Hyperhomocysteinemia and distribution features of allelic polymorphism of folate group genes in patients with malignant neoplasms

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

INTRODUCTION: Malignant neoplasms (MNs) are currently widespread in the population. The study of the etiology of various tumor diseases is an important field of medical science. In recent years, elevated level of homocysteine (HC) in blood has been shown to be closely associated with cancer, as well as with unfavorable course after surgical interventions and during chemotherapy.

AIM: To assess the role of hyperhomocysteinemia (HHC) and polymorphism of folate cycle genes in the development of tumor processes and venous thromboembolic complications (VTEC).

MATERIALS AND METHODS: The PubMed and eLibrary.ru databases were searched for publications for the period from January 1, 2005 to December 31, 2024, including abstracts and articles with the results of original studies (primary sources), meta-analyses and reviews (secondary sources), foreign and Russian clinical guidelines (tertiary sources) using the keywords ‘malignant neoplasms’, ‘hyperhomocysteinemia’, ‘folate cycle gene polymorphism’, ‘folic acid’, ‘venous thromboembolic complications’. The role of HHC, folate cycle gene polymorphism in the development of tumor processes and venous thrombosis was analyzed and assessed.

RESULTS: This review analyzes the relationship between elevated plasma HC levels and the risk of developing malignant neoplasms of various locations and discusses clinical prospects. The article presents evidence of interaction between allelic polymorphism of folate cycle genes involved in HC metabolism, and the risk of development and course of cancer in humans. The article systematizes data on the role of HHC in the development of VTEC in patients with cancer.

CONCLUSION: The content of HC in blood plasma can be used as a potential tumor biomarker for various types of MNs, and HHC can be an important prognostic marker for the course of tumor processes and a risk factor for the development of VTEC. Understanding the effect of HC levels on the growth and proliferation of tumor cells will allow the creation of new promising strategies to combat MNs. Further clinical studies are needed for a more accurate assessment of these positions.

About the authors

Alexey S. Petrikov

Rostov State Medical University

Author for correspondence.
Email: petricov_alex@mail.ru
ORCID iD: 0000-0002-6501-3289
SPIN-code: 4612-6452

MD, Dr. Sci. (Medicine), Associate Professor

Russian Federation, Rostov-on-Don

Vladimir I. Belykh

Altai State Medical University

Email: dr_bvi@mail.ru
ORCID iD: 0009-0004-0841-0028
SPIN-code: 4758-4688

MD, Dr. Sci. (Medicine), Associate Professor

Russian Federation, Barnaul

Alexandra D. Pavlova

Altai State Medical University

Email: pavlovaaleksandra2002@gmail.com
ORCID iD: 0009-0005-6475-4308
SPIN-code: 2927-1721
Russian Federation, Barnaul

