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

Amber L. Johns, Skye H. McKay, Jeremy L. Humphris, Mark Pinese, Lorraine A. Chantrill, R. Scott Mead, Katherine Tucker, Lesley Andrews, Annabel Goodwin, Conrad Leonard, Hilda A. High, Katia Nones, Ann Marie Patch, Neil D. Merrett, Nick Pavlakis, Karin S. Kassahn, Jaswinder S. Samra, David K. Miller, David K. Chang, Marina Pajic & 84 others Australian Pancreatic Cancer Genome Initiative, John V. Pearson, Sean M. Grimmond, Nicola Waddell, Nikolajs Zeps, Anthony J. Gill, Andrew V. Biankin, Venessa T. Chin, Angela Chou, Angela Steinmann, Mehreen Arshi, Ali Drury, Danielle Froio, Ashleigh Morgan, Paul Timpson, David Hermann, Claire Vennin, Sean Warren, Jianmin Wu, Andreia V. Pinho, Felicity Newell, Pamela Mukhopadhyay, Venkateswar Addala, Stephen Kazakoff, Oliver Holmes, Scott Wood, Christina Xu, Oliver Hofmann, Peter J. Wilson, Angelika Christ, Tim Bruxner, Jennifer Arena, Anubhav Mittal, Ray Asghari, Darren Pavey, Amitabha Das, Peter H. Cosman, Kasim Ismail, Chelsie O'Connnor, David Williams, Allan Spigellman, Vincent W. Lam, Duncan McLeod, Adnan M. Nagrial, Judy Kirk, Virginia James, Peter Grimison, Caroline L. Cooper, Charbel Sandroussi, Cindy Forest, Krishna P. Epari, Mo Ballal, David R. Fletcher, Sanjay Mukhedkar, Maria Beilin, Kynan Feeney, Nan Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley, Mark E. Brooke-Smith, Virginia Papangelis, Andrew D. Clouston, Patrick Martin, Andrew P. Barbour, Thomas J. O'Rourke, Jonathan W. Fawcett, Kellee Slater, Michael Hatzifotis, Peter Hodgkinson, Ralph H. Hruban, Christopher L. Wolfgang, Mary Hodgin, Rita T. Lawlor, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni, Claudio Bassi, Peter Bailey, Sancha Martin, Elizabeth A. Musgrove, Marc D. Jones, Craig Nourse, Nigel B. Jamieson, R. Eshleman James

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
Article number41
Pages1-9
Number of pages9
JournalGenome Medicine
Volume9
Issue number1
DOIs
Publication statusPublished - 28 Apr 2017
Externally publishedYes

Fingerprint

Genome
Pancreatic Neoplasms
Research
Neoplasms
Genes
Exome
Penetrance
Germ-Line Mutation
Genomics
Computer Simulation
Guidelines
Delivery of Health Care
Phenotype
DNA

Bibliographical note

Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • Genomic data
  • Research ethics
  • Return of results
  • Whole-genome sequencing

