title: HLA-G 3'UTR Polymorphisms Impact the Prognosis of Stage II-III CRC Patients in Fluoropyrimidine-Based Treatment.
abstract: An important hallmark of CRC is the evasion of immune surveillance. HLA-G is a negative regulator of host's immune response. Overexpression of HLA-G protein in primary tumour CRC tissues has already been associated to worse prognosis; however a definition of the role of immunogenetic host background is still lacking. Germline polymorphisms in the 3'UTR region of HLA-G influence the magnitude of the protein by modulating HLA-G mRNA stability. Soluble HLA-G has been associated to 3'UTR +2960 Ins/Ins and +3035 C/T (lower levels) and +3187 G/G (high levels) genotypes. HLA-G 3'UTR SNPs have never been explored in CRC outcome. The purpose of this study was to investigate if common HLA-G 3'UTR polymorphisms have an impact on DFS and OS of 253 stage II-III CRC patients, after primary surgery and ADJ-CT based on FL. The 3'UTR was sequenced and SNPs were analyzed for their association with survival by Kaplan-Meier and multivariate Cox models; results underwent internal validation using a resampling method (bootstrap analysis). In a multivariate analysis, we estimated an association with improved DFS in Ins allele (Ins/Del +Ins/Ins) carriers (HR 0.60, 95% CI 0.38-0.93, P = 0.023) and in patients with +3035 C/T genotype (HR 0.51, 95% CI 0.26-0.99, P = 0.045). The +3187 G/G mutated carriers (G/G vs A/A+A/G) were associated to a worst prognosis in both DFS (HR 2.46, 95% CI 1.19-5.05, P = 0.015) and OS (HR 2.71, 95% CI 1.16-6.63, P = 0.022). Our study shows a prognostic and independent role of 3 HLA-G 3'UTR SNPs, +2960 14-bp INDEL, +3035 C>T, and +3187 A>G.
authors.affiliation: Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico (CRO), IRCCS, Aviano National Cancer Institute, via F. Gallini 2, 33081 Aviano, Italy.
authors.forename: Marica
authors.initials: M
authors.lastname: Garziera
authors.affiliation: Epidemiology and Biostatistic Unit, Centro di Riferimento Oncologico (CRO), IRCCS, Aviano National Cancer Institute, via F. Gallini 2, 33081 Aviano, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Bidoli
authors.affiliation: Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico (CRO), IRCCS, Aviano National Cancer Institute, via F. Gallini 2, 33081 Aviano, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Cecchin
authors.affiliation: Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Mini
authors.affiliation: Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Nobili
authors.affiliation: Medical Oncology Unit 1, Istituto Oncologico Veneto-IRCCS, Padua, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Lonardi
authors.affiliation: Division of Medical Oncology B; Centro di Riferimento Oncologico (CRO), IRCCS, Aviano National Cancer Institute, via F. Gallini 2, 33081 Aviano, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Buonadonna
authors.affiliation: Medical Oncology Unit, Ospedale Civile di Vittorio Veneto, Vittorio Veneto (TV), Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Errante
authors.affiliation: Medical Oncology Unit, University Hospital, Piazza S. Maria Della Misericordia, Udine, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Pella
authors.affiliation: Medical Oncology Unit, "San Filippo Neri Hospital", Piazza Di S. Maria Della Pietà, Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: D'Andrea
authors.affiliation: Surgical Oncology Department, Centro di Riferimento Oncologico (CRO), IRCCS, Aviano National Cancer Institute, via F. Gallini 2, 33081 Aviano, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: De Marchi
authors.affiliation: Radiotherapy Department, Centro di Riferimento Oncologico (CRO), IRCCS, Aviano National Cancer Institute, via F. Gallini 2, 33081 Aviano, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: De Paoli
authors.affiliation: Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico (CRO), IRCCS, Aviano National Cancer Institute, via F. Gallini 2, 33081 Aviano, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Zanusso
authors.affiliation: Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico (CRO), IRCCS, Aviano National Cancer Institute, via F. Gallini 2, 33081 Aviano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: De Mattia
authors.affiliation: Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Tassi
authors.affiliation: Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico (CRO), IRCCS, Aviano National Cancer Institute, via F. Gallini 2, 33081 Aviano, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Toffoli
mesh_terms: D020413:3' Untranslated Regions; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D018572:Disease-Free Survival; D005260:Female; D005838:Genotype; D059951:HLA-G Antigens / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis
chemical_list: D020413:3' Untranslated Regions; D059951:HLA-G Antigens