References

  1. Wu S, Powers S, Zhu W, Hannun YA. Substantial contribution of extrinsic risk factors to cancer development. Nature. 2016;529(7584):43–47. doi: 10.1038/nature16166
  2. Miroshnichenko II, Ptitsyna SN, Kuznetsova NN, Kalmykov YUM. Gomo-tsistein — prediktor patologicheskikh izmeneniy v organizme cheloveka. Russkiy Meditsinskiy Zhurnal. 2009;17(4):224–227. (In Russ.) EDN: PBMHJF
  3. Zobova DA, Kozlov SA. The role of homocysteine in pathogenesis of certain diseases. University Proceedings. Volga Region. Medical Sciences. 2016;(3):132–144. doi: 10.21685/2072-3032-2016-3-15 EDN: XBVMWZ
  4. Perła–Kaján J, Twardowski T, Jakubowski H. Mechanisms of homocysteine toxicity in humans. Amino Acids. 2007;32(4):561–572. doi: 10.1007/s00726-006-0432-9 EDN: JLXXLI
  5. Kostyuchenko GI, Barkagan ZS. Diagnostika i metody korrektsii giper-gomotsisteinemii v kardiologicheskoy praktike. Moscow; 2004. (In Russ.)
  6. Petrikov AS, Shoykhet YAN, Belykh VI. Otsenka riska trombozov ven nizhnikh konechnostey i tromboembolii legochnoy arterii na osnove analiza geneticheskikh faktorov. Barnaul: Izdatel'stvo Altayskogo gosudarstvennogo universiteta; 2015. (In Russ.) EDN: UJEGCX
  7. Pan D, Su M, Huang G, et al. MTHFR C677T genetic polymorphism in combination with serum vitamin B2, B12 and aberrant DNA methylation of P16 and P53 genes in esophageal squamous cell carcinoma and esophageal precancerous lesions: a case-control study. Cancer Cell Int. 2019;19(1):288. doi: 10.1186/s12935-019-1012-x EDN: XPKEAV
  8. Li W-X, Dai S-X, Zheng J-J, et al. Homocysteine Metabolism Gene Polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) Jointly Elevate the Risk of Folate Deficiency. Nutrients. 2015;7(8):6670–6687. doi: 10.3390/nu7085303 EDN: VGFVLF
  9. Liu Y-X, Wang B, Wan M-H, et al. Meta-analysis of the relationship between the Metholenetetrahydrofolate reductase C677T genetic polymorphism, folate intake and esophageal cancer. Asian Pac J Cancer Prev. 2011;12(1):247–252.
  10. Swartz MD, Peterson CB, Lupo PJ, et al. Investigating multiple candidate genes and nutrients in the folate metabolism pathway to detect genetic and nutritional risk factors for lung cancer. PLoS One. 2013;8(1): e53475. doi: 10.1371/journal.pone.0053475
  11. Chang S-C, Chang P-Y, Butler B, et al. Single nucleotide polymorphisms of one-carbon metabolism and cancers of the esophagus, stomach, and liver in a Chinese population. PLoS One. 2014;9(10):e109235. doi: 10.1371/journal.pone.0109235
  12. Davydchyk EV, Snezhitskiy VA, Nikonova LV. Relationship of hyperhomocysteinemia with coronary heart disease and diabetes mellitus. Journal of the Grodno State Medical University. 2015;(1):9–13. EDN: TNBTAR
  13. Liu B, Chen Z, Dong X, Qin G. Association of prehypertension and hyperhomocysteinemia with subclinical atherosclerosis in asymptomatic Chinese: a cross-sectional study. BMJ Open. 2018;8(3): e019829. doi: 10.1136/bmjopen-2017-019829
  14. Refsum H, Nurk E, Smith AD, et al. The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease. J Nutr. 2006;136(6 Suppl):1731S–1740S. doi: 10.1093/jn/136.6.1731s
  15. Shilova AN, Shkoda OS, Lomivorotov VV, Shilova JN. Association of the folate metabolism genes with the risk for lung, prostate, breast and uterine cancer. Russian Journal of Oncology. 2017;22(4):203–208. doi: 10.18821/1028-9984-2017-22-4-203-208 EDN: ZHFCYB
  16. Plazar N, Jurdana M. Hyperhomocysteinemia and the role of B vitamins in cancer. Radiol Oncol. 2010;44(2):79–85. doi: 10.2478/v10019-010-0022-z EDN: LSVZAY
