Letter to the Editor Role of MTHFR C677T polymorphism in systemic carcinogenesis, besides its role in the pathogenesis of colo-rectal carcinomas

Abstract Abstract 5065 Introduction: Myeloproliferative Neoplasms (MPN) are commonly associated with thrombotic complications, which constitute the major cause for morbidity and mortality in these patients. While the pathogenesis of Thrombosis is not yet fully elucidated, the impact of inherited thrombophilia on MPN patients is unknown. MTHFR-C677T polymorphism is a usual variation of the MTHFR gene and exerts weak, if any, prothrombotic role mainly through increased homocysteine levels. Up to date there are no specific guidelines for treatment of thrombotic events in MPN patients. Objectives: The purpose of our study is to determine the impact of inherited thrombophilia factors on thrombotic risk in patients with newly diagnosed BCR- abl (-) myeloproliferative neoplasms. We also tried to assess the role of the MTHFR- C677T polymorphism in thrombotic risk in our MPN patients. Material and Methods: Our study population consisted of 68 patients diagnosed with BCR- abl (-) myeloproliferative neoplasms in the Hematology Department of our Hospital during the period 2005– 2008. Diagnosis was set according to the World Health Organization and Updated European Clinical and Pathological criteria for the Diagnosis, Clasification and Staging of the Philadelphia chromosome (-) chronic myeloproliferative disorders. Age, Sex, Platelet count, serum homocysteine levels, presence of Jak-2 mutation, together with genetic polymorphisms of Factor V-Leiden and FII- G121120A prothrombin mutations, and MTHFR- C677T polymorphism were assessed. Among our patients, whose median age was 65 years (range 21– 83), 40 were male and 28 female. 41 patients were diagnosed with essential thrombocythemia (ET), 22 with Polycythemia Vera (PV), 3 with essential myelofibrosis and 2 with Unclassified Chronic bcr- abl (-) MPN. Statistical analysis was conducted with SPSS 20. 0. At first a monovariate statistical model was used with significant level set at p= 0. 05. For the multivariable statistical analysis model we used all variables with p<0, 05 from the previous model and those mentioned at recent medical literature as significantly related with thrombotic risk. Results: From our patients, 31 suffered a thrombotic event (arterial or venous thrombosis, microvascular disorders). Regarding their thrombophilia profile patients were found to be: 4 carriers of the FVL mutation, 4 carriers of the FII- G121120A and 13 were carrying the MTHFR- C677T polymorphism. Moreover, 56 patients were tested for Jak-2V617F, and 42 of them were found to be positive (100% patients with P. V., 79% ET patients). We tried to define whether the following variables are high risk factors for thrombotic events in our population: Platelet count, serum homocystein levels, presence of Jak-2 mutation, Factor V-Leiden and FII- G121120A, mutations, and MTHFR- C677T. Surprisingly, the presence of MTHFR- C677T reached statistical significance on the monovariate analysis (p= 0. 001), while published data on general thrombosis population don't show any correlation of the MTHFR- C677T with thrombotic events. Jak-2 mutation was studied in a subgroup of patients, which didn't include patients with PV and was found to be statistically significant thrombosis risk factor in the monovariate analysis. Multiple regression analysis revealed MTHFR- C677T genetic polymorphism as independent risk factor concerning thrombotic events in patients with BCR- abl (-) MPNs (p= 0. 01, Exp (B)= 39. 227, 95%CI: 2. 41 –638. 547). The mean concentration of serum homocystein and the mean platelet count didn't show any statistically significant difference between patients carying MTHFR- C677T polymorphism and MTHFR- C677T negative patients. So serum homocystein levels and platelet count were not found to be confounding factors. In addition the co- existence of MTHFR- C677T with either G121120A or FVL mutations was detected in 4 patients, and all of them suffered from thrombotic events. Conclusions: Our study is the first to demonstrate a prothrombotic role of MTHFR- C677T polymorphism in a MPN population. Thrombophilia studies are needed in MPN patients in order to better assess the thrombotic risk for the patients but foremost to properly tailor anticoagulant treatment after a thrombotic episode. Disclosures: No relevant conflicts of interest to declare.

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Letter to the editor: a meta-analysis of MTHFR C677T polymorphism and colorectal cancer risk in East Asians

International Journal of Colorectal Disease ◽

10.1007/s00384-012-1479-6 ◽

2012 ◽

Vol 28 (3) ◽

pp. 429-430 ◽

Cited By ~ 2

Author(s):

Yunhe Jia ◽

Mingqi Li ◽

Weinan Xue ◽

Binbin Cui

Keyword(s):

Colorectal Cancer ◽

Cancer Risk ◽

Meta Analysis ◽

Mthfr C677t ◽

Colorectal Cancer Risk ◽

C677t Polymorphism ◽

East Asians ◽

Mthfr C677t Polymorphism ◽

Letter To The Editor

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The Role of MTHFR C677T Polymorphism on Blood Homocysteine Concentration and the Effect of Both of this on Susceptibility to Stroke

