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; null Australian Pancreatic Cancer Genome Initiative; John V. Pearson; Sean M. Grimmond; Nicola Waddell; Nikolajs Zeps; Anthony J. Gill; Andrew V. Biankin

doi:10.1186/s13073-017-0430-4

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 PajicAustralian Pancreatic Cancer Genome Initiative, John V. Pearson, Sean M. Grimmond, Nicola Waddell, Nikolajs Zeps, Anthony J. Gill, Andrew V. Biankin

Western Sydney University

Research output: Contribution to journal › Article › peer-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.

Original language	English
Article number	41
Number of pages	9
Journal	Genome Medicine
Volume	9
DOIs	https://doi.org/10.1186/s13073-017-0430-4
Publication status	Published - 2017

Open Access - Access Right Statement

© This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Keywords

cancer
ethics
gene mapping
genomics
pancreas
research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s13073-017-0430-4

Cite this

Johns, A. L., McKay, S. H., Humphris, J. L., Pinese, M., Chantrill, L. A., Mead, R. S., Tucker, K., Andrews, L., Goodwin, A., Leonard, C., High, H. A., Nones, K., Patch, A.-M., Merrett, N. D., Pavlakis, N., Kassahn, K. S., Samra, J. S., Miller, D. K., Chang, D. K., ... Biankin, A. V. (2017). Lost in translation : returning germline genetic results in genome-scale cancer research. Genome Medicine, 9, Article 41. https://doi.org/10.1186/s13073-017-0430-4

@article{b64e4b5ecc7248f99fa7e6ef2ce3108d,

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 = "cancer, ethics, gene mapping, genomics, pancreas, research",

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 Ann-Marie Patch 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.}",

year = "2017",

doi = "10.1186/s13073-017-0430-4",

language = "English",

volume = "9",

journal = "Genome Medicine",

issn = "1756-994X",

publisher = "BioMed Central",

}

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, A-M, 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, 41. https://doi.org/10.1186/s13073-017-0430-4

TY - JOUR

T1 - Lost in translation : returning germline genetic results in genome-scale cancer research

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, null

AU - Pearson, John V.

AU - Grimmond, Sean M.

AU - Waddell, Nicola

AU - Zeps, Nikolajs

AU - Gill, Anthony J.

AU - Biankin, Andrew V.

PY - 2017

Y1 - 2017

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.

KW - cancer

KW - ethics

KW - gene mapping

KW - genomics

KW - pancreas

KW - research

UR - http://handle.westernsydney.edu.au:8081/1959.7/uws:40509

U2 - 10.1186/s13073-017-0430-4

DO - 10.1186/s13073-017-0430-4

M3 - Article

SN - 1756-994X

VL - 9

JO - Genome Medicine

JF - Genome Medicine

M1 - 41

ER -

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

Abstract

Open Access - Access Right Statement

Keywords

UN SDGs

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