  17. Zotova LA, Yakushin SS. Venous thromboembolic complications in cancer patients. Prevention and treatment of venous thromboembolism associated with oncological diseases. Modern Problems of Science and Education. 2022;(3):142. Available from: https://science-education.ru/article/view?id = 31687. Accessed: 20.12.2024. doi: 10.17513/spno.31687 EDN: FOIONH
  18. Sushinskaya TV, Stuklov NI, Dobrokhotova YuE. Hemostasis and cancer-associated thrombosis: modern prevention and treatment. P.A. Herzen Journal of Oncology. 2018;(4):64–72. doi: 10.17116/onkolog20187464 EDN: XWAXLV
  19. Stathopoulou A, Vlachonikolis I, Mavroudis D, et al. Molecular detection of cytokeratin-19-positive cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic significance. J Clin Oncol. 2002;20(16):3404–3412. doi: 10.1200/jco.2002.08.135
  20. Hasan T, Arora R, Bansal AK, et l. Disturbed homocysteine metabolism is associated with cancer. Exp Mol Med. 2019;51(2):1–13. doi: 10.1038/s12276-019-0216-4
  21. Bakanova ML, Soboleva OA, Minina VI, et al. Association of polymorphism of folate metabolism genes and chromosomal aberrations in blood cells of lung cancer patients. Medical Genetics. 2017;16(3):12–19. EDN: YPIFOX
  22. Tastekin D, Erturk K, Bozbey HU, et al. Plasma homocysteine, folate and vitamin B12 levels in patients with lung cancer. Exp Oncol. 2015; 37(3):218–222.
  23. Qiang Y, Li Q, Xin Y, et al. Intake of Dietary One-Carbon Metabolism-Related B Vitamins and the Risk of Esophageal Cancer: A Dose-Response Meta-Analysis. Nutrients. 2018;10(7):835. doi: 10.3390/nu10070835 EDN: CXHESG
  24. Xu J, Zhao X, Sun S, et al. Homocysteine and Digestive Tract Cancer Risk: A Dose-Response Meta-Analysis. J Oncol. 2018;2018:3720684. doi: 10.1155/2018/3720684
  25. Wang T, Ren C, Ni J, et al. Genetic Association of Plasma Homocysteine Levels with Gastric Cancer Risk: A Two-Sample Mendelian Randomization Study. Cancer Epidemiol Biomarkers Prev. 2020;29(2):487–492. doi: 10.1158/1055-9965.epi-19-0724 EDN: TNTTJH
  26. Markovsky AV. Polymorphism of folate metabolism genes and malignant diseases. The Transbaikalian Medical Bulletin. 2018;(1):164–171. EDN: YVPBWL
  27. Xu W, Cheng Y, Zhu H. Evaluation of an Association of Blood Homocysteine Levels With Gastric Cancer Risk From 27 Case-Control Studies. Medicine (Baltimore). 2016;95(20):e3700. doi: 10.1097/md.0000000000003700 EDN: YCYIYZ
  28. Lajous M, Lazcano–Ponce E, Hernandez–Avila M, et al. Folate, vitamin B(6), and vitamin B(12) intake and the risk of breast cancer among Mexican women. Cancer Epidemiol Biomarkers Prev. 2006;15(3):443–448. doi: 10.1158/1055-9965.epi-05-0532 EDN: MFNNCJ
  29. Durda K, Kąklewski K, Gupta S, et al. Serum folate concentration and the incidence of lung cancer. PLoS One. 2017;12(5):e0177441. doi: 10.1371/journal.pone.0177441
  30. Chang S-C, Goldstein BY, Mu L, et al. Plasma folate, vitamin B12, and homocysteine and cancers of the esophagus, stomach, and liver in a Chinese population. Nutr Cancer. 2015;67(2):212–223. doi: 10.1080/01635581.2015.989375
  31. Shi Q, Zhang Z, Neumann AS, et al. Case-control analysis of thymidylate synthase polymorphisms and risk of lung cancer. Carcinogenesis. 2005;26(3):649–656. doi: 10.1093/carcin/bgh351 EDN: IMTCTT
  32. Fang Y, Xiao F, An Z, Hao L. Systematic review on the relationship between genetic polymorphisms of methylenetetrahydrofolate reductase and esophageal squamous cell carcinoma. Asian Pac J Cancer Prev. 2011;12(7):1861–1866.
  33. Shi Q, Zhang Z, Li G, et al. Polymorphisms of methionine synthase and methionine synthase reductase and risk of lung cancer: a case-control analysis. Pharmacogenet Genomics. 2005;15(8):547–555. doi: 10.1097/01.fpc.0000170916.96650.70
