title: 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.
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.
authors: Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy.
authors: Claudia M
authors: CM
authors: Hattinger
authors: National Institute of Health and Medical Research (INSERM), Unity 892, University of Medicine of Angers, Angers, France.
authors: Paola
authors: P
authors: Biason
authors: Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy.
authors: Erika
authors: E
authors: Iacoboni
authors: Experimental and Clinical Pharmacology Unit, National Cancer Institute, Aviano, Italy.
authors: Sara
authors: S
authors: Gagno
authors: Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy.
authors: Marilù
authors: M
authors: Fanelli
authors: Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy.
authors: Elisa
authors: E
authors: Tavanti
authors: Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy.
authors: Serena
authors: S
authors: Vella
authors: Chemotherapy Ward of Muscoloskeletal Tumours, Orthopaedic Rizzoli Institute, Bologna, Italy.
authors: Stefano
authors: S
authors: Ferrari
authors: Department of Computer Science and Engineering (DISI), University of Bologna, Cesena, Italy.
authors: Andrea
authors: A
authors: Roli
authors: Experimental and Clinical Pharmacology Unit, National Cancer Institute, Aviano, Italy.
authors: Rossana
authors: R
authors: Roncato
authors: Experimental and Clinical Pharmacology Unit, National Cancer Institute, Aviano, Italy.
authors: Luciana
authors: L
authors: Giodini
authors: Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy.
authors: Katia
authors: K
authors: Scotlandi
authors: Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy.
authors: Piero
authors: P
authors: Picci
authors: Experimental and Clinical Pharmacology Unit, National Cancer Institute, Aviano, Italy.
authors: Giuseppe
authors: G
authors: Toffoli
authors: Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy.
authors: Massimo
authors: M
authors: Serra
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D001859:Bone Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002945:Cisplatin / Q000008:administration & dosage; D015331:Cohort Studies; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005838:Genotype; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D007558:Italy; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D020360:Neoadjuvant Therapy; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000235:genetics*; D011110:Polymorphism, Genetic; D016896:Treatment Outcome; D055815:Young Adult; D011623:gamma-Glutamyl Hydrolase / Q000235:genetics
chemical_list: C000715087:ABCC2 protein, human; D014408:Biomarkers, Tumor; D000089762:Multidrug Resistance-Associated Protein 2; D004317:Doxorubicin; D011623:gamma-Glutamyl Hydrolase; D002945:Cisplatin; D007069:Ifosfamide; D008727:Methotrexate
keywords: drug response biomarkers; germline polymorphisms; osteosarcoma; personalized medicine; toxicity