WGS for the 100,000 Genomes · Population and Medical Genomics Group Applying Genomics to Cancer, ... DNA sample to answer in 4 days ... HAS (Isaac) (H2’15) 96.9 99.8 92.3 98.3
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WGS for the 100,000
Genomes
Mark T. Ross
Population and Medical Genomics Group
Applying Genomics to Cancer, 21 Sept 2015
2
100,000 genomes
Cancer and rare genetic disease
ISO-accredited workflow (2016)
Data delivered electronically,
stored securely and analysed in
England Data Centre
Combine with extracted clinical
information for analysis,
interpretation, and aggregation
Genomics England Partnership
3
A Clinical Ecosystem for Precision Medicine
Patient information Treatment choice
Knowledge base Researcher Clinician
Timeline
Birth Biopsy
Surgery
Relapse
Event Metastasis
Chemo Relapse
Sequencing
Death
4
Fast WGS for genetic diagnosis of intensive care patient
Undiagnosed condition: – Male child presents at 5 months with developmental regression,
hypotonia, and seizures
One WGS test: DNA sample to answer in 4 days
Filter annotations rapidly using generic queries: Number of transcripts with functional variants: 13,367
‘With 2 variants’** and <5% allele frequency: 1,458
And predicted to be functional: 287
And in a gene linked to disease: 35
And predicted to be deleterious: 21
Evolutionarily conserved: 6
Apply control genomes filter: 1
Confirm Menkes diagnosis – A novel hemizygous variant in ATP7A, a gene with mutations
known to disrupt copper metabolism
Kingsmore et al. (Children’s Mercy Hospital)
** shorthand for homozygous., compound heterozygous, hemizygous positions
5
miR-26a-2 PTEN
PDGFRA
c-kit
PI3K AKT Growth
44-year old with glioblastoma recurrence
Not responding to treatments
Sequence genomes from three biopsies and normal genome
WGS of brain tumour defines new treatment options
Swanton et al. (CRUK London Research Institute)
DNA rearrangements amplify
growth regulator genes
PDGFRA gene
normal
amplified
New treatment indicated
(10 days from start)
PDGFRA
c-kit
Amplify
+ + +
+
Growth
C-kit
miR-26a-2
Cancer
+
Cancer
Imatinib
Sunitinib
Pazopanib
6
Trinucleotide contexts around somatic mutations reveal signatures of exposure