HLA-G 3’UTR +2960 14-bp INDEL (Ins/Del) polymorphism is associated to improved DFS of stage II-III CRC patients.

Background: An important hallmark of Colorectal Cancer (CRC) is the evasion of immune surveillance. Human leukocyte antigen-G (HLA-G) HLA-G is a negative regulator of host immune response involved in tumor escape mechanisms. A reduced Overall Survival (OS) has been independently associated to HLA-G protein overexpression in primary CRC lesions.The 3'UTR +2960 14-bp INDEL (Ins/Del) SNP influence the protein magnitude by modulating HLA-G mRNA stability. The presence of the 14-bp Insertion has been associated to lower HLA-G protein levels. HLA-G3'UTR 14-bp SNP has never been explored in CRC outcome. The purpose of this study was to investigate if HLA-G 3'UTR +2960 14-bp Ins/Del polymorphism have an impact on survival of non-metastatic CRC patients. Patients and methods: A total of stage II-III 253 CRC patients was included from a prospective non-selected patient collection from Experimental and Clinical Pharmacology Unit of CRO-Aviano based on two previous published studies. Overall patients after diagnosis received adjuvant chemotherapy (ADJ-CT) based on fluoropyrimidine (FL) after primary surgery. The 3'UTR of the HLA-Ggene was amplified from genomic DNA by PCR and direct genotyping was performed. Our primary endpoints, Disease Free Survival (DFS) and OS, were analyzed by using Kaplan-Meier and multivariate Cox-regression models for survival analysis. Results: Median age was 62.5 years (range 24-82) at onset. Median follow-up time was 56.3 months (range 1.2-186.3) for DFS and 62.8 months (range 4.6-186.3) for OS. In multivariate analysis after adjustments with clinical variables, we estimated an association with improved DFS in Ins/Del heterozygous (HR 0.59, 95% 0.36-0.96, p = 0.035) and in Insallele (Ins/Del +Ins/Ins, dominant model) carriers (HR 0.60, 95% 0.38-0.93, p = 0.023). Del/Del genotype was associated to a reduced 5-years DFS % (54%) compared to both Ins/Del (70%) and Ins/Ins genotypes (70%).Insallele was associated to improved OS even if not significantly. Conclusions: This work for the first time estimates associations between HLA-G3'UTR +2960 14-bp Ins/Del and the prognosis of stage II-III CRC patients treated with FL-based ADJ-CT. Our study shows a prognostic and independent potential in multivariate analysis with a protective role for Insallele (lower HLA-G producer) in DFS. HLA-G3'UTR 14-bp Ins/Del polymorphism has emerged as novel prognostic biomarker in determining survival outcome of CRC. A validation in independent CRC cohorts is required.