Ronald Trent - University of Sydney - Managing Incidental Findings in Genomic Analysis of Clinical Sample


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Ronald J A Trent, Head, Department of Molecular & Clinical Genetics, Royal Prince Alfred Hospital and Professor of Medical Molecular Genetics, Sydney Medical School, University of Sydney presented "Managing Incidental Findings in Genomic Analysis of Clinical Samples" at the National Pathology Forum 2013.

This annual conference provides a platform for the public and private sectors to come together and discuss all the latest issues affecting the pathology sector in Australia. For more information, please visit the conference website:

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Ronald Trent - University of Sydney - Managing Incidental Findings in Genomic Analysis of Clinical Sample

  1. 1. Royal Prince Alfred Hospital 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
  2. 2. 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  The road to incidental (secondary) findings – AKA “incidentalome”  Potential consequences  Options for dealing with them in the clinical context  What next?
  3. 3. 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+
  4. 4. Human Genome Project 1990 - 2000 → Omics Sequence first human (other other) genomes Develop new technology Expand informatics (data storage & analysis) Consider ELSI (ethical, legal, social issues) Today “omics” or “all” Genomics Proteomics Transcriptomics Metabolomics Epigenomics Phenomics Move from single genes (genetics) to multiple or all genes (genomics)
  5. 5. Practical Application Genetics -DNA Testing 1970s – 1990s Single mutations sought 1990s – 2000s Move to DNA sequencing 2000s → Technology now the driver Radioactivity, carcinogens Automation and now looking at small genes by DNA sequencing cf specific DNA mutations Faster, cheaper and better DNA sequencing machines Individual mutations + 2/52 TAT Interpretation easy Counselling just starting Interpretation starting to become difficult (annotation of DNA variants) Counselling more professional Goal = $1,000 for whole genome sequence (WGS) – cost BRCA1,2 sequence = $2,000 Interpretation (informatics) the limitation Counselling ???
  6. 6. 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 Third Generation single molecule sequencing Platforms now being rolled out in USA Where we are now Few publications Goal = WGS (whole genome sequence) Paradigm for patient care will be shift from Dx testing to Screening Save on preparation steps but added informatics Faster, cheaper but Tb to Pb of data Gibabytes (Gb) of data Accuracy is an issue?
  7. 7. 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
  8. 8. 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
  10. 10.  The road to incidental (secondary) findings – AKA “incidentalome”  Potential consequences  How to deal with them in the clinical context  What next?
  11. 11. Case study: Incidental findings  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 11
  12. 12. 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” ???
  13. 13. 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.
  14. 14. 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
  15. 15. Incidental Findings & Research Nature 2008 11 June  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.
  16. 16.  The road to incidental (secondary) findings – AKA “incidentalome”  Potential consequences  How to deal with them in the clinical context  What next?
  17. 17. Some views on how to handle “incidental (secondary) findings” 1. Contents of report based on patient consent 2. No different CXR or MRI i.e. should be reported 3. In genome studies the results from about 30 risk genes SHOULD be sought irrespective of indication for testing and results given. 2013
  18. 18. 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
  19. 19. No different to a CXR or MRI i.e. should be reported The problem is that there are some differences  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)
  20. 20. 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)
  21. 21. 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
  22. 22.  The road to incidental (secondary) findings – AKA “incidentalome”  Potential consequences  Options for dealing with them in the clinical context  What next?
  23. 23. Incidental Findings – will only get bigger Targeted sequencing Today, $2,000 for BRCA1, BRCA2 genes Conventional DNA sequencing Exome sequencing Whole genome sequencing $4,000 for sequencing all exons of the 20K human genes Goal is $1,000 or less per Whole Genome Sequence “New” DNA sequencing  Driver becomes cost  ELSI (ethical legal social issues) will be resolved
  24. 24. Personalised Medicine Predictive Testing Pharmacogenetics & Somatic cell cancer genetics 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 Models: Cancer Rx, pharmacogenetics & Direct to Consumer DNA testing
  25. 25. Somatic Cell Cancer 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
  26. 26. Somatic cell DNA Genomics  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 Issues of incidental findings needs to be resolved
  27. 27. Direct-to-Consumer DNA Testing 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
  28. 28. Whole Exome or Genome Sequencing: New Paradigms for Clinical Care – European models Concept of “Rare” diseases Leadership from UK Government Lancet 2010;375:1525 Genetics in Medicine 2011
  29. 29. Brave new world ahead NGS + non-invasive prenatal testing or newborn screening Sci Transl Med 2012;4:137 Conclusion: Resolving issue of “Incidental findings” priority