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Mutational profiling of the RAS, PI3K, MET and b-catenin pathways in cancer of unknown primary: a retrospective study of the Hellenic Cooperative Oncology Group

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Abstract

Cancer of unknown primary origin (CUP) had a poor prognosis, determined by clinico-histological characteristics, partly due to the lack of insights on its biology. We screened tumour DNA from 87 patients with CUP for CTNNB1 (coding exons 2,3,4,5), MET (coding exon 18), PIK3CA (coding exons 9,20), KRAS (coding exons 1,2), BRAF (coding exon 15) gene mutations by using dd-sequencing and evaluated their impact on prognosis. Mutated gene incidences in the 87 CUP cases were: KRAS 11 (12.6 %), BRAF 5 (5.7 %), PIK3CA 8 (9 %), MET 6 (6.7 %) and CTNNB1 18 (20.7 %). Several mutations in the KRAS gene were not the commonly encountered mutations in other solid tumours. Activating mutations were observed in 10.2 % in KRAS, 4.5 % in BRAF, 6.6 % in PIK3CA, 4.5 % in MET, and 19.5 % in CTNNB1. Activating mutations in PIK3CA coding exon 9 were inversely correlated with MET coding exon 18 activating mutations (p = 0.036). MET activating mutations were prognostic for poor Progression-Free Survival (median PFS 5 vs 9 months, p = 0.009) and Overall Survival (median OS 7 vs 20 months, p = 0.005). The complex profile of either CTNNB1 or MET mutations also had an adverse prognostic significance (median OS 11 vs 21 months, p = 0.015). No other gene mutation exhibited prognostic significance. In multivariate analysis, poor performance status, male gender, visceral disease and adenocarcinoma histology, but not gene mutations, were independently associated with poor patient outcome. CTNNB1 gene mutations are frequent, and along with MET mutations have an adverse prognostic effect in patients with CUP.

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Acknowledgments

This research work has been funded by Novartis Hellas. The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors in any way.

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Authors and Affiliations

  1. Department of Medical Oncology, School of Medicine, University of Ioannina, Ioannina, Greece

    G. Pentheroudakis, E. A. Kotteas & N. Pavlidis

  2. Department of Pathology, School of Medicine, Aristotle University of Thessaloniki, Thessaloníki, Greece

    V. Kotoula, K. Papadopoulou & E. Charalambous

  3. Department of Hematology and Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain

    A. Cervantes

  4. Ion Chircuta Cancer Institute, Cluj-Napoca, Cluj, Romania

    T. Ciuleanu

  5. Department of Medical Oncology, Papageorgiou Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloníki, Greece

    G. Fountzilas

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  1. G. Pentheroudakis
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  2. E. A. Kotteas
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  3. V. Kotoula
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  4. K. Papadopoulou
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  5. E. Charalambous
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  6. A. Cervantes
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  7. T. Ciuleanu
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  8. G. Fountzilas
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  9. N. Pavlidis
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Correspondence to G. Pentheroudakis.

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Pentheroudakis, G., Kotteas, E.A., Kotoula, V. et al. Mutational profiling of the RAS, PI3K, MET and b-catenin pathways in cancer of unknown primary: a retrospective study of the Hellenic Cooperative Oncology Group. Clin Exp Metastasis 31, 761–769 (2014). https://doi.org/10.1007/s10585-014-9666-1

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  • DOI: https://doi.org/10.1007/s10585-014-9666-1

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