Enliven Journal of Genetics Molecular and Cellular Biology ◽

10.18650/2379-5700.23005 ◽

2015 ◽

Vol 2 (3) ◽

Author(s):

Dwivedi M K ◽

Sinha Depak

Keyword(s):

Mthfr C677t ◽

C677t Polymorphism ◽

Mthfr C677t Polymorphism ◽

Homocysteine Concentration

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The role of the MTHFR C677T polymorphism in methotrexate-induced toxicity in pediatric osteosarcoma patients

Pharmacogenomics ◽

10.2217/pgs-2017-0013 ◽

2017 ◽

Vol 18 (8) ◽

pp. 787-795 ◽

Cited By ~ 7

Author(s):

Loes Lambrecht ◽

Charlotte Sleurs ◽

Veerle Labarque ◽

Catharina Dhooge ◽

Annouschka Laenen ◽

...

Keyword(s):

Mthfr C677t ◽

C677t Polymorphism ◽

Mthfr C677t Polymorphism ◽

Pediatric Osteosarcoma

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Plasma Homocysteine Levels, Methelene TetraHydroFolate Reductase (MTHFR) Polymorphism, and the Risk of Thromboembolism in Children: A Single Institution Experience

Blood ◽

10.1182/blood.v112.11.5351.5351 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5351-5351

Author(s):

Akash Nahar ◽

Yaddanapudi Ravindranath ◽

Jeanne M. Lusher ◽

Meera B. Chitlur ◽

Mary Jane Frey ◽

...

Keyword(s):

Risk Factor ◽

Demographic Data ◽

Mthfr C677t ◽

C677t Polymorphism ◽

Standard Laboratory ◽

Normal Range ◽

Mthfr Polymorphism ◽

Mthfr C677t Polymorphism ◽

Normal Ranges

Abstract Introduction: Hyperhomocystenemia (HHcy) has been identified as a moderate risk factor for thrombosis in adults. A polymorphism in the folate-metabolizing enzyme Methelene TetraHydroFolate Reductase (MTHFR) has been implicated in causing a mild to moderate elevation in homocysteine (Hcy). Data on the role of HHcy and MTHFR polymorphism in pediatric thromboembolism (TE) are sparse. We reviewed, in our series of 125 patients, the role of elevated Hcy and MTHFR C677T polymorphism as a risk factor for TE in children. Materials and Methods: Inpatient and outpatient clinic charts of patients with documented TE, followed at the Hemostasis and Thrombosis Center at Children’s Hospital of Michigan were reviewed for demographic data, Hcy level and the presence of the MTHFR C677T polymorphism. Hcy levels were recorded at the time of diagnosis. Normal Hcy levels were defined both as per the standard laboratory normal range and established age-specific normal ranges available from literature. The 97.5% value was taken as the upper normal range. The data were thus analyzed separately with both stratifications. Results: A total of 171 patient charts were reviewed from January 1989 to June 2008. Hcy and MTHFR data were available on 125 patients. Thus, a total of 125 patients with a documented venous and/or arterial TE (60 venous and 45 arterial) were analyzed. 61 were females and 64 males. Mean age of presentation was 14 years (range of 1 day to 30 years). When no age segregation was done, normal Hcy plasma concentration was taken as 4 – 12 μmol/L for all ages. Elevated Hcy (>12 μmol/L) was seen in a total of 8 patients (6.5 %), out of which 5 had CT genotype and 3 had the CC genotype. None of these patients were homozygous (TT) for the MTHFR polymorphism (Table 1). When the HHcy was analyzed by stratifying normal Hcy ranges based on age (Table 2), total of 15 patients (12%) were found to have elevated Hcy. Six patients had CT genotype and 9 patients had CC genotype. Again, none of the homozygote for MTHFR polymorphism had an elevated Hcy even after stratifying by age. Seven patients were homozygous with TT genotype, 49 patients had the CT genotype and the reminder 69 had normal CC genotype. The median homocysteine levels in these three groups were 5.7 μmol/L (4.3 – 8.5); 6 μmol/L (3–49.1) and 6.5 μmol/L (1.2 – 19.1) respectively (Table 3). Of the 6 patients with CT genotype and elevated homocysteine, 3 patients had end stage renal disease and the corresponding homocysteine levels were 18.3 μmol/L, 18.8 μmol/L and 49.1 μmol/L. Conclusions: HHcy was a risk factor in 8 out of 125 patients (6.5%) when the normal range was based on standard laboratory normal range and in 15 out of 125 (15%) when age stratified normal ranges were used. There was no difference in the median Hcy levels in patients with CC, CT or TT genotype for MTHFR polymorphism. Our data suggest that MTHFR polymorphism is not associated with elevation in Hcy and is not a risk factor in pediatric TE. Thus, genetic testing for MTHFR C677T polymorphism in pediatric patients with TE may not be justified at this time.

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