J Pediatr Genet 2018; 07(03): 103-113
DOI: 10.1055/s-0038-1667037
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Oxidative Stress and Polymorphism in MTHFR SNPs (677 and 1298) in Paternal Sperm DNA is Associated with an Increased Risk of Retinoblastoma in Their Children: A Case–Control Study

Shilpa Bisht
1   Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
Bhavna Chawla
2   Ocular Oncology and Pediatric Ophthalmology Service, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
Rima Dada
1   Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
› Author Affiliations
Funding Financial assistance by the Council of Scientific & Industrial Research (Human Resource Development Group), New Delhi, India, in the form of a Senior Research Fellowship to Ms. Shilpa Bisht is thankfