Multicenter Study

. 2017 Apr 28;9(1):41.

doi: 10.1186/s13073-017-0430-4.

Lost in translation: returning germline genetic results in genome-scale cancer research

Amber L Johns¹, Skye H McKay¹, Jeremy L Humphris¹, Mark Pinese¹, Lorraine A Chantrill^{1

2

3}, R Scott Mead^{1

4

5}, Katherine Tucker⁶, Lesley Andrews⁶, Annabel Goodwin⁷, Conrad Leonard⁸, Hilda A High⁹, Katia Nones⁸, Ann-Marie Patch⁸, Neil D Merrett^{10

11}, Nick Pavlakis¹², Karin S Kassahn¹³, Jaswinder S Samra¹⁴, David K Miller¹⁵, David K Chang^{1

16

17

10

18}, Marina Pajic¹; Australian Pancreatic Cancer Genome Initiative; John V Pearson⁸, Sean M Grimmond¹⁹, Nicola Waddell⁸, Nikolajs Zeps^{20

21}, Anthony J Gill^{1

22}, Andrew V Biankin^{23

24

25

26}

Affiliations

¹ Cancer Research Program, Garvan Institute of Medical Research, Kinghorn Cancer Centre, Sydney, Australia.
² St Vincents Hospital, Darlinghurst, Australia.
³ Western Sydney University Clinical School, Sydney, Australia.
⁴ Genetics Department, SEALS Pathology, Prince of Wales Hospital, Randwick, Sydney, Australia.
⁵ School of Medicine, University of New South Wales, Sydney, Australia.
⁶ Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, Sydney, Australia.
⁷ Cancer Genetics Department, Royal Prince Alfred Hospital and Liverpool Hospital, Sydney, NSW, Australia.
⁸ QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁹ Sydney Cancer Genetics, Sydney, Australia.
¹⁰ Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, Australia.
¹¹ Division of Surgery, School of Medicine, Western Sydney University, Sydney, Australia.
¹² Department of Medical Oncology, Royal North Shore Hospital and Faculty of Medicine, University of Sydney, Sydney, Australia.
¹³ Genetic and Molecular Pathology, SA Pathology, Women's and Children's Hospital, North Adelaide, Adelaide, Australia.
¹⁴ Department of Surgery, Royal North Shore Hospital, Sydney, Australia.
¹⁵ Illumina Inc, 5200 Illumina Way, San Diego, CA, 92122, USA.
¹⁶ Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK.
¹⁷ West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.
¹⁸ South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, Australia.
¹⁹ University of Melbourne, Parkville, Australia.
²⁰ St John of God Subiaco, Perth, Australia.
²¹ School of Surgery, The University of Western Australia, Perth, Australia.
²² Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney Australia and University of Sydney, Sydney, Australia.
²³ Cancer Research Program, Garvan Institute of Medical Research, Kinghorn Cancer Centre, Sydney, Australia. andrew.biankin@glasgow.ac.uk.
²⁴ West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. andrew.biankin@glasgow.ac.uk.
²⁵ South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, Australia. andrew.biankin@glasgow.ac.uk.
²⁶ Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow, UK. andrew.biankin@glasgow.ac.uk.

PMID: 28454591
PMCID: PMC5408494
DOI: 10.1186/s13073-017-0430-4

Multicenter Study

Lost in translation: returning germline genetic results in genome-scale cancer research

Amber L Johns et al. Genome Med. 2017.

. 2017 Apr 28;9(1):41.

doi: 10.1186/s13073-017-0430-4.

Authors

Affiliations

¹ Cancer Research Program, Garvan Institute of Medical Research, Kinghorn Cancer Centre, Sydney, Australia.
² St Vincents Hospital, Darlinghurst, Australia.
³ Western Sydney University Clinical School, Sydney, Australia.
⁴ Genetics Department, SEALS Pathology, Prince of Wales Hospital, Randwick, Sydney, Australia.
⁵ School of Medicine, University of New South Wales, Sydney, Australia.
⁶ Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, Sydney, Australia.
⁷ Cancer Genetics Department, Royal Prince Alfred Hospital and Liverpool Hospital, Sydney, NSW, Australia.
⁸ QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁹ Sydney Cancer Genetics, Sydney, Australia.
¹⁰ Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, Australia.
¹¹ Division of Surgery, School of Medicine, Western Sydney University, Sydney, Australia.
¹² Department of Medical Oncology, Royal North Shore Hospital and Faculty of Medicine, University of Sydney, Sydney, Australia.
¹³ Genetic and Molecular Pathology, SA Pathology, Women's and Children's Hospital, North Adelaide, Adelaide, Australia.
¹⁴ Department of Surgery, Royal North Shore Hospital, Sydney, Australia.
¹⁵ Illumina Inc, 5200 Illumina Way, San Diego, CA, 92122, USA.
¹⁶ Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK.
¹⁷ West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.
¹⁸ South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, Australia.
¹⁹ University of Melbourne, Parkville, Australia.
²⁰ St John of God Subiaco, Perth, Australia.
²¹ School of Surgery, The University of Western Australia, Perth, Australia.
²² Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney Australia and University of Sydney, Sydney, Australia.
²³ Cancer Research Program, Garvan Institute of Medical Research, Kinghorn Cancer Centre, Sydney, Australia. andrew.biankin@glasgow.ac.uk.
²⁴ West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. andrew.biankin@glasgow.ac.uk.
²⁵ South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, Australia. andrew.biankin@glasgow.ac.uk.
²⁶ Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow, UK. andrew.biankin@glasgow.ac.uk.

PMID: 28454591
PMCID: PMC5408494
DOI: 10.1186/s13073-017-0430-4

Abstract

Background: The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies.

Methods: We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium-high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy.

Results: A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR.

Conclusion: Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning individual results is currently low.

Keywords: Genomic data; Research ethics; Return of results; Whole-genome sequencing.

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References

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Lost in translation: returning germline genetic results in genome-scale cancer research

Affiliations

Lost in translation: returning germline genetic results in genome-scale cancer research

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical