S.F. and A.S. shared last authorshipCorrespondence to: Stefan Fröhling, National Center for Tumor Diseases (NCT) Heidelberg, Im Neuenheimer Feld 460, 69120 Germany, Tel.: +49-6221-566990, Fax: +49-6221-566967, E-mail: [email protected]; or Albrecht Stenzinger, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany, Tel.: +49-6221-5634380, Fax: +49-6221-565251, E-mail: [email protected]Search for more papers by this author

Jonas Leichsenring,

Jonas Leichsenring

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

J.L. and P.H. shared first authorshipSearch for more papers by this author

Peter Horak,

Peter Horak

National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany

German Cancer Consortium (DKTK), Heidelberg, Germany

J.L. and P.H. shared first authorshipSearch for more papers by this author

Simon Kreutzfeldt,

Simon Kreutzfeldt

National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany

German Cancer Consortium (DKTK), Heidelberg, Germany

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Christoph Heining,

Christoph Heining

National Center for Tumor Diseases (NCT), Dresden, Germany

University Hospital Carl Gustav Carus, Dresden, Germany

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Petros Christopoulos,

Petros Christopoulos

Thoraxklinik, Heidelberg, Germany

Translational Lung Cancer Research Heidelberg (TLCR-H), German Center for Lung Research (DZL), Giessen, Germany

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Anna-Lena Volckmar,

Anna-Lena Volckmar

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

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Olaf Neumann,

Olaf Neumann

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

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Martina Kirchner,

Martina Kirchner

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

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Carolin Ploeger,

Carolin Ploeger

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

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Jan Budczies,

Jan Budczies

orcid.org/0000-0002-1959-2240

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

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Christoph E. Heilig,

Christoph E. Heilig

National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany

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Barbara Hutter,

Barbara Hutter

German Cancer Research Center (DKFZ), Heidelberg, Germany

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Martina Fröhlich,

Martina Fröhlich

German Cancer Research Center (DKFZ), Heidelberg, Germany

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Sebastian Uhrig,

Sebastian Uhrig

German Cancer Research Center (DKFZ), Heidelberg, Germany

Faculty of Biosciences, Heidelberg University, Heidelberg, Germany

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Daniel Kazdal,

Daniel Kazdal

orcid.org/0000-0001-8187-3281

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

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Michael Allgäuer,

Michael Allgäuer

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

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Alexander Harms,

Alexander Harms

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

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Eugen Rempel,

Eugen Rempel

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

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Ulrich Lehmann,

Ulrich Lehmann

Institute of Pathology, Hannover Medical School, Hanover, Germany

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Michael Thomas,

Michael Thomas

orcid.org/0000-0001-9511-055X

Thoraxklinik, Heidelberg, Germany

Translational Lung Cancer Research Heidelberg (TLCR-H), German Center for Lung Research (DZL), Giessen, Germany

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Nicole Pfarr,

Nicole Pfarr

Institute of Pathology, Technische Universität München, Munich, Germany

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Ninel Azoitei,

Ninel Azoitei

Clinic of Internal Medicine I, University Hospital Ulm, Ulm, Germany

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Irina Bonzheim,

Irina Bonzheim

Institute of Pathology, University Hospital Tübingen, Tübingen, Germany

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Ralf Marienfeld,

Ralf Marienfeld

Institute of Pathology, University Hospital Ulm, Ulm, Germany

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Peter Möller,

Peter Möller

Institute of Pathology, University Hospital Ulm, Ulm, Germany

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Martin Werner,

Martin Werner

Institute of Pathology, Medical Center, University of Freiburg, Breisgau, Germany

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Falko Fend,

Falko Fend

Institute of Pathology, University Hospital Tübingen, Tübingen, Germany

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Melanie Boerries,

Melanie Boerries

German Cancer Consortium (DKTK), Heidelberg, Germany

German Cancer Research Center (DKFZ), Heidelberg, Germany

Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany

MIRACUM Consortium of the Medical Informatics Initiative, Freiburg, Germany

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Nikolas von Bubnoff,

Nikolas von Bubnoff

orcid.org/0000-0001-9593-8947

German Cancer Consortium (DKTK), Heidelberg, Germany

German Cancer Research Center (DKFZ), Heidelberg, Germany

Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

Department of Hematology and Oncology, Medical Center, University of Schleswig-Holstein, Lübeck, Germany

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Silke Lassmann,

Silke Lassmann

Institute of Pathology, Medical Center, University of Freiburg, Breisgau, Germany

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Thomas Longerich,

Thomas Longerich

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

Heidelberg-Göttingen-Hannover Medizininformatik (HiGHmed) Konsortium, Heidelberg, Germany

