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Proteogenomics of Colorectal Cancer Liver Metastases: Complementing Precision Oncology with Phenotypic Data

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Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Otto-Hahn-Str. 6b, 44227 Dortmund, Germany
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Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC H3T1E2, Canada
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Exactis Innovation, 5450 Cote-des-Neiges, Suite 522, Montreal, QC H3T1Y6, Canada
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Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, and McGill University, Montreal, QC H4A3T2, Canada
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Medizinische Fakultät, Medizinisches Proteom-Center (MPC), Ruhr-Universität Bochum, 44801 Bochum, Germany
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Department of Chemistry, College of Physical Sciences, University of Aberdeen, Aberdeen AB243FX, UK
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Gerald Bronfman Department of Oncology, Jewish General Hospital, McGill University, Montreal, QC H4A3T2, Canada
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this paper.
Cancers 2019, 11(12), 1907; https://doi.org/10.3390/cancers11121907
Received: 1 November 2019 / Revised: 22 November 2019 / Accepted: 26 November 2019 / Published: 1 December 2019
(This article belongs to the Special Issue The Cancer Proteome)
Hotspot testing for activating KRAS mutations is used in precision oncology to select colorectal cancer (CRC) patients who are eligible for anti-EGFR treatment. However, even for KRASwildtype tumors anti-EGFR response rates are <30%, while mutated-KRAS does not entirely rule out response, indicating the need for improved patient stratification. We performed proteogenomic phenotyping of KRASwildtype and KRASG12V CRC liver metastases (mCRC). Among >9000 proteins we detected considerable expression changes including numerous proteins involved in progression and resistance in CRC. We identified peptides representing a number of predicted somatic mutations, including KRASG12V. For eight of these, we developed a multiplexed parallel reaction monitoring (PRM) mass spectrometry assay to precisely quantify the mutated and canonical protein variants. This allowed phenotyping of eight mCRC tumors and six paired healthy tissues, by determining mutation rates on the protein level. Total KRAS expression varied between tumors (0.47–1.01 fmol/µg total protein) and healthy tissues (0.13–0.64 fmol/µg). In KRASG12V-mCRC, G12V-mutation levels were 42–100%, while one patient had only 10% KRASG12V but 90% KRASwildtype. This might represent a missed therapeutic opportunity: based on hotspot sequencing, the patient was excluded from anti-EGFR treatment and instead received chemotherapy, while PRM-based tumor-phenotyping indicates the patient might have benefitted from anti-EGFR therapy. View Full-Text
Keywords: proteogenomics; KRAS; targeted mass spectrometry; PRM; absolute quantitation; mutation rates proteogenomics; KRAS; targeted mass spectrometry; PRM; absolute quantitation; mutation rates
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Blank-Landeshammer, B.; Richard, V.R.; Mitsa, G.; Marques, M.; LeBlanc, A.; Kollipara, L.; Feldmann, I.; Couetoux du Tertre, M.; Gambaro, K.; McNamara, S.; Spatz, A.; Zahedi, R.P.; Sickmann, A.; Batist, G.; Borchers, C.H. Proteogenomics of Colorectal Cancer Liver Metastases: Complementing Precision Oncology with Phenotypic Data. Cancers 2019, 11, 1907.

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