  34. Aksoy-Sagirli P, Erdenay A, Kaytan-Saglam E, Kizir A. Association of Three Single Nucleotide Polymorphisms in MTR and MTRR Genes with Lung Cancer in a Turkish Population. Genet Test Mol Biomarkers. 2017;21(7):428–432. doi: 10.1089/gtmb.2017.0062
  35. Choi SW, Mason JB. Folate and carcinogenesis: an integrated scheme. J Nutr. 2000;130(2):129–132. doi: 10.1093/jn/130.2.129
  36. Johansson M, Relton C, Ueland PM, et al. Serum B vitamin levels and risk of lung cancer. JAMA. 2010;303(23):2377–2385. doi: 10.1001/jama.2010.808
  37. Zhao T, Gu D, Xu Z, et al. Polymorphism in one-carbon metabolism pathway affects survival of gastric cancer patients: Large and comprehensive study. Oncotarget. 2015;6(11):9564–9576. doi: 10.18632/oncotarget.3259
  38. Yoo J-Y, Kim S-Y, Hwang J-A, et al. Association Study between Folate Pathway Gene Single Nucleotide Polymorphisms and Gastric Cancer in Koreans. Genomics Inform. 2012;10(3):184–193. doi: 10.5808/gi.2012.10.3.184
  39. Brasky TM, White E, Chen C-L. Long-Term, Supplemental, One-Carbon Metabolism-Related Vitamin B Use in Relation to Lung Cancer Risk in the Vitamins and Lifestyle (VITAL) Cohort. J Clin Oncol. 2017;35(30):3440–3448. doi: 10.1200/jco.2017.72.7735
  40. Miranti EH, Stolzenberg–Solomon R, Weinstein SJ, et al. Low vitamin B12 increases risk of gastric cancer: A prospective study of one-carbon metabolism nutrients and risk of upper gastrointestinal tract cancer. Int J Cancer. 2017;141(6):1120–1129. doi: 10.1002/ijc.30809
  41. Vollset SE, Igland J, Jenab M, et al. The association of gastric cancer risk with plasma folate, cobalamin, and methylenetetrahydrofolate reductase polymorphisms in the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol Biomarkers Prev. 2007;16(11):2416–2424. doi: 10.1158/1055-9965.epi-07-0256
  42. Xiao Q, Freedman ND, Ren J, et al. Intakes of folate, methionine, vitamin B6, and vitamin B12 with risk of esophageal and gastric cancer in a large cohort study. Br J Cancer. 2014;110(5):1328–1333. doi: 10.1038/bjc.2014.17
  43. Qin X, Cui Y, Shen L, et al. Folic acid supplementation and cancer risk: a meta-analysis of randomized controlled trials. Int J Cancer. 2013; 133(5):1033–1041. doi: 10.1002/ijc.28038
  44. Stanisławska–Sachadyn A, Borzyszkowska J, Krzemiński M, et al. Folate/homocysteine metabolism and lung cancer risk among smokers. PLoS One. 2019;14(4):e0214462. doi: 10.1371/journal.pone.0214462 EDN: OPFHDR
  45. Ebbing M, Bønaa KH, Nygård O, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA. 2009;302(19):2119–2126. doi: 10.1001/jama.2009.1622
  46. Vannella L, Lahner E, Osborn J, Annibale B. Systematic review: gastric cancer incidence in pernicious anaemia. Aliment Pharmacol Ther. 2013;37(4):375–382. doi: 10.1111/apt.12177
  47. Murphy G, Dawsey SM, Engels EA, et al. Cancer Risk After Pernicious Anemia in the US Elderly Population. Clin Gastroenterol Hepatol. 2015; 13(13):2282-9.e1-4. doi: 10.1016/j.cgh.2015.05.040
  48. Urbanski G, Hamel J-F, Prouveur B, et al. Strength of the Association of Elevated Vitamin B12 and Solid Cancers: An Adjusted Case-Control Study. J Clin Med. 2020;9(2):474. doi: 10.3390/jcm9020474 EDN: VNWUSU
  49. Gospodarczyk A, Marczewski K, Gospodarczyk N, et al. Homocysteine and cardiovascular disease — a current review. Wiad Lek. 2022;75(11 Pt 2):2862–2866. doi: 10.36740/wlek202211224 EDN: WIEIJL
  50. Seliverstov EI, Lobastov KV, Ilyukhin EA, et al. Prevention, Diagnostics and Treatment of Deep Vein Thrombosis. Russian Experts Consensus. Journal of Venous Disorders. 2023;17(3):152–296. doi: 10.17116/flebo202317031152 EDN: RHOTOW
