TY - JOUR
T1 - Lost in translation
T2 - Returning germline genetic results in genome-scale cancer research
AU - Australian Pancreatic Cancer Genome Initiative
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 - Waddell, Nicola
AU - Kassahn, Karin S.
AU - Samra, Jaswinder S
AU - Miller, David K.
AU - Chang, David K.
AU - Pajic, Marina
AU - Pearson, John V.
AU - Grimmond, Sean M.
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 - Stoita, Alina
AU - Williams, David
AU - Spigellman, Allan
AU - Lam, Vincent W.
AU - McLeod, Duncan
AU - Nagrial, Adnan M.
AU - Kirk, Judy
AU - James, Virginia
AU - Kench, James G
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 - Chen, John
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 - Nikfarjam, Mehrdad
AU - Eshleman, James R
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.
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.
KW - Genomic data
KW - Research ethics
KW - Return of results
KW - Whole-genome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85019003541&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/631701
UR - http://purl.org/au-research/grants/NHMRC/535903
UR - http://purl.org/au-research/grants/NHMRC/427601
UR - http://purl.org/au-research/grants/NHMRC/1112113
U2 - 10.1186/s13073-017-0430-4
DO - 10.1186/s13073-017-0430-4
M3 - Article
C2 - 28454591
AN - SCOPUS:85019003541
VL - 9
JO - Genome Medicine: medicine in the post-genomic era
JF - Genome Medicine: medicine in the post-genomic era
SN - 1756-994X
IS - 1
M1 - 41
ER -