Cite this

Johns, A. L., McKay, S. H., Humphris, J. L., Pinese, M., Chantrill, L. A., Mead, R. S., ... Biankin, A. V. (2017). Lost in translation: returning germline genetic results in genome-scale cancer research. Genome Medicine, 9(1), 1-9. [41]. https://doi.org/10.1186/s13073-017-0430-4
Johns, Amber L. ; McKay, Skye H. ; Humphris, Jeremy L. ; Pinese, Mark ; Chantrill, Lorraine A. ; Mead, R. Scott ; Tucker, Katherine ; Andrews, Lesley ; Goodwin, Annabel ; Leonard, Conrad ; High, Hilda A. ; Nones, Katia ; Patch, Ann Marie ; Merrett, Neil D. ; Pavlakis, Nick ; Kassahn, Karin S. ; Samra, Jaswinder S. ; Miller, David K. ; Chang, David K. ; Pajic, Marina ; Australian Pancreatic Cancer Genome Initiative ; Pearson, John V. ; Grimmond, Sean M. ; Waddell, Nicola ; Zeps, Nikolajs ; Gill, Anthony J. ; Biankin, Andrew V. / Lost in translation : returning germline genetic results in genome-scale cancer research. In: Genome Medicine. 2017 ; Vol. 9, No. 1. pp. 1-9.
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title = "Lost in translation: returning germline genetic results in genome-scale cancer research",
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",
author = "Johns, {Amber L.} and McKay, {Skye H.} and Humphris, {Jeremy L.} and Mark Pinese and Chantrill, {Lorraine A.} and Mead, {R. Scott} and Katherine Tucker and Lesley Andrews and Annabel Goodwin and Conrad Leonard and High, {Hilda A.} and Katia Nones and Patch, {Ann Marie} and Merrett, {Neil D.} and Nick Pavlakis and Kassahn, {Karin S.} and Samra, {Jaswinder S.} and Miller, {David K.} and Chang, {David K.} and Marina Pajic and {Australian Pancreatic Cancer Genome Initiative} and Pearson, {John V.} and Grimmond, {Sean M.} and Nicola Waddell and Nikolajs Zeps and Gill, {Anthony J.} and Biankin, {Andrew V.} and Chin, {Venessa T.} and Angela Chou and Angela Steinmann and Mehreen Arshi and Ali Drury and Danielle Froio and Ashleigh Morgan and Paul Timpson and David Hermann and Claire Vennin and Sean Warren and Jianmin Wu and Pinho, {Andreia V.} and Felicity Newell and Pamela Mukhopadhyay and Venkateswar Addala and Stephen Kazakoff and Oliver Holmes and Scott Wood and Christina Xu and Oliver Hofmann and Wilson, {Peter J.} and Angelika Christ and Tim Bruxner and Jennifer Arena and Anubhav Mittal and Ray Asghari and Darren Pavey and Amitabha Das and Cosman, {Peter H.} and Kasim Ismail and Chelsie O'Connnor and David Williams and Allan Spigellman and Lam, {Vincent W.} and Duncan McLeod and Nagrial, {Adnan M.} and Judy Kirk and Virginia James and Peter Grimison and Cooper, {Caroline L.} and Charbel Sandroussi and Cindy Forest and Epari, {Krishna P.} and Mo Ballal and Fletcher, {David R.} and Sanjay Mukhedkar and Maria Beilin and Kynan Feeney and Nguyen, {Nan Q.} and Ruszkiewicz, {Andrew R.} and Chris Worthley and Brooke-Smith, {Mark E.} and Virginia Papangelis and Clouston, {Andrew D.} and Patrick Martin and Barbour, {Andrew P.} and O'Rourke, {Thomas J.} and Fawcett, {Jonathan W.} and Kellee Slater and Michael Hatzifotis and Peter Hodgkinson and Hruban, {Ralph H.} and Wolfgang, {Christopher L.} and Mary Hodgin and Lawlor, {Rita T.} and Stefania Beghelli and Vincenzo Corbo and Maria Scardoni and Claudio Bassi and Peter Bailey and Sancha Martin and Musgrove, {Elizabeth A.} and Jones, {Marc D.} and Craig Nourse and Jamieson, {Nigel B.} and James, {R. Eshleman}",
note = "Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",
year = "2017",
month = "4",
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doi = "10.1186/s13073-017-0430-4",
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Johns, AL, McKay, SH, Humphris, JL, Pinese, M, Chantrill, LA, Mead, RS, Tucker, K, Andrews, L, Goodwin, A, Leonard, C, High, HA, Nones, K, Patch, AM, Merrett, ND, Pavlakis, N, Kassahn, KS, Samra, JS, Miller, DK, Chang, DK, Pajic, M, Australian Pancreatic Cancer Genome Initiative, Pearson, JV, Grimmond, SM, Waddell, N, Zeps, N, Gill, AJ & Biankin, AV 2017, 'Lost in translation: returning germline genetic results in genome-scale cancer research', Genome Medicine, vol. 9, no. 1, 41, pp. 1-9. https://doi.org/10.1186/s13073-017-0430-4

Lost in translation : returning germline genetic results in genome-scale cancer research. / Johns, Amber L.; McKay, Skye H.; Humphris, Jeremy L.; Pinese, Mark; Chantrill, Lorraine A.; Mead, R. Scott; Tucker, Katherine; Andrews, Lesley; Goodwin, Annabel; Leonard, Conrad; High, Hilda A.; Nones, Katia; Patch, Ann Marie; Merrett, Neil D.; Pavlakis, Nick; Kassahn, Karin S.; Samra, Jaswinder S.; Miller, David K.; Chang, David K.; Pajic, Marina; Australian Pancreatic Cancer Genome Initiative; Pearson, John V.; Grimmond, Sean M.; Waddell, Nicola; Zeps, Nikolajs; Gill, Anthony J.; Biankin, Andrew V.

