Integration of next-generation sequencing in clinical diagnostic molecular pathology laboratories for analysis of solid tumours; an expert opinion on behalf of IQN Path ASBL

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Abstract

The clinical demand for mutation detection within multiple genes from a single tumour sample requires molecular diagnostic laboratories to develop rapid, high-throughput, highly sensitive, accurate and parallel testing within tight budget constraints. To meet this demand, many laboratories employ next-generation sequencing (NGS) based on small amplicons. Building on existing publications and general guidance for the clinical use of NGS and learnings from germline testing, the following guidelines establish consensus standards for somatic diagnostic testing, specifically for identifying and reporting mutations in solid tumours. These guidelines cover the testing strategy, implementation of testing within clinical service, sample requirements, data analysis and reporting of results. In conjunction with appropriate staff training and international standards for laboratory testing, these consensus standards for the use of NGS in molecular pathology of solid tumours will assist laboratories in implementing NGS in clinical services.

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The online version of this article (doi:10.1007/s00428-016-2025-7) contains supplementary material, which is available to authorized users.

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Most cited references 20

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Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial.

Christophe Le Tourneau, Jean-Pierre Delord, Anthony Goncalves … (2015)

Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed.

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Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results.

Sharon Plon, Diana Eccles, Douglas Easton … (2008)

Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk. (c) 2008 Wiley-Liss, Inc.

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Whole-exome sequencing and clinical interpretation of FFPE tumor samples to guide precision cancer medicine

Eliezer Allen, Nikhil Wagle, Petar Stojanov … (2014)

Translating whole exome sequencing (WES) for prospective clinical use may impact the care of cancer patients; however, multiple innovations are necessary for clinical implementation. These include: (1) rapid and robust WES from formalin-fixed paraffin embedded (FFPE) tumor tissue, (2) analytical output similar to data from frozen samples, and (3) clinical interpretation of WES data for prospective use. Here, we describe a prospective clinical WES platform for archival FFPE tumor samples. The platform employs computational methods for effective clinical analysis and interpretation of WES data. When applied retrospectively to 511 exomes, the interpretative framework revealed a “long tail” of somatic alterations in clinically important genes. Prospective application of this approach identified clinically relevant alterations in 15/16 patients. In one patient, previously undetected findings guided clinical trial enrollment leading to an objective clinical response. Overall, this methodology may inform the widespread implementation of precision cancer medicine.

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Author and article information

Contributors

Zandra C Deans: sandi.deans@ed.ac.uk

Journal

Journal ID (nlm-ta): Virchows Arch

Journal ID (iso-abbrev): Virchows Arch

Title: Virchows Archiv

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0945-6317

ISSN (Electronic): 1432-2307

Publication date (Electronic): 27 September 2016

Publication date PMC-release: 27 September 2016

Publication date (Print): 2017

Volume: 470

Issue: 1

Pages: 5-20

Affiliations

[1 ]ISNI 0000 0001 0709 1919, GRID grid.418716.d, UK NEQAS for Molecular Genetics, Department of Laboratory Medicine, , Royal Infirmary of Edinburgh, ; Edinburgh, EH16 4SA UK

[2 ]ISNI 0000 0001 1503 7226, GRID grid.5808.5, i3S Instituto de Investigação e Inovação em Saúde/IPATIMUP Institute of Molecular Pathology and Immunology, , University of Porto, ; Porto, Portugal

[3 ]GRID grid.15628.38, Department of Pathology, , University Hospital Coventry and Warwickshire, ; Coventry, CV2 2DX UK

[4 ]ISNI 0000 0001 0668 7884, GRID grid.5596.f, Biomedical Quality Assurance Research Unit, Department of Public Health and Primary Care, , KU Leuven-University of Leuven, ; Leuven, Belgium

[5 ]GRID grid.426217.4, Clinical Pathology, Laboratory Medicine, Medical Services, , Region Skåne, ; Lund, Sweden

[6 ]ISNI 0000 0001 2171 1133, GRID grid.4868.2, Genomics England, , Queen Mary University of London, ; Dawson Hall, Charterhouse Square, London, EC1M 6BQ UK

[7 ]ISNI 0000 0001 2218 4662, GRID grid.6363.0, Institute of Pathology, Berlin, Germany and the DGP, German Society of Pathology, , Charite, University Medicine Berlin, ; Berlin, Germany

[8 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Department of Pathology and Department of Human Genetics, , Radboud University Medical Center, ; Nijmegen, The Netherlands

[9 ]Oncologica UK Ltd, Suite 15-16, The Science Village, Chesterford Research Park, Cambridge, CB10 1XL UK

[10 ]ISNI 0000 0001 2181 4941, GRID grid.412451.7, Center of Predictive Molecular Medicine, CeSI-MeT, , University of Chieti, ; Chieti, Italy

[11 ]Cell Biology and Biotherapy Unit, Istituto Nazionale Tumouri “Fondazione Giovanni Pascale” IRCCS, Naples, Italy

[12 ]Department of Medical Biology and Pathology, Genetic and Pathology Molecular Service, Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France

[13 ]Department of Pathology, University of Groningen, University Medical Center of Groningen, Groningen, The Netherlands

[14 ]ISNI 0000 0004 0435 165X, GRID grid.16872.3a, Pathology, , VU University Medical Center, ; Amsterdam, the Netherlands

[15 ]International Quality Network for Pathology (IQN Path) Association Sans But Lucratif (A.S.B.L), 17 Boulevard Royal, L2449 Luxembourg City, Luxembourg

[16 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Division of Cancer, Department of Surgery and Cancer, , Imperial College London, ; London, UK

Article

Publisher ID: 2025

DOI: 10.1007/s00428-016-2025-7

PMC ID: 5243883

PubMed ID: 27678269

SO-VID: 1e0e25ef-0345-44b4-9b64-d73b2c6dc2c2

License:

Open Access 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.

History

Date received : 15 April 2016

Date revision received : 27 August 2016

Date accepted : 16 September 2016

Custom metadata

ScienceOpen disciplines: Pathology

Keywords: next-generation sequencing,best practice,molecular pathology,solid tumours,quality

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ScienceOpen disciplines: Pathology

Keywords: next-generation sequencing, best practice, molecular pathology, solid tumours, quality

Integration of next-generation sequencing in clinical diagnostic molecular pathology laboratories for analysis of solid tumours; an expert opinion on behalf of IQN Path ASBL

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Most cited references 20

Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial.

Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results.

Whole-exome sequencing and clinical interpretation of FFPE tumor samples to guide precision cancer medicine

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