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Cited by 79BRCA gene mutations in cancerGenomics and Rare DiseasesEthics in Clinical Research

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

Open access
Australian Pancreatic Cancer Genome Initiative, Johns, Amber L., McKay, Skye H., Humphris, Jeremy L., Pinese, Mark, Chantrill, Lorraine A., Mead, R. Scott, Tucker, Katherine +19 more·2017·Genome Medicine
DOI 10.1186/s13073-017-0430-4PMC PMC5408494
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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.

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  • Genomic risk contributes to up to 8% of PDAC cases.

    “Recent studies estimate that genomic risk contributes to up to 8% of PDAC cases,180–184”

    From Artificial Intelligence and Early Detection of Pancreatic Cancer: 2020 Summative Review (2021) · cites this paper as [181]

    The Results report pathogenic germline variants in patients with sporadic pancreatic cancer, supporting a role for inherited genetic risk. But the paper does not estimate that genomic risk contributes to up to 8% of PDAC cases; its Discussion reports a 5.1% rate of actionable findings in its cohort, which measures something different. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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References 40 · Cited by 79

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Authors
Initiative, A. P. C. G., 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., Pajic, M., Pearson, J. V., Grimmond, S. M., Waddell, N., Zeps, N., Gill, A. J., & Biankin, A. V.
Affiliations
  • Garvan Institute of Medical Research (AU)
  • Prince of Wales Hospital (AU)
  • Royal Prince Alfred Hospital (AU)
  • QIMR Berghofer Medical Research Institute (AU)
  • The University of Sydney (AU)
  • South Australia Pathology (AU)
  • Illumina (United States) (US)
  • The University of Melbourne (AU)
  • St John of God Subiaco Hospital (AU)
Corresponding author
Biankin, Andrew V.
ORCID
Venue
Genome Medicine
Publisher
Springer Science and Business Media LLC
Published
2017-04-28
Volume
9
Issue
1
Pages
41-41
ISSN
1756-994X (ISSN-L)
DOI
10.1186/s13073-017-0430-4
PMC
PMC5408494
OpenAlex
W2608845725
Cited by
79
References
40
Citations by year
2024: 1 · 2023: 4 · 2022: 2 · 2021: 30 · 2020: 17 · 2019: 9 · 2018: 12 · 2017: 4
FWCI
7.62
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Genome Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
  • UNSWorks (UNSW Sydney) (submittedVersion, cc-by-nc-nd)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
  • UWA Profiles and Research Repository (University of Western Australia) (submittedVersion, cc-by)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • eSpace (Curtin University) (submittedVersion, cc-by)
Funders
  • National Health and Medical Research Council of Australia
  • Queensland Government
  • Cancer Council NSW
  • Garvan Institute of Medical Research
  • Avner Nahmani Pancreatic Cancer Foundation
  • Jane Hemstritch in memory of Philip Hemstritch
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Ethics in Clinical Research
Keywords
return of research results, germline mutations, pancreatic cancer, actionable findings, cancer susceptibility genes, whole genome sequencing, exome sequencing
MeSH terms
Adult, Aged, Aged, 80 and over, Australia, Computer Simulation, DNA Mutational Analysis, Humans, Middle Aged, Pancreatic Neoplasms, Genome, Human, Germ-Line Mutation, Genetic Predisposition to Disease, Genomics

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