Transcript Medical genetic testing - Festival of Genomics London

Genomic medicine: are we
answering the right questions?
Nazneen Rahman
Head of Cancer Genetics
ICR and RMH
@rahman_nazneen
#genomicsfest
Genomes sequenced
Sequencing
REBYHINEIHESTTOTE
Sequencing
Analysis
Interpretation
THE BOY IS IN THE TREE
HE MIGHT BE STUCK
- GET A LADDER
Patient Sample
Sequencing
Analysis
Interpretation
Clinical Actions
Patient Sample
Sequencing
Analysis
Interpretation
Clinical Actions
Patient Sample
Sequencing
Analysis
Interpretation
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 =
Patient Sample
Sequencing
Analysis
Interpretation
Clinical Actions
Patient Sample
Sequencing
Analysis
Interpretation
Clinical Actions
Current variant interpretation
Class
5
4
3
2
1
Description
Definitely Pathogenic
Likely Pathogenic
Uncertain
Likely Not Pathogenic
Not Pathogenic
Probability of being Pathogenic
>0.99
0.95–0.99
0.05–0.949
0.001–0.049
<0.001
Plon et al Hum Mutat 2008 29:1282-91
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.
Current variant interpretation
V6
Definitely pathogenic >0.99
Likely pathogenic 0.95-0.99
tool1
V1
tool2
V6
V7
tool3
V2 V5 V1
tool4
V10
V8
V3
tool5
V9
V4
V8
V5
V2
V3
Uncertain 0.05-0.949
(VUS)
??
V7
V10
tool6
V4
V9
Likely not pathogenic 0.001-0.049
Not pathogenic <0.001
Clinical
Action
Interpretation requirements
1. High-throughput + large volume
2. Fast turnaround
3. Intelligible and usable by non-expert/patients
Current variant interpretation
V6
Definitely pathogenic >0.99
Likely pathogenic 0.95-0.99
tool1
V1
tool2
V6
V7
tool3
V2 V5 V1
tool4
V10
V8
V3
tool5
V9
V4
V8
V5
V2
V3
Uncertain 0.05-0.949
(VUS)
??
V7
V10
tool6
V4
V9
Likely not pathogenic 0.001-0.049
Not pathogenic <0.001
Clinical
Action
We urgently need innovative approaches for
delivering variant interpretation for the clinic
V6
V7
V2 V5 V1
V10
V8
V3
V9
V4
Clinical
Action
Clinical variant management
Action 3
Action 2
Action 1
Manage as not clinically relevant
Clinical variant management
Action 3
Action 2
V1
V8
V5
V2
Action 1
V3
V10
V9
V6
V7
V4
Manage as not clinically relevant
Clinical variant management
Action 3
V8
Action 2
Fulfil explicit criteria
V1
V5
V2
Action 1
V3
V10
V9
V6
V7
V4
Manage as not clinically relevant
Frequency of phenotype
Mechanism of
pathogenicity
Population variation
Variability of gene
Gene structure/function
Variant
Phenotype Inheritance pattern
Attribution of gene for
phenotype
Penetrance of gene for
phenotype
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)
All BRCA variants
Nonsynonymous BRCA variants
>5% freq
100%
>5% freq
100%
up to 5% freq
44%
up to 5% freq
37%
up to 1% freq
27%
up to 1% freq
18%
up to 0.1% freq
13%
up to 0.1% freq
9%
10% of healthy population have a rare BRCA variant (VUS)
Clinical management of BRCA 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.
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.
Pathogenic non- truncating BRCA
mutations are very rare and in key domains
RING
BRCA1
BRCT
1863 aa
DBD
BRCA2
3418 aa
BRCA clinical variant management
Pathogenic
Mutation
Manage as clinically relevant (16%)
Variant requiring evaluation (<0.2%)
Variant
Manage as not clinically relevant (74%)
• Fast, consistent
• Automated interpretation for >95% variants
>95% automatic
Every variant has to be triaged into a
clinical management category
<5% expert hand curation
- Ongoing iteration essential
Q: Is the variant pathogenic or nonpathogenic?
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
30
20
• Only breast and ovarian
cancer types contain a
significant number of
pathogenic mutations in
BRCA
15
10
5
P = 0.05
0
OV
BR
LUSC
CESC
THCA
UCEC
BLCA
HNSC
STAD
COAD
ESCA
GBM
LIHC
PAAD
PRAD
READ
SARC
SKCM
KIRP
LUAD
PCPG
ACC
DLBC
KICH
KIRC
LAML
LGG
UCS
-log10(Fisher-exact P-value)
-1log10(P value)
25
ACC
BLCA
BR
CESC
COAD
DLBC
ESCA
GBM
HNSC
KICH
KIRC
KIRP
LAML
LGG
LIHC
LUAD
LUSC
OV
PAAD
PCPG
PRAD
READ
SARC
SKCM
STAD
THCA
UCEC
UCS
Adrenocortical
Bladder
Breast
Cervical
Colon
Diffuse Large B-cell
Esophageal
Glioblastoma
Head and Neck
Kidney Chromophobe
Kidney renal clear cell
Kidney renal papillary cell
Acute Myeloid Leukemia
Brain Lower Grade Glioma
Liver
Lung adenocarcinoma
Lung squamous
Ovarian
Pancreatic
Pheochromocytoma or Paraganglioma
Prostate
Rectum
Sarcoma
Melanoma
Stomach
Thyroid
Uterine Corpus Endometrioid
Uterine
BRCA mutations have context-dep risks
Familial BC
Ford D, Easton E et al, Am.J.Hum.Genet 1998
BRCA mutations have context-dep risks
Familial BC
Unselected BC
??Population risk
Antoniou A, Pharoah PD et al, Am.J.Hum.Genet 2003
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?
Patient Sample
Sequencing
Analysis
Interpretation
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 testing
in 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 appointment
 No Mutation – likely no extra Genetics input needed.
 Testing in unaffecteds done through Genetics.
cha the next few years
www.mcgprogamme.com
Angela George
Helen Hanson
Simple training for non-geneticists
• Takes ~20 mins
4 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.
Acknowledgements
ICR 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 Units
UK Cancer Genetics services