In: Genome Medicine, Vol. 9, No. 1, 41, 28.04.2017, p. 1-9.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Lost in translation

T2 - Genome Medicine

AU - Johns, Amber L.

AU - McKay, Skye H.

AU - Humphris, Jeremy L.

AU - Pinese, Mark

AU - Chantrill, Lorraine A.

AU - Mead, R. Scott

AU - Tucker, Katherine

AU - Andrews, Lesley

AU - Goodwin, Annabel

AU - Leonard, Conrad

AU - High, Hilda A.

AU - Nones, Katia

AU - Patch, Ann Marie

AU - Merrett, Neil D.

AU - Pavlakis, Nick

AU - Kassahn, Karin S.

AU - Samra, Jaswinder S.

AU - Miller, David K.

AU - Chang, David K.

AU - Pajic, Marina

AU - Australian Pancreatic Cancer Genome Initiative

AU - Pearson, John V.

AU - Grimmond, Sean M.

AU - Waddell, Nicola

AU - Zeps, Nikolajs

AU - Gill, Anthony J.

AU - Biankin, Andrew V.

AU - Chin, Venessa T.

AU - Chou, Angela

AU - Steinmann, Angela

AU - Arshi, Mehreen

AU - Drury, Ali

AU - Froio, Danielle

AU - Morgan, Ashleigh

AU - Timpson, Paul

AU - Hermann, David

AU - Vennin, Claire

AU - Warren, Sean

AU - Wu, Jianmin

AU - Pinho, Andreia V.

AU - Newell, Felicity

AU - Mukhopadhyay, Pamela

AU - Addala, Venkateswar

AU - Kazakoff, Stephen

AU - Holmes, Oliver

AU - Wood, Scott

AU - Xu, Christina

AU - Hofmann, Oliver

AU - Wilson, Peter J.

AU - Christ, Angelika

AU - Bruxner, Tim

AU - Arena, Jennifer

AU - Mittal, Anubhav

AU - Asghari, Ray

AU - Pavey, Darren

AU - Das, Amitabha

AU - Cosman, Peter H.

AU - Ismail, Kasim

AU - O'Connnor, Chelsie

AU - Williams, David

AU - Spigellman, Allan

AU - Lam, Vincent W.

AU - McLeod, Duncan

AU - Nagrial, Adnan M.

AU - Kirk, Judy

AU - James, Virginia

AU - Grimison, Peter

AU - Cooper, Caroline L.

AU - Sandroussi, Charbel

AU - Forest, Cindy

AU - Epari, Krishna P.

AU - Ballal, Mo

AU - Fletcher, David R.

AU - Mukhedkar, Sanjay

AU - Beilin, Maria

AU - Feeney, Kynan

AU - Nguyen, Nan Q.

AU - Ruszkiewicz, Andrew R.

AU - Worthley, Chris

AU - Brooke-Smith, Mark E.

AU - Papangelis, Virginia

AU - Clouston, Andrew D.

AU - Martin, Patrick

AU - Barbour, Andrew P.

AU - O'Rourke, Thomas J.

AU - Fawcett, Jonathan W.

AU - Slater, Kellee

AU - Hatzifotis, Michael

AU - Hodgkinson, Peter

AU - Hruban, Ralph H.

AU - Wolfgang, Christopher L.

AU - Hodgin, Mary

AU - Lawlor, Rita T.

AU - Beghelli, Stefania

AU - Corbo, Vincenzo

AU - Scardoni, Maria

AU - Bassi, Claudio

AU - Bailey, Peter

AU - Martin, Sancha

AU - Musgrove, Elizabeth A.

AU - Jones, Marc D.

AU - Nourse, Craig

AU - Jamieson, Nigel B.

AU - James, R. Eshleman

N1 - Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2017/4/28

Y1 - 2017/4/28

N2 - 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.

AB - 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.

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Johns AL, McKay SH, Humphris JL, Pinese M, Chantrill LA, Mead RS et al. Lost in translation: returning germline genetic results in genome-scale cancer research. Genome Medicine. 2017 Apr 28;9(1):1-9. 41. https://doi.org/10.1186/s13073-017-0430-4