MTHFR-1298 A&gt;C (rs1801131) is a predictor of survival in two cohorts of stage II/III colorectal cancer patients treated with adjuvant fluoropyrimidine chemotherapy with or without oxaliplatin

Cecchin, Erika; Perrone, Gabriele; Nobili, Stefania; Polesel, Jerry; Mattia, Elena De; Zanusso, Chiara; Petreni, Paolo; Pella, Nicoletta; D’Andrea, Mario; Errante, D.; Rizzolio, Flavio; Mazzei, Teresita; Landini, Ida; Mini, Enrico; Toffoli, Giuseppe

doi:10.1038/tpj.2014.64

Cited by 17 publications

(21 citation statements)

References 36 publications

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“…A total of 253 CRC patients with newly diagnosed, untreated, histopathologically confirmed CRC, were included from an existing prospective collection of only blood samples stored at the Experimental and Clinical Pharmacology Unit of Centro di Riferimento Oncologico (CRO)-Aviano, based on previous multicenter pharmacogenomic studies [ 43 , 44 ]. Eligible criteria were: stage II-III CRC, radiologically-confirmed absence of distant metastasis, age >18 years, performance status (WHO) 0–2, normal bone marrow, renal and liver function, and Caucasian ethnicity.…”

Section: Methodsmentioning

confidence: 99%

“…Eligible criteria were: stage II-III CRC, radiologically-confirmed absence of distant metastasis, age >18 years, performance status (WHO) 0–2, normal bone marrow, renal and liver function, and Caucasian ethnicity. Overall patients after diagnosis underwent primary surgery and received ADJ-CT based on fluoropyrimidine (FL) (i.e., 5-fluorouracil/folinic acid or capecitabine) [ 44 ], or FL plus oxaliplatin (FL+OXA) [ 43 ].…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2015

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

et al. 2015

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“…Studies performed in the adjuvant CRC setting have also discovered a predictive role of SNPs. Cecchin et al [ 64 ] conducted a study concerning MTHFR 1298A>C (rs1801131) polymorphism as a predictor of survival in two cohorts of stage II/III setting of CRC patients treated with adjuvant fluoropyrimidine chemotherapy with or without oxaliplatin. MTHFR 1298CC genotype carriers had worse disease free survival and also worse overall survival in both cohorts.…”

Section: Single Nucleotide Polymorphisms In Resectable Colorectal mentioning

confidence: 99%

Single Nucleotide Polymorphisms as Prognostic and Predictive Factors of Adjuvant Chemotherapy in Colorectal Cancer of Stages I and II

Horvat

Potočnik

Repnik

et al. 2016

Gastroenterology Research and Practice

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Colorectal cancer (CRC) is a highly heterogeneous disease regarding the stage at time of diagnosis and there is special attention regarding adjuvant chemotherapy in unselected patients with stage I and stage II. The clinicohistologically based TNM staging system with emphasis on histological evaluation of primary tumor and resected regional lymph nodes remains the standard of staging, but it has restricted sensitivity resulting in false downward stage migration. Molecular characteristics might predispose tumors to a worse prognosis and identification of those enables identifying patients with high risk of disease recurrence. Suitable predictive markers also enable choosing the most appropriate therapy. The current challenge facing adjuvant chemotherapy in stages I and II CRC is choosing patients with the highest risk of disease recurrence who are going to derive most benefit without facing unnecessary adverse effects. Single nucleotide polymorphisms (SNPs) are one of the potential molecular markers that might help us identify patients with unfavorable prognostic factors regarding disease initiation and recurrence and could determine selection of an appropriate chemotherapy regimen in the adjuvant and metastatic setting. In this paper, we discuss SNPs of genes involved in the multistep processes of cancerogenesis, metastasis, and the metabolism of chemotherapy that might prove clinically significant.

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“…These investigations focused mainly on polymorphisms in genes encoding phase I and II enzymes (GSTP1), proteins involved in DNA repair (XRCC1 and XPD), folate-pathways (TYMS) and 5,10-methylenetetrahydrofolate reductase (MTHFR), and cell cycle control (CCDN1) ( Libra et al, 2004 ; De Mattia et al, 2015 ; Smolle et al, 2015 ; Horvat et al, 2016 ; Kap et al, 2016 ). This group previously reported a clinical-genetic score based on the MTHFR polymorphism rs1801133, which significantly stratified a group of stages II–III CRC patients, receiving adjuvant FL-based treatment, according to DFS ( Cecchin et al, 2015 ). However, the current methods for selecting CRC patients who would benefit from an adjuvant treatment are still sub-optimal.…”

Section: Introductionmentioning

confidence: 99%

“…The present study was planned to broaden our immunogenetic analysis to genes encoding proteins involved in the immune system and related networks to highlight germ-line markers of DFS in two cohorts of stage II-III CRC patients receiving FL-based adjuvant therapy. The aim was to integrate these immunogenetic markers in our previously published clinical-genetic score ( Cecchin et al, 2015 ) to improve the pre-treatment identification of patients who may benefit from an adjuvant FL-based treatment.…”

Section: Introductionmentioning

confidence: 99%

A Clinical-Genetic Score to Identify Surgically Resected Colorectal Cancer Patients Benefiting From an Adjuvant Fluoropyrimidine-Based Therapy

et al. 2018

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There are clinical challenges related to adjuvant treatment in colorectal cancer (CRC) and novel molecular markers are needed for better risk stratification of patients. Our aim was to integrate our previously reported clinical-genetic prognostic score with new immunogenetic markers of 5-year disease-free survival (DFS) to evaluate the recurrence risk stratification before fluoropyrimidine (FL)-based adjuvant therapy. The study population included a total of 270 stage II-III CRC patients treated with adjuvant FL with (FL + OXA, n = 119) or without oxaliplatin (FL, n = 151). Patients were genotyped for a panel of 192 tagging polymorphisms in 34 immune-related genes. The IFNG-rs1861494 polymorphism was associated with worse DFS in the FL + OXA (HR = 2.14, 95%CI 1.13–4.08; P = 0.020, q-value = 0.249) and FL (HR = 1.97, 95%CI 1.00–3.86; P = 0.049) cohorts, according to a dominant model. The integration of IFNG-rs1861494 in our previous clinical genetic multiparametric score of DFS improved the patients’ risk stratification (Log-rank P = 0.0026 in the pooled population). These findings could improve the discrimination of patients who would benefit from adjuvant treatment. In addition, the results may help better elucidate the interplay between the immune system and chemotherapeutics and help determine the efficacy of anti-tumor strategies.

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MTHFR-1298 A>C (rs1801131) is a predictor of survival in two cohorts of stage II/III colorectal cancer patients treated with adjuvant fluoropyrimidine chemotherapy with or without oxaliplatin

Cited by 17 publications

References 36 publications

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

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

Single Nucleotide Polymorphisms as Prognostic and Predictive Factors of Adjuvant Chemotherapy in Colorectal Cancer of Stages I and II

A Clinical-Genetic Score to Identify Surgically Resected Colorectal Cancer Patients Benefiting From an Adjuvant Fluoropyrimidine-Based Therapy

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