  51. Ohashi Ya, Ikeda M, Kunitoh H, et al. Venous thromboembolism in cancer patients: report of baseline data from the multicentre, prospective Cancer-VTE Registry. Jpn J Clin Oncol. 2020;50(11):1246–1253. doi: 10.1093/jjco/hyaa112 Erratum in: Jpn J Clin Oncol. 2020;50(11):1346. doi: 10.1093/jjco/hyaa160 EDN: BUJSRY
  52. Somova OV, Antukh EA, Varadyan AV, et al. Prakticheskiye rekomendatsii po profilaktike i lecheniyu tromboembolicheskikh oslozhneniy u onkologicheskikh bol'nykh. Malignant Tumours. 2022;12(3s2):159–170. (In Russ.) doi: 10.18027/2224-5057-2022-12-3s2-159-170 EDN: IGQAUH
  53. Muñoz Martín AJ, Ortega I, Font C, et al. Multivariable clinical-genetic risk model for predicting venous thromboembolic events in patients with cancer. Br J Cancer. 2018;118(8):1056–1061. doi: 10.1038/s41416-018-0027-8 EDN: IYYASW
  54. Kulikova AN, Tonkacheva AA. Risk factors for developing thrombo-embolic complications in oncological patients (a literature review). Angiology and Vascular Surgery. 2022;28(4):119–125. doi: 10.33029/1027-6661-2022-28-4-119-125 EDN: GYWCFF
  55. Puurunen MK, Gona PN, Larson MG, et al. Epidemiology of venous thromboembolism in the Framingham Heart Study. Thromb Res. 2016; 145:27–33. doi: 10.1016/j.thromres.2016.06.033
  56. Walker AJ, Card TR, West J, et al. Incidence of venous thrombo-embolism in patients with cancer — a cohort study using linked United Kingdom databases. Eur J Cancer. 2013;49(6):1404–1413. doi: 10.1016/j.ejca.2012.10.021 EDN: TEZVAP
  57. Gran OV, Smit EN, Brækkan SK, et al. Joint effects of cancer and variants in the factor 5 gene on the risk of venous thromboembolism. Haematologica. 2016; 101(9):1046–1053. doi: 10.3324/haematol.2016.147405
  58. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood. 2013;122(10):1712–1723. doi: 10.1182/blood-2013-04-460121 EDN: OJDFFW
  59. Khorana AA, Carrier M, Garcia DA, Lee AY. Guidance for the prevention and treatment of cancer-associated venous thromboembolism. J Thromb Thrombolysis. 2016;41(1):81–91. doi: 10.1007/s11239-015-1313-4 EDN: WOOIGZ
  60. Königsbrügge O, Pabinger I, Ay C. Risk factors for venous thromboembolism in cancer: novel findings from the Vienna Cancer and Thrombosis Study (CATS). Thromb Res. 2014;133(Suppl 2):S39–S43. doi: 10.1016/s0049-3848(14)50007-2 EDN: IQIYVT
  61. Pabinger I, Thaler J, Ay C. Biomarkers for prediction of venous thromboembolism in cancer. Blood. 2013;122(12):2011–2018. doi: 10.1182/blood-2013-04-460147 EDN: SQTFQP
  62. Watson HG, Keeling DM, Laffan M, et al. Guideline on aspects of cancer-related venous thrombosis. Br J Haematol. 2015;170(5):640–648. doi: 10.1111/bjh.13556
  63. Horowitz N, Brenner B. Thrombophilia and cancer. Pathophysiol Haemost Thromb. 2008;36(3–4):131–136. doi: 10.1159/000175151 EDN: YAULBN
  64. Makatsariya AD, Vorob'yev AV. Problemy trombofilii i trombozov u onkologicheskikh bol'nykh. Effektivnaya Farmakoterapiya. 2008;(6):10–21. (In Russ.) EDN: TCGYAD
  65. Ludwig RJ, Alban S, Bistrian R, et al. The ability of different forms of heparins to suppress P-selectin function in vitro correlates to their inhibitory capacity on bloodborne metastasis in vivo. Thromb Haemost. 2006;95(3):535–540. doi: 10.1160/th05-07-0515
  66. Sideras K, Schaefer PL, Okuno SH, et al. Low-molecular-weight heparin in patients with advanced cancer: a phase 3 clinical trial. Mayo Clin Proc. 2006;81(6):758–767. doi: 10.4065/81.6.758
  67. Gatt A, Makris A, Cladd H, et al. Hyperhomocysteinemia in women with advanced breast cancer. Int J Lab Hematol. 2007;29(6):421–425. doi: 10.1111/j.1751-553x.2007.00907.x
  68. Smith AD, Kim Y-I, Refsum H. Is folic acid good for everyone? Am J Clin Nutr. 2008;87(3):517–533. doi: 10.1093/ajcn/87.3.517

