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Impact of RAS mutation subtype on clinical outcome—a cross-entity comparison of patients with advanced non-small cell lung cancer and colorectal cancer

Oncogene volume 38, pages 2953–2966 (2019)Cite this article

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Abstract

Mutated RAS onco-proteins are key drivers across many cancers. The distribution of somatic RAS mutations varies between cancer entities. Retrospective analyses have associated some RAS mutations with distinct clinical outcomes. However, the clinical impact of the full spectrum of RAS mutations in their disease contextuality remains to be defined. To improve upon this situation, we studied genomically and clinically annotated, prospectively recruited cohorts of patients with RAS-mutated metastatic lung cancer and colorectal cancer. Mutational spectra were compared with predictions derived from analyzing the mutagenic impact at the genome level for each entity. Interestingly, we found concordance of predicted signatures with those actually observed in our patients. Thus, composition of the functionally active RAS mutational subtypes is primarily determined by the mutagenic context. Most RAS mutations seemed dominant oncogenic drivers with entity-dependent clinical outcomes. RAS comutations were enriched in tumors harboring class 2/3 BRAF mutations, highlighting the functional dependency of some mutated BRAF isoforms on RAS. With our dataset, we established a probabilistic model for cross-entity comparison of the prognostic impact of specific RAS mutational subtypes. The resulting prognostic clusters showed largely consistent clinical categorizations in both entities. This suggests mutant subtype-specific functional properties leading to similar clinical effects. A notable exception is KRAS G12C, which imparted an adverse prognosis only in colorectal cancer. Our findings provide a framework for risk stratification of specific RAS mutations across several cancer entities, which is required to guide the analysis of clinical findings in patients treated with direct RAS inhibitors or agents targeting downstream pathways.

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Acknowledgements

We thank the patients and their families for participation in the Precision Oncology Program of the West German Cancer Center. The invaluable support of the staff of all departments and institutes of the University Hospital Essen and Ruhrlandklinik participating in the WTZ Precision Oncology Program is gratefully acknowledged.

Funding

This work was supported by the Oncology Center of Excellence Program of the Deutsche Krebshilfe (grant number 110534); the German Federal and North Rhine-Westphalian State governments via the German Cancer Consortium (DKTK); Novartis Pharma AG (research grant); the Medical Faculty of the University Duisburg-Essen (IFORES fellowship to M.W.). The funding sources had no influence on the analysis and interpretation of data, and contents of the manuscript.

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Authors and Affiliations

  1. Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany

    Marcel Wiesweg, Stefan Kasper, Linda Sara, Martin Metzenmacher, Annalena Abendroth & Martin Schuler

  2. Genome Informatics, Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany

    Marcel Wiesweg & Sven Rahmann

  3. German Cancer Consortium (DKTK), Partner site University Hospital Essen, Hufelandstrasse 55, 45122, Essen, Germany

    Stefan Kasper, Martin Stuschke, Kurt W. Schmid & Martin Schuler

  4. Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany

    Karl Worm, Thomas Herold, Henning Reis & Kurt W. Schmid

  5. Department of Pulmonary Medicine, Section of Interventional Pneumology, Ruhrlandklinik – University Hospital Essen, University Duisburg-Essen, Tüschener Weg 40, Essen, 45239, Germany

    Kaid Darwiche

  6. Department of Thoracic Surgery and Endoscopy, Ruhrlandklinik – University Hospital Essen, University Duisburg-Essen, Tüschener Weg 40, Essen, 45239, Germany

    Clemens Aigner

  7. Department of Gastroenterology and Hepatology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany

    Heiner H. Wedemeyer

  8. Department of General, Visceral and Transplantation Surgery, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany

    Fabian A. Helfritz & Andreas Paul

  9. Department of Radiotherapy, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany

    Martin Stuschke

  10. Department of Gastroenterology, Elisabeth Hospital Essen, Klara-Kopp-Weg 1, 45138, Essen, Germany

    Brigitte Schumacher

  11. Department of General, Visceral and Trauma Surgery, Elisabeth Hospital Essen, Klara-Kopp-Weg 1, 45138, Essen, Germany

    Peter Markus

  12. Division of Thoracic Oncology, Ruhrlandklinik – University Hospital Essen, University Duisburg-Essen, Tüschener Weg 40, Essen, 45239, Germany

    Martin Schuler

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  1. Marcel Wiesweg
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Correspondence to Martin Schuler.

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Conflict of interest

We declare the following potential conflicts of interest: Prof. Dr. M. Schuler: Consultancy: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), Lilly, Novartis; Honoraria for CME presentations: Alexion, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Lilly, Novartis; Research funding to institution: Boehringer Ingelheim, Bristol Myers-Squibb, Novartis; Other: Universität Duisburg-Essen (Patents). Prof. Dr. S. Kasper: Consultancy, Honoraria and Travel Support: Roche, Bristol-Myers Squibb, Merck Sharp & Dohme. All remaining authors declare that they have no conflict of interest.

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Wiesweg, M., Kasper, S., Worm, K. et al. Impact of RAS mutation subtype on clinical outcome—a cross-entity comparison of patients with advanced non-small cell lung cancer and colorectal cancer. Oncogene 38, 2953–2966 (2019). https://doi.org/10.1038/s41388-018-0634-0

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