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An exploratory study by DMET array identifies a germline signature associated with imatinib response in gastrointestinal stromal tumor

The Pharmacogenomics Journal volume 19, pages 390–400 (2019)Cite this article

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Abstract

Imatinib represents the standard therapy for gastrointestinal stromal tumor (GIST) patients with metastatic/unresectable disease. Despite  the excellent results achieved with its introduction, the majority of patients quite invariably experience disease progression. The aim of this study was to understand the contribution of germline DNA polymorphisms in discriminating between imatinib clinical response [evaluated as progression free survival (PFS)] and toxicity. In particular, a discovery cohort (34 GIST with a KIT exon 11 primary mutation, and no toxicity) was analyzed through DMET array that interrogates 1936 variants in 231 genes of the ADME process. We further confirmed the genotype of selected variants in an extended cohort of 49 patients (the original cohort and 15 new cases, all with exon 11 primary mutation), identifying 6 SNPs— ABCB4 rs1202283, ABCC2 rs2273697, ABCG1 rs1541290, CYP11B1 rs7003319, CYP7B1 rs6987861, and NQO1 rs10517—significantly associated with response to imatinib. Three SNPs, ABCB4 rs1202283, ABCC2 rs2273697, and NQO1 rs10517, which had a significant association after adjusted multivariate analysis, were included in a genetic prediction model. We confirmed that these SNPs could stratify the cohort of 49 patients according to the risk of developing progression under imatinib treatment. In conclusion, we identified a genetic signature of response to imatinib therapy in GIST patients able to stratify patients at low and high risk to progress, according to their genotype.

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Acknowledgements

Gloria Ravegnini is supported by a MSD Italia fellowship granted by and on behalf of Merck Sharp & Dohme Corporation.

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Author notes

  1. These authors jointly supervised: Sabrina Angelini, Maria A. Pantaleo.

Authors and Affiliations

  1. Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy

    Gloria Ravegnini, Patrizia Hrelia & Sabrina Angelini

  2. “Giorgio Prodi” Cancer Research Center, University of Bologna, Bologna, Italy

    Milena Urbini, Chiara Genovese, Annalisa Astolfi, Manuela Ianni, Valentina Indio, Guido Biasco & Maria A. Pantaleo

  3. Medical Statistics Unit, University of Campania “Luigi Vanvitelli”, Napoli, Italy

    Vittorio Simeon & Guido Biasco

  4. Department of Specialized, Experimental and Diagnostic Medicine, Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy

    Margherita Nannini, Lidia Gatto, Maristella Saponara, Giovanni Brandi, Guido Biasco & Maria A. Pantaleo

  5. Laboratory of Pre-Clinical and Translational Research Reference Cancer Center of Basilicata, Scientific Institute of Hospitalization and treatment, Rionero in Vulture, Potenza, Italy

    Stefania Trino

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Correspondence to Sabrina Angelini or Maria A. Pantaleo.

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Ravegnini, G., Urbini, M., Simeon, V. et al. An exploratory study by DMET array identifies a germline signature associated with imatinib response in gastrointestinal stromal tumor. Pharmacogenomics J 19, 390–400 (2019). https://doi.org/10.1038/s41397-018-0050-4

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