Managing incidental

findings in genomic

analysis of clinical samples

Prof Ron Trent Department of Medical Genomics, Royal Prince Alfred Hospital

Sydney Medical School, University of Sydney

Royal Prince Alfred Hospital

The road to incidental (secondary) findings – AKA

“incidentalome” Potential consequences

Options for dealing with them in the clinical context

What next?

Oxford definition: Incidental “casual, following as subordinate event, introduced during the action”

Latin incidentalis, from Latin incident- 'falling upon, happening to' (from the verb incidere)

Incidental findings: Result (DNA) found by chance in the course of obtaining a particular DNA test

History of Mendelian genetics

single gene – mutation – high penetrance – family pedigree

Theory & observations (1880s) e.g. segregation

Clinical acumen e.g. CF & salt, dysmorphology, syndromes

Proteins e.g. factor VIII protein & haemophilia

DNA (1950s)

DNA genetic testing (1970s)

Human Genome Project 1990-2000

Genetics Genomics (Complex Genetics) 2000+

Human Genome Project 1990 - 2000 → Omics

Today “omics” or “all”

Genomics

Proteomics Transcriptomics Metabolomics Epigenomics Phenomics

Sequence first human (other other) genomes

Develop new technology

Expand informatics

(data storage & analysis)

Consider ELSI (ethical, legal, social issues)

Move from single genes (genetics) to multiple or all genes (genomics)

Practical Application Genetics -DNA Testing

1970s – 1990s Single mutations

sought

Radioactivity, carcinogens

Individual mutations

+ 2/52 TAT

Interpretation easy

Counselling just starting

1990s – 2000s Move to DNA sequencing

Automation and now looking at small genes by DNA sequencing cf

specific DNA mutations

Interpretation

starting to become difficult (annotation

of DNA variants)

Counselling more professional

2000s → Technology now the

driver

Faster, cheaper and better DNA sequencing machines

Goal = $1,000 for whole

genome sequence (WGS) – cost BRCA1,2 sequence =

$2,000

Interpretation (informatics) the limitation

Counselling ???

Terminology DNA sequencing

First Generation DNA (Sanger) sequencing

1980 Nobel Prize

Radioactive to

chemical sequencing

Limited utility until automated

Human Genome Project is driver

Megabyes (106) of data

Second (Next) Generation (NGS)

or massively parallel sequencing

Where we are now

Goal = WGS (whole genome sequence)

Paradigm for patient

care will be shift from Dx testing to Screening

Gibabytes (Gb) of data

Third Generation single molecule

sequencing

Platforms now being rolled out in USA

Few publications

Save on preparation

steps but added informatics

Faster, cheaper but Tb

to Pb of data

Accuracy is an issue?

DNA sequencing of genes now preferred approach to DNA genetic testing for mutations in genes

1 2

3 4

Technology getting better ………. interpretation getting more difficult

Formats for Reporting Genetic DNA Tests

Causative mutation(s) - evidence ranges from minimal to strong

Benign DNA variant(s) – variable evidence

Variant(s) of unknown significance (VUS) – none of above

Incidental findings – DNA variants that were not sought as part of clinical picture but were detected & may have clinical significance e.g. BRCA1 mutation

GENETICS

ANALYSIS

+

GENOMICS

ANALYSIS

INTERPRETATION

+

INTERPRETATION

The road to incidental (secondary) findings – AKA

“incidentalome”

Potential consequences

How to deal with them in the clinical context

What next?

11

2007 - whole genome sequence for Jim Watson (Nobel Laureate) has ~100 “lethal” DNA changes

Functional interpretation not easy but clearly not affecting longevity (aged 79)

Implications for patient AND family members – Jim Watson excluded some potential neuropychiatric genes from publication

Case study: Incidental findings

Incidental Findings & Healthcare

Prevention is “king”. Obligation to follow up and take action if prevention is possible (justification for genetics)?

For any one large gene sequenced for clinical purposes, the challenge is to understand what DNA variant(s) mean in the medical context i.e. clinical validity and utility. UK GTN lists >700 genetic DNA tests having clinical utility(?) Few genomic tests evaluated for clinical utility.

Massive undertaking to assess incidental findings – worthwhile, is it feasible; what about the “worried well” ???

Actionable, pathogenic, incidental findings in 1,000 participants’ exomes

Am J Hum Genet 2013; 93: 1-10

Review of 500 European + 500 African-descent participants from a USA exome sequencing project

114 genes selected = associated with medically actionable genetic conditions in adults [HGMD mutation reference]

~3.4% Europeans and ~1.2% African descent individuals had high penetrance actionable or likely pathogenic variants 23 individuals = 17 Europeans and 6 of African descent

HGMD – quality data variable; significant work to analyse variants

Incidental or: secondary, unanticipated, opportunistic, unrelated,

ancilliary etc.

