genomic medicine: are we answering the right questions? nazneen rahman head of cancer genetics icr...
DESCRIPTION
SequencingTRANSCRIPT
Genomic medicine: are we answering the right questions?
Nazneen Rahman Head of Cancer Genetics
ICR and RMH@rahman_nazneen#genomicsfest
Genomes sequenced
Sequencing
Sequencing
Analysis
Interpretation
REBYHINEIHESTTOTE
THE BOY IS IN THE TREE
HE MIGHT BE STUCK- GET A LADDER
Sequencing
Analysis
Interpretation
Patient Sample
Clinical Actions
Sequencing
Analysis
Interpretation
Patient Sample
Clinical Actions
Sequencing
Analysis
Interpretation
Patient Sample
Clinical Actions
Q: How do we upscale clinical pathways to accommodate the extraordinary advance in genome sequencing?
Q: How do we create radical innovative clinical pathways to complement the extraordinary advance in genome sequencing?
OLD DNA SEQUENCING =
NEW DNA SEQUENCING =
Sequencing
Analysis
Interpretation
Patient Sample
Clinical Actions
Sequencing
Analysis
Interpretation
Patient Sample
Clinical Actions
Current variant interpretation
Class Description Probability of being Pathogenic5 Definitely Pathogenic >0.994 Likely Pathogenic 0.95–0.993 Uncertain 0.05–0.9492 Likely Not Pathogenic 0.001–0.0491 Not Pathogenic <0.001
Problems:Variant-centric: doesn’t use gene-based, phenotype-based data Largely arbitrary and based on many assumptions. Very laborious, low-throughput, non-scalable.5 variant classes but never 5 clinical management classes.
Plon et al Hum Mutat 2008 29:1282-91
Current variant interpretation
V3
V10V1
V5
V2
V6
V4
V7
V8V9
tool4
tool2
tool3
tool1
tool5
tool6
V5
V6
V9V4
V1
V2 V3
V8
V7 V10
Definitely pathogenic >0.99Likely pathogenic 0.95-0.99
Uncertain 0.05-0.949(VUS)
Likely not pathogenic 0.001-0.049Not pathogenic <0.001
ClinicalAction??
Interpretation requirements
1. High-throughput + large volume2. Fast turnaround3. Intelligible and usable by non-expert/patients
Current variant interpretation
V3
V10V1
V5
V2
V6
V4
V7
V8V9
tool4
tool2
tool3
tool1
tool5
tool6
V5
V6
V9V4
V1
V2 V3
V8
V7 V10
Definitely pathogenic >0.99Likely pathogenic 0.95-0.99
Uncertain 0.05-0.949(VUS)
Likely not pathogenic 0.001-0.049Not pathogenic <0.001
ClinicalAction??
We urgently need innovative approaches for delivering variant interpretation for the clinic
V3
V10V1
V5
V2
V6
V4
V7
V8V9
ClinicalAction
Clinical variant management
Manage as not clinically relevant
Action 3
Action 2
Action 1
Clinical variant management
Manage as not clinically relevant
Action 3
Action 2
Action 1 V6
V9 V4
V1
V2 V3
V8 V5
V7 V10
Clinical variant management
Manage as not clinically relevant
Action 3
Action 2
Action 1
Fulfil explicit criteria
V6
V9 V4
V1
V2 V3
V8
V5
V7 V10
Variant Phenotype
Frequency of phenotype
Mechanism of pathogenicity
Inheritance pattern
Attribution of gene for phenotype
Penetrance of gene for phenotype
Population variation
Variability of gene
Gene structure/function
How does it work in practice?
BRCA1 and BRCA2
Cancer predisposition genes.
Mutations confer increased risks of breast and ovarian cancer.
Rare BRCA variants are common!
• 1000 UK population controls • 4 pathogenic BRCA mutations (all truncating)
>5% freq 100%
up to 5% freq 44%
up to 1% freq 27%
up to 0.1% freq 13%
>5% freq 100%
up to 5% freq 37%
up to 1% freq 18%
up to 0.1% freq 9%
All BRCA variants Nonsynonymous BRCA variants
10% of healthy population have a rare BRCA variant (VUS)
• Should be managed as a negative BRCA test: – Not used in cancer management. – Not used for cancer risk prediction in relatives.
• Actually managed very inconsistently: – Often predictive testing + cancer surveillance in relatives.– Risk reducing surgery (30%).
Very significant harms at patient and societal level.
Clinical management of BRCA VUS
Which BRCA variants are pathogenic?
Evidence from the last 20 years have shown:•>95% of pathogenic BRCA mutations are truncating.•>95% of truncating mutations are pathogenic.•>95% of non-truncating variants are not pathogenic.
