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

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 <i>HLA-G</i> 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-<i>G/G</i> polymorphism was associated with increased risk of G3-4 neutropenia (OR = 3.76, <i>p</i> = 0.015) and neurotoxicity (OR = 8.78, <i>p</i> = 0.016); rs371194629-<i>Ins/Ins</i> was associated with increased risk of neurotoxicity (OR = 5.49, <i>p</i> = 0.027). <i>HLA-G</i> 3'UTR-2, which contains rs1610696-<i>G/G</i> and rs371194629-<i>Ins/Ins</i> polymorphisms, was associated with increased risk of G3-4 neutropenia (OR = 3.92, <i>p</i> = 0.017) and neurotoxicity (OR = 11.29, <i>p</i> = 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 <i>HLA-G</i> 3'UTR polymorphisms/haplotypes as potential predictive markers of G3-4 toxicities in CRC.