Dataset Information

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.

SUBMITTER: Garziera M

PROVIDER: S-EPMC4669157 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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HLA-G 3'UTR Polymorphisms Impact the Prognosis of Stage II-III CRC Patients in Fluoropyrimidine-Based Treatment.

Garziera Marica M Bidoli Ettore E Cecchin Erika E Mini Enrico E Nobili Stefania S Lonardi Sara S Buonadonna Angela A Errante Domenico D Pella Nicoletta N D'Andrea Mario M De Marchi Francesco F De Paoli Antonino A Zanusso Chiara C De Mattia Elena E Tassi Renato R Toffoli Giuseppe G

PloS one 20151203 12

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/I ...[more]

PMID: 26633805

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Project description:BackgroundCurrent guidelines recommend neoadjuvant therapy for patients with stage II or III rectal cancer. The addition of platinum derivatives to fluoropyrimidine-based chemoradiotherapy has been frequently investigated, but their role in this setting remains controversial.MethodsPubMed, Cochrane Library, and Web of Science were systematically searched for randomized trials comparing chemoradiotherapy with or without platinum agents in stage II or III rectal cancer. Main outcome parameters were overall and disease-free survival, additional outcomes included pathological complete response, isolated local recurrence, distant recurrence, toxicity, and perioperative morbidity. Time-to-event data were pooled as hazard ratios (HRs) by the inverse variance method and binary outcomes as odds ratios (ORs) by the Peto method with their respective 95% confidence interval (CI). All statistical tests were two-sided.ResultsTen randomized controlled trials with data on 5599 patients were included in the meta-analysis. Platinum derivatives did not statistically significantly improve overall survival (HR = 0.93, 95% CI = 0.82 to 1.05, P?=?.23), disease-free survival (HR = 0.91, 95% CI = 0.83 to 1.01, P?=?.07), or local recurrence (OR = 0.83, 95% CI = 0.66 to 1.05, P?=?.12). However, it led to a statistically significant increase of pathological complete response (OR = 1.31, 95% CI = 1.10 to 1.55, P?=?.002) and a statistically significant reduction of distant recurrence (OR = 0.78, 95% CI = 0.66 to 0.92, P?=?.004). Benefits were accompanied by higher rates of grade 3 or 4 toxicities.ConclusionsIntensified neoadjuvant chemoradiotherapy with the addition of platinum derivatives cannot be recommended routinely because it did not improve overall or disease-free survival and was associated with increased toxicity. It needs to be elucidated whether the benefits in distant recurrence and pathological complete response may be advantageous for selected high-risk patients.

Project description:Distant metastasis is the major causes of death in colorectal cancer (CRC) patients. In order to identify genes influencing the prognosis of patients with CRC, we compared gene expression in primary tumors with and without distant metastasis using an oligonucleotide microarray. We also examined the expression of the candidate gene in 100 CRC patients by quantitative real-time reverse transcription PCR and studied the relationship between its expression and the prognosis of patients with CRC. As a result, we identified MUC12 as a candidate gene involved in metastasis processes by microarray analysis. Quantitative real-time reverse transcription PCR showed that MUC12 expression was significantly lower in cancer tissues than in adjacent normal tissues (P < 0.001). In stage II and stage III CRC, patients with low expression showed worse disease-free survival (P = 0.038). Multivariate analysis disclosed that MUC12 expression status was an independent prognostic factor in stage II and stage III CRC (relative risk, 9.532; 95% confidence interval, 2.303-41.905; P = 0.002). This study revealed the prognostic value of MUC12 expression in CRC patients. Moreover, our result suggests MUC12 expression is a possible candidate gene for assessing postoperative adjuvant therapy for CRC patients. Total of 111 microarray datasets (77 for LCM samples, and 17 pairs for homogenized samples from tumor and adjacent tissues) were normalized using robust multi-array average (RMA) method under R 2.6.2 statistical software together with BioConductor package, as described previously. Then, the gene expression levels were log2-transformed, and 62 control probe sets were removed for further analysis. In order to identify a set of genes associated with development of metastatic recurrence, we performed Wilcoxon rank-sum test for gene expression differences of 54,613 probe sets between recurrence and non-recurrence groups. Similarly, Wilcoxon singed-rank test was conducted to select genes which showed significant expression difference between tumor and adjacent tissue. Then, we selected a set of genes that satisfied both of above two criteria.

Dataset Information

HLA-G 3'UTR Polymorphisms Impact the Prognosis of Stage II-III CRC Patients in Fluoropyrimidine-Based Treatment.

Publications

HLA-G 3'UTR Polymorphisms Impact the Prognosis of Stage II-III CRC Patients in Fluoropyrimidine-Based Treatment.

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