genomic medicine: are we answering the right questions? nazneen rahman head of cancer genetics icr...

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

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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