Incidental findings and “ELSI”

Germline genetics = patient + families (not with somatic cell genetics).

Consent: Informed vs open ended (in genomics) Autonomy of patient (& families)

Privacy of patient (& families)

In Australia, amendments to Privacy Acts from 2006

allowing disclosure to family members

Life (income protection and travel) insurance – risk rated i.e. based on disclosure

Important shift in research focus to the “patient” or “community”

Targeted or strategic research = public funding

Next is the move to “cross the valley of death” more efficiently (faster)

Pure research organisations (CSIRO, MRIs etc) now into clinical care

Blurring of research and evidence based clinical care.

Nature 2008 11 June

Incidental Findings & Research

The road to incidental (secondary) findings – AKA

“incidentalome” Potential consequences

How to deal with them in the clinical context

What next?

Some views on how to handle “incidental (secondary) findings”

2. No different CXR

or MRI i.e. should be

reported

1. Contents of report based on

patient consent

3. In genome studies the results from about

30 risk genes SHOULD be sought irrespective of indication for testing and results given.

2013

Contents of report based on patient consent

Ethics underpinning medical practice

Beneficence: Non-maleficence: Autonomy: Justice: Informed consent

So if patient understands and agrees to “incidental findings”

being provided should be ok

Debate about informed vs open consent

Until the type of consent is resolved, difficult to know what to do with incidental findings

No different to a CXR or MRI i.e. should be reported

Incidental finding on CXR usually means pathology CXR result unlikely to be genetic i.e. have a predictive

(unknown) component to it In contrast, family members are more likely to be affected

by any genetics / genomics findings (relevant or irrelevant) Bioinformatic “filtering” in genomics is possible – not for

CXRs (or MRIs)

The problem is that there are some differences

To Filter or Not to Filter – That is the Question

If you believe that incidental findings are not the same as CXRs there ARE options for dealing with them

Can be done through software Allows information to be “hidden” or

“stored” until required (if ever) Main risk is security (privacy)

In genome studies the results from about 30 risk genes SHOULD be sought irrespective of indication for testing and results given.

2013

In the process of the genomic test there is an active search for results from ~30 genes known to cause disease

In effect now undertaking DNA screening, NOT getting incidental findings

Contentious: Patient not consenting cannot have the test so question of autonomy

The road to incidental (secondary) findings – AKA

“incidentalome” Potential consequences

Options for dealing with them in the clinical context

What next?

Driver becomes cost ELSI (ethical legal social issues) will be resolved

Targeted sequencing

Exome sequencing

Whole genome sequencing

Today, $2,000 for BRCA1, BRCA2 genes Conventional DNA sequencing

$4,000 for sequencing all exons of the 20K human genes “New” DNA sequencing

Goal is $1,000 or less per Whole Genome Sequence

Incidental Findings – will only get bigger

Using a DNA test to PREDICT a disease will develop in the future

Using a DNA test to SELECT a drug / assess risk of TOXICITY

to a drug

Predictive Testing

Pharmacogenetics & Somatic cell cancer genetics

Personalised Medicine

Models: Cancer Rx, pharmacogenetics & Direct to Consumer DNA testing

Cetuximab - MAb Rx unresponsive metastatic colon cancer. Expensive and

most likely to work when KRAS gene does NOT have mutations (60% cancers)*

Herceptin- MAb Rx unresponsive metastatic breast cancer when HER2 gene is

amplified (20-30%). Apart from expense, significant side effects*

Vemurafenib - Rx metastatic melanoma. Effective when have BRAF V600E

mutation.

• Implications for drug delivery pipeline and drug approvals

• Will save $$ from PBS - funded as co-dependent technology

• Oncologists – want all mutations i.e. NGS approach

Somatic Cell Cancer DNA Testing

Now feasible through NGS

DNA test uses tumour but seeks all DNA variants both somatic and germline – WES to WGS incidental findings

Pharmacogenomics based testing – cheaper through WES or WGS rather than targeted gene sequencing incidental findings

Somatic cell genomics – growth area; pharmacogenomics – sleeping giant

Somatic cell DNA Genomics

Issues of incidental findings needs to be resolved

Sergey Brin (Google) &

Anne Wojcicki (23andMe)

Empowering individuals to take genetic information into own hands

eBay like model attractive …. but product is flawed

Regulation and oversight not practical for offshore based facilities

Direct-to-Consumer DNA Testing

Genetics in Medicine 2011

Lancet 2010;375:1525

Whole Exome or Genome Sequencing: New Paradigms for Clinical Care – European models

Concept of “Rare” diseases

Leadership from UK Government

Brave new world ahead NGS + non-invasive prenatal testing or newborn screening

Conclusion: Resolving issue of “Incidental findings” priority

Sci Transl Med 2012;4:137