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Int. J. Mol. Sci. 2017, 18(7), 1366; doi:10.3390/ijms18071366

HLA-G 3′UTR Polymorphisms Predict Drug-Induced G3-4 Toxicity Related to Folinic Acid/5-Fluorouracil/Oxaliplatin (FOLFOX4) Chemotherapy in Non-Metastatic Colorectal Cancer

1
Experimental and Clinical Pharmacology Unit, CRO Aviano National Cancer Institute, IRCCS, via F. Gallini 2, Aviano (PN) 33081, Italy
2
Unit of Cancer Epidemiology, CRO Aviano National Cancer Institute, IRCCS, via F. Gallini 2, Aviano (PN) 33081, Italy
3
Medical Oncology Unit, “San Filippo Neri Hospital”, Piazza Di S. Maria Della Pietà, Rome 00135, Italy
4
Medical Oncology Unit, University Hospital, Piazzale Santa Maria della Misericordia 15, Udine (UD) 33100, Italy
5
Medical Oncology Unit B, CRO Aviano National Cancer Institute, IRCCS, via F. Gallini 2, Aviano (PN) 33081, Italy
6
Medical Oncology Unit, Ospedale Cà Foncello, Piazzale Ospedale 1, Treviso (TV) 31100, Italy
*
Author to whom correspondence should be addressed.
Received: 17 May 2017 / Revised: 7 June 2017 / Accepted: 20 June 2017 / Published: 27 June 2017
(This article belongs to the Special Issue Major Histocompatibility Complex)
View Full-Text   |   Download PDF [255 KB, uploaded 27 June 2017]   |  

Abstract

Polymorphisms in drug-metabolizing enzymes might not completely explain inter-individual differences in toxicity profiles of patients with colorectal cancer (CRC) that receive folinic acid/5-fluorouracil/oxaliplatin (FOLFOX4). Recent data indicate that the immune system could contribute to FOLFOX4 outcomes. In light of the immune inhibitory nature of human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, we aimed to identify novel genomic markers of grades 3 and 4 (G3-4) toxicity related to FOLFOX4 therapy in patients with CRC. We retrospectively analyzed data for 144 patients with stages II-III CRC to identify HLA-G 3′ untranslated region (3′UTR) polymorphisms and related haplotypes and evaluate their impact on the risk of developing G3-4 toxicities (i.e., neutropenia, hematological/non-hematological toxicity, neurotoxicity) with logistic regression. The rs1610696-G/G polymorphism was associated with increased risk of G3-4 neutropenia (OR = 3.76, p = 0.015) and neurotoxicity (OR = 8.78, p = 0.016); rs371194629-Ins/Ins was associated with increased risk of neurotoxicity (OR = 5.49, p = 0.027). HLA-G 3′UTR-2, which contains rs1610696-G/G and rs371194629-Ins/Ins polymorphisms, was associated with increased risk of G3-4 neutropenia (OR = 3.92, p = 0.017) and neurotoxicity (OR = 11.29, p = 0.009). A bootstrap analysis confirmed the predictive value of rs1610696 and rs371194629, but the UTR-2 haplotype was validated only for neurotoxicity. This exploratory study identified new HLA-G 3′UTR polymorphisms/haplotypes as potential predictive markers of G3-4 toxicities in CRC. View Full-Text
Keywords: colorectal cancer; human leukocyte antigen-G 3′UTR; polymorphism; toxicity; folinic acid/5-fluorouracil/oxaliplatin; immunogenetics colorectal cancer; human leukocyte antigen-G 3′UTR; polymorphism; toxicity; folinic acid/5-fluorouracil/oxaliplatin; immunogenetics
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Garziera, M.; Virdone, S.; De Mattia, E.; Scarabel, L.; Cecchin, E.; Polesel, J.; D’Andrea, M.; Pella, N.; Buonadonna, A.; Favaretto, A.; Toffoli, G. HLA-G 3′UTR Polymorphisms Predict Drug-Induced G3-4 Toxicity Related to Folinic Acid/5-Fluorouracil/Oxaliplatin (FOLFOX4) Chemotherapy in Non-Metastatic Colorectal Cancer. Int. J. Mol. Sci. 2017, 18, 1366.

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