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MTHFR gene variants and non-MALT lymphoma development in primary Sjogren's syndrome.

ABSTRACT: Primary Sjogren's syndrome (pSS) confers increased risk for non-Hodgkin lymphoma (NHL) development. Two common polymorphisms, the c. 677C?>?T and c. 1298A?>?C, of the methylene-tetrahydrofolate reductase (MTHFR) gene, an enzyme essential in DNA synthesis and methylation, have been associated with susceptibility to NHL. Herein, we tested the hypothesis that MTHFR variants contribute to pSS-related lymphomagenesis. 356 pSS patients, of whom 75 had MALT and 19 non-MALT NHL and 600 healthy controls were genotyped for the detection of MTHFR polymorphisms. DNA methylation levels were assessed by pyrosequencing of the LINE-1 retroelement promoter in DNA from 55 salivary gland tissues from pSS patients. DNA double-strand breaks were determined in peripheral blood mononuclear cells from 13 pSS patients, using comet assay. ?nalysis according to lymphoma subtype revealed increased frequency of c. 677C?>?T TT genotype and T allele, as well as reduced prevalence of the c. 1298A?>?C C allele in the pSS non-MALT group compared to controls and patients without NHL. MTHFR c. 677C?>?T TT genotype was associated with reduced DNA methylation levels, while MTHFR c. 1298A?>?C AC genotype with reduced DNA double-strand breaks levels. MTHFR variants may be involved in SS non-MALT NHL development, through contribution to defective DNA methylation and genomic instability.

SUBMITTER: Fragkioudaki S

PROVIDER: S-EPMC5544668 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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MTHFR gene variants and non-MALT lymphoma development in primary Sjogren's syndrome.

Fragkioudaki Sofia S Nezos Adrianos A Souliotis Vassilis L VL Chatziandreou Ilenia I Saetta Angelica A AA Drakoulis Nikolaos N Tzioufas Athanasios G AG Voulgarelis Michael M Sfikakis Petros P PP Koutsilieris Michael M Crow Mary K MK Moutsopoulos Haralampos M HM Mavragani Clio P CP

Scientific reports 20170804 1

Primary Sjogren's syndrome (pSS) confers increased risk for non-Hodgkin lymphoma (NHL) development. Two common polymorphisms, the c. 677C > T and c. 1298A > C, of the methylene-tetrahydrofolate reductase (MTHFR) gene, an enzyme essential in DNA synthesis and methylation, have been associated with susceptibility to NHL. Herein, we tested the hypothesis that MTHFR variants contribute to pSS-related lymphomagenesis. 356 pSS patients, of whom 75 had MALT and 19 non-MALT NHL and 600 healthy controls ...[more]

PMID: 28779180

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Project description:Non-Hodgkin's lymphoma (NHL) development in Sjögren's syndrome (SS) remains a potentially lethal complication and efforts should focus on the identification of predictors that could aid in appropriate therapeutic decisions.In order to identify potential prognostic factors for outcome in SS-associated NHL, we retrospectively analyzed a cohort of 77 patients, diagnosed with NHL according to WHO classification criteria and meeting the American-European Consensus Classification (AECC) criteria for SS and examined the effect of SS-activity (defined as the EULAR SS disease activity index-ESSDAI) in the prognosis of SS-related NHLs, as defined in terms of overall and event-free survivals (OS and EFS). An event was defined as lymphoma relapse, treatment failure, disease progression, histological transformation or death. The effect of NHL clinical and laboratory characteristics was also investigated.MALT lymphomas constituted the majority (66.2%) of lymphomas. During the follow-up (median = 57.93 months), the 5-year OS was 90.91% (95% CI: 82.14-95.80%) and the EFS was 77.92% (95% CI: 67.37-85.82%). Patients with high ESSDAI score at lymphoma diagnosis had a greater risk for death (OR = 5.241, 95% CI: 1.034-26.568) or for event (OR = 4.317, 95% CI: 1.146-9.699, p = 0.008). These patients had also significantly worse EFS (HR = 4.541, 95% CI: 1.772-11.637) and OS (HR = 5.946, 95% CI: 1.259-28.077). In addition, post-chemotherapy ESSDAI improvement was significantly lower in patients who had experienced an event (p = 0.005). An unfavorable International prognostic index (IPI) score (high-intermediate/high) was associated with high risk of death and event (OR = 13.867, 95% CI: 2.656-72.387 and OR = 12.589, 95% CI: 3.911-40.526, respectively), worse EFS (log-rank p<0.001, HR = 8.718, 95% CI: 3.477-21.858), as well as with worse OS (log-rank p<0.001, HR = 11.414, 95% CI: 2.414-53.974). After adjustment for identified risk factors, IPI score retained a significant prognostic role following by a strong effect of ESSDAI in survival outcomes.At the point of NHL diagnosis, IPI and ESSDAI might be proved useful predictive tools in SS-associated lymphoma prognosis, directing to a more patient-tailored approach.

Dataset Information

MTHFR gene variants and non-MALT lymphoma development in primary Sjogren's syndrome.

Publications

MTHFR gene variants and non-MALT lymphoma development in primary Sjogren's syndrome.

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