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Michael Bitzer,

Michael Bitzer

Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany

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Thomas Seufferlein,

Thomas Seufferlein

Clinic of Internal Medicine I, University Hospital Ulm, Ulm, Germany

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Nisar Malek,

Nisar Malek

Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany

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Wilko Weichert,

Wilko Weichert

Institute of Pathology, Technische Universität München, Munich, Germany

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Peter Schirmacher,

Peter Schirmacher

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

German Cancer Consortium (DKTK), Heidelberg, Germany

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Roland Penzel,

Roland Penzel

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

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Volker Endris,

Volker Endris

orcid.org/0000-0003-2550-3563

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

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Benedikt Brors,

Benedikt Brors

National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany

German Cancer Consortium (DKTK), Heidelberg, Germany

German Cancer Research Center (DKFZ), Heidelberg, Germany

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Frederick Klauschen,

Frederick Klauschen

Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany

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Hanno Glimm,

Hanno Glimm

National Center for Tumor Diseases (NCT), Dresden, Germany

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Stefan Fröhling,

Stefan Fröhling

[email protected]

orcid.org/0000-0001-7907-4595

National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany

German Cancer Consortium (DKTK), Heidelberg, Germany

DKFZ-Heidelberg Center for Personalized Oncology (HIPO), Heidelberg, Germany

S.F. and A.S. shared last authorshipSearch for more papers by this author

Albrecht Stenzinger,

Corresponding Author

Albrecht Stenzinger

[email protected]

orcid.org/0000-0003-1001-103X

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

DKFZ-Heidelberg Center for Personalized Oncology (HIPO), Heidelberg, Germany

First published: 22 April 2019

https://doi.org/10.1002/ijc.32358

Citations: 93

Conflict of interests: AS: advisory board honoraria from Bayer, Novartis, BMS, AstraZeneca, ThermoFisher, Illumina; speaker's honoraria from Takeda, Roche, BMS, Illumina, AstraZeneca, Novartis, ThermoFisher, Bayer, MSD and research funding from Chugai and BMS. VE: advisory board honoraria from Thermo Fischer. Speaker's honoraria from AstraZeneca. ALV: speaker's honoraria from AstraZeneca. PS: advisory board honoraria, research funding and speaker's honoraria from Novartis and AstraZeneca. WW: Advisory board and speaker's bureau from Roche, MSD, BMS, AstraZeneca, Pfizer, Merck, Lilly, Boehringer, Novartis, Takeda. Research funding from Roche, MSD, BMS, Bruker. PC: Speakers honoraria from Roche, Novartis, Chugai. NP: Speaker's honoraria and travel costs from Novartis, Roche, BMS. SL: Research funding from Agilent, Illumina, Qiagen, BMS. Advisory boards: AstraZeneca, Novartis, Roche. Travel grants from Illumina, Agilent. MW: Advisory boards: Roche, Novartis. Research funding from Agilent, Novartis, Roche. Honoraria and travel grants from Diakovere. MT: advisory board honoraria from Novartis, Lilly, BMS, MSD, Roche, Celgene, Takeda, AbbVie, Boehringer, speaker's honoraria from Lilly, MSD, Takeda, research funding from AstraZeneca, BMS, Celgene, Roche, and travel grants from BMS, MSD, Novartis, Boehringer. NvB: Honoraria from AstraZeneca, Amgen, Novartis, BMS. Research funding from Novartis. All other authors declared no conflicts of interest.

[Correction added on September 21, 2019 after first online publication: affiliation updated.]

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Abstract

Next-generation sequencing has become a cornerstone of therapy guidance in cancer precision medicine and an indispensable research tool in translational oncology. Its rapidly increasing use during the last decade has expanded the options for targeted tumor therapies, and molecular tumor boards have grown accordingly. However, with increasing detection of genetic alterations, their interpretation has become more complex and error-prone, potentially introducing biases and reducing benefits in clinical practice. To facilitate interdisciplinary discussions of genetic alterations for treatment stratification between pathologists, oncologists, bioinformaticians, genetic counselors and medical scientists in specialized molecular tumor boards, several systems for the classification of variants detected by large-scale sequencing have been proposed. We review three recent and commonly applied classifications and discuss their individual strengths and weaknesses. Comparison of the classifications underlines the need for a clinically useful and universally applicable variant reporting system, which will be instrumental for efficient decision making based on sequencing analysis in oncology. Integrating these data, we propose a generalizable classification concept featuring a conservative and a more progressive scheme, which can be readily applied in a clinical setting.

Abstract

What's new?

With increasingly comprehensive molecular profiling of cancers, the clinical interpretation of genetic alterations is becoming more and more challenging. Here the authors review several classifications for gene variant interpretation that were recently introduced to guide clinical management. They highlight shared features and differences and point out major influencing factors and unresolved issues that still need to be addressed. Based on this analysis, they propose a unified classification concept that may become broadly implemented when remaining issues are solved.

Supporting Information

References

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Volume145, Issue11

1 December 2019

Pages 2996-3010

Variant classification in precision oncology

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