Hla-g 30utr polymorphisms predict drug-induced g3-4 toxicity related to folinic acid/5-fluorouracil/oxaliplatin (Folfox4) chemotherapy in non-metastatic colorectal cancer

Marica Garziera, Saverio Virdone, Elena de Mattia, Lucia Scarabel, Erika Cecchin, Jerry Polesel, Mario D’Andrea, Nicoletta Pella, Angela Buonadonna, Adolfo Favaretto, Giuseppe Toffoli

Research output: Contribution to journalReview article

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 30 untranslated region (30UTR) 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 30UTR polymorphisms/haplotypes as potential predictive markers of G3-4 toxicities in CRC.

Original languageEnglish
Article number1366
Number of pages13
JournalInternational Journal of Molecular Sciences
Volume18
Issue number7
DOIs
Publication statusPublished - Jul 1 2017

Keywords

  • Colorectal cancer
  • Folinic acid/5-fluorouracil/oxaliplatin
  • Human leukocyte antigen-G 30UTR
  • Immunogenetics
  • Polymorphism
  • Toxicity

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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