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Homocysteine metabolism: MTHFR — methylenetetrahydrofolate reductase.

Download (60KB)
Indexing metadata

Copyright (c) 2025 Eco-Vector

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
 


Согласие на обработку персональных данных с помощью сервиса «Яндекс.Метрика»

1. Я (далее – «Пользователь» или «Субъект персональных данных»), осуществляя использование сайта https://journals.rcsi.science/ (далее – «Сайт»), подтверждая свою полную дееспособность даю согласие на обработку персональных данных с использованием средств автоматизации Оператору - федеральному государственному бюджетному учреждению «Российский центр научной информации» (РЦНИ), далее – «Оператор», расположенному по адресу: 119991, г. Москва, Ленинский просп., д.32А, со следующими условиями.

2. Категории обрабатываемых данных: файлы «cookies» (куки-файлы). Файлы «cookie» – это небольшой текстовый файл, который веб-сервер может хранить в браузере Пользователя. Данные файлы веб-сервер загружает на устройство Пользователя при посещении им Сайта. При каждом следующем посещении Пользователем Сайта «cookie» файлы отправляются на Сайт Оператора. Данные файлы позволяют Сайту распознавать устройство Пользователя. Содержимое такого файла может как относиться, так и не относиться к персональным данным, в зависимости от того, содержит ли такой файл персональные данные или содержит обезличенные технические данные.

3. Цель обработки персональных данных: анализ пользовательской активности с помощью сервиса «Яндекс.Метрика».

4. Категории субъектов персональных данных: все Пользователи Сайта, которые дали согласие на обработку файлов «cookie».

5. Способы обработки: сбор, запись, систематизация, накопление, хранение, уточнение (обновление, изменение), извлечение, использование, передача (доступ, предоставление), блокирование, удаление, уничтожение персональных данных.

6. Срок обработки и хранения: до получения от Субъекта персональных данных требования о прекращении обработки/отзыва согласия.

7. Способ отзыва: заявление об отзыве в письменном виде путём его направления на адрес электронной почты Оператора: info@rcsi.science или путем письменного обращения по юридическому адресу: 119991, г. Москва, Ленинский просп., д.32А

8. Субъект персональных данных вправе запретить своему оборудованию прием этих данных или ограничить прием этих данных. При отказе от получения таких данных или при ограничении приема данных некоторые функции Сайта могут работать некорректно. Субъект персональных данных обязуется сам настроить свое оборудование таким способом, чтобы оно обеспечивало адекватный его желаниям режим работы и уровень защиты данных файлов «cookie», Оператор не предоставляет технологических и правовых консультаций на темы подобного характера.

9. Порядок уничтожения персональных данных при достижении цели их обработки или при наступлении иных законных оснований определяется Оператором в соответствии с законодательством Российской Федерации.

10. Я согласен/согласна квалифицировать в качестве своей простой электронной подписи под настоящим Согласием и под Политикой обработки персональных данных выполнение мною следующего действия на сайте: https://journals.rcsi.science/ нажатие мною на интерфейсе с текстом: «Сайт использует сервис «Яндекс.Метрика» (который использует файлы «cookie») на элемент с текстом «Принять и продолжить».