1863 aaBRCA1RING BRCT
BRCA2 3418 aaDBD
Pathogenic non- truncating BRCA mutations are very rare and in key
domains
BRCA clinical variant management
Manage as not clinically relevant (74%) Variant
Pathogenic Mutation
Manage as clinically relevant (16%)
Variant requiring evaluation (<0.2%)
• Fast, consistent • Automated interpretation for >95% variants
Every variant has to be triaged into a clinical management category
>95% automatic
<5% expert hand curation- Ongoing iteration essential
Q: Is the variant pathogenic or non-pathogenic?
Q: What is the potential human impact of the variant?
Genotype-phenotype is very complex
1. A specific BRCA mutation can confer different risks of different cancers.
2. Different BRCA mutations can confer different risks of a particular cancer.
3. A specific BRCA mutation can confer different risks of a particular cancer in different contexts.
Cancers other than breast and ovarian are prob not causally related to the BRCA mutation
-1lo
g10(
P v
alue
)
P = 0.05
ACC AdrenocorticalBLCA BladderBR BreastCESC CervicalCOAD ColonDLBC Diffuse Large B-cellESCA EsophagealGBM GlioblastomaHNSC Head and NeckKICH Kidney ChromophobeKIRC Kidney renal clear cell KIRP Kidney renal papillary cell LAML Acute Myeloid LeukemiaLGG Brain Lower Grade GliomaLIHC Liver LUAD Lung adenocarcinomaLUSC Lung squamousOV OvarianPAAD PancreaticPCPG Pheochromocytoma or ParagangliomaPRAD ProstateREAD RectumSARC SarcomaSKCM MelanomaSTAD StomachTHCA ThyroidUCEC Uterine Corpus Endometrioid UCS Uterine
• Only breast and ovarian cancer types contain a significant number of pathogenic mutations in BRCA
OV
BR
LUS
CC
ES
CTH
CA
UC
EC
BLC
AH
NS
CS
TAD
CO
AD
ES
CA
GB
MLI
HC
PA
AD
PR
AD
RE
AD
SA
RC
SK
CM
KIR
PLU
AD
PC
PG
AC
CD
LBC
KIC
HK
IRC
LAM
LLG
GU
CS
-log1
0(Fi
sher
-exa
ct P
-val
ue)
0
5
10
15
20
25
30
BRCA mutations have context-dep risks
Ford D, Easton E et al, Am.J.Hum.Genet 1998
Familial BC
Antoniou A, Pharoah PD et al, Am.J.Hum.Genet 2003
BRCA mutations have context-dep risks
Familial BC
Unselected BC
??Population risk
Q: Should we tell people about incidental findings?
Q: Have we sorted out the pertinent findings?
Q: What can we tell people about incidental findings?
Sequencing
Analysis
Interpretation
Patient Sample
Clinical Actions
Q: How can we provide genetic counselling to everyone having a gene test?
Q: How do we provide the information people need to consent to and understand their gene test?
Medical genetic testing in people with disease
is different from
Predictive genetic testingin healthy individuals
How does it work in practice?
Mainstream Model
Medical testing (i.e. in cancer patients) through ‘trained’ cancer team. All test results interpreted by Genetics Mutation – all sent Genetics appointmentNo Mutation – likely no extra Genetics input needed.
Testing in unaffecteds done through Genetics. cha the next few years
Angela GeorgeHelen Hanson
www.mcgprogamme.com
Simple training for non-geneticists
• Takes ~20 mins4 short e-learning modules on Read documentation Complete checklist• Receive certificate.
www.mcgprogramme.com/BRCAtesting
Feedback
Patient feedback• 100% pleased had test.• 100% happy to have test at
oncology appt.• 98% understood may have
implications for themselves and their families.
Clinician feedback• 100%: I welcome the
opportunity to carry out BRCA gene testing for cancer patients through oncology appointments.
• 100%: I feel confident to consent a patient for a BRCA gene test; and inform patients of their results.
Effective and Efficient
Effective and Efficient
Save NHS £2M per year on genetic consultations alone
Take home
The revolutionary change in sequencing requires us to look with fresh eyes at all aspects of genomic medicine. We need to be equally creative and proactive in building paradigm-shifting innovations to clinical processes to maximise benefits and minimise harms.
AcknowledgementsICR Genetic Susceptibility Team MCG Programme & TGLclinical Elise Ruark, Shazia Mahamadallie, Angela George, Ann Strydom, Sheila Seal, Shawn Yost, Tara Mills, Anthony Renwick, Daniel Riddell, Imran Uddin, Vicky Cloke, Rachel Linger, Emma Ramsay, Harriet Wylie, Anna Elliot, Helen Hanson, Zoe Kemp, Ingrid Slade, WTCHG - Gerton Lunter, Márton Münz, Anna Fowler, RM Genetics, Gynae and Breast UnitsUK Cancer Genetics services