Oncotarget

Research Papers:

Candidate germline polymorphisms of genes belonging to the pathways of four drugs used in osteosarcoma standard chemotherapy associated with risk, survival and toxicity in non-metastatic high-grade osteosarcoma

Claudia M. Hattinger, Paola Biason, Erika Iacoboni, Sara Gagno, Marilù Fanelli, Elisa Tavanti, Serena Vella, Stefano Ferrari, Andrea Roli, Rossana Roncato, Luciana Giodini, Katia Scotlandi, Piero Picci, Giuseppe Toffoli and Massimo Serra _

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Oncotarget. 2016; 7:61970-61987. https://doi.org/10.18632/oncotarget.11486

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Abstract

Claudia M. Hattinger1, Paola Biason2, Erika Iacoboni1, Sara Gagno3, Marilù Fanelli1, Elisa Tavanti1, Serena Vella1, Stefano Ferrari4, Andrea Roli5, Rossana Roncato3, Luciana Giodini3, Katia Scotlandi1, Piero Picci1, Giuseppe Toffoli3, Massimo Serra1

1Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy

2National Institute of Health and Medical Research (INSERM), Unity 892, University of Medicine of Angers, Angers, France

3Experimental and Clinical Pharmacology Unit, National Cancer Institute, Aviano, Italy

4Chemotherapy Ward of Muscoloskeletal Tumours, Orthopaedic Rizzoli Institute, Bologna, Italy

5Department of Computer Science and Engineering (DISI), University of Bologna, Cesena, Italy

Correspondence to:

Massimo Serra, email: [email protected]

Keywords: osteosarcoma, germline polymorphisms, toxicity, drug response biomarkers, personalized medicine

Received: June 01, 2016     Accepted: July 29, 2016     Published: August 22, 2016

ABSTRACT

This study aimed to identify associations between germline polymorphisms and risk of high-grade osteosarcoma (HGOS) development, event-free survival (EFS) and toxicity in HGOS patients treated with neo-adjuvant chemotherapy and surgery.

Germline polymorphisms of 31 genes known to be relevant for transport or metabolism of all four drugs used in HGOS chemotherapy (methotrexate, doxorubicin, cisplatin and ifosfamide) were genotyped in 196 patients with HGOS and in 470 healthy age and gender-matched controls. Of these 196 HGOS patients, a homogeneously treated group of 126 patients was considered for survival analyses (survival cohort). For 57 of these, treatment-related toxicity data were available (toxicity cohort).

Eleven polymorphisms were associated with increased risk of developing HGOS (p < 0.05). The distribution of polymorphisms in patients was characterized by a higher Shannon entropy. In the survival cohort (n = 126, median follow-up = 126 months), genotypes of ABCC2_1249A/G, GGH_452T/C, TP53_IVS2+38G/C and CYP2B6*6 were associated with EFS (p < 0.05). In the toxicity cohort (n = 57), genotypes of ABCB1_1236T/C, ABCC2_1249A/G, ABCC2_3972A/G, ERCC1_8092T/G, XPD_23591A/G, XRCC3_18067T/C, MTHFR_1298A/C and GGH_16T/C were associated with elevated risk for toxicity development (p < 0.05).

The results obtained in this retrospective study indicate that the aforementioned germline polymorphisms significantly impact on the risk of HGOS development, EFS and the occurrence of chemotherapy-related toxicity. These findings should be prospectively validated with the aim of optimizing and tailoring HGOS treatment in the near future.


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