fraction Allele fraction Plasma sample Plasma sample Plasma sample Plasma sample ormed on 2–5 plasma samples before treatment at progression before treatment at progression of treatment, at selected time Treatment Treatment our mutations in plasma was Why For two cases, exome synchronoussequence ctDNA? – Tumour evolution! ming genome-wide represensma. Quantification of allele ed representation of mutant of therapy resistance. These 3CA (phosphatidylinositol-4,5it alpha) following treatment n in RB1 (retinoblastoma 1) Exome Exome ; a truncating mutationsequencing in sequencing 1) following treatment with following subsequent treatmutation in GAS6 (growth ; and a resistance-conferring Analysis of mutations Analysis of mutations actor receptor; T790M) followin plasma DNA in plasma DNA esults establish proof of princulating tumour DNA could Mutations MutationsMutations Mutations approaches to identify mutasistance in advanced cancers. Identification Identification Exome Exome of mutations of mutations lasma constitutes a new paraselected by selected by n in human cancers. treatment treatment me is required to identify the 2 . Serial tumour Figure 1 |mutational rug ure 1resistance | Identification of treatment-associated changes from Identification of treatment-associated mutational changes from me sequencing serial plasma samples. of the study plasma design: samples. Overview of the study design: nable. Tumoursofare heterogenexomeOverview sequencing of serial sma was collected treatment and at multiple time-points during plasma was collected before treatment and at multiple time-points during if several biopsiesbefore are obtained, 16 tment and follow-up patients. sequencing was cancer patients. Exome sequencing was treatment andExome follow-up of advanced mporally. Analysis of ofadvanced isolated cancer ctDNA exome sequencing! Breast cancer ID: DETECT-52 ER-positive Her2-positive Murtaza et al, Nature. 2013 May 17 Early relapse detection! Misale et al, Nature. 2012 June 18 Conclusion and future directions! ! Sensi(ve and quan(ta(ve muta(on detec(on in plasma ! Possible uses as “liquid biopsy” ! First de novo muta(on by plasma sequencing ! New clinical cohorts, Improved sensi(vity, different sample types ! New UCL transla(onal cancer gene(cs lab 19 Acknowledgments! Nitzan Davina Francesco Rosenfeld Gale Marass Dana Tsui Muhammed Murtaza Keval Patel James Brenton Christine Parkinson Ania Piskorz Mercedes JimenezLinan Heather Biggs Carlos Caldas Sarah-Jane Dawson Tan Min Chin Fluidigm Andy May Fiona Kaper Illumina David Bentley Florent Mouliere, Andrea RuizValdepeñas, Suzanne Murphy Genomics core facility James Hadfield Sarah Leigh Brown Michelle Osborne Claire Fielding Hannah Haydon Fatimah Madni Bioinformatics core facility Ben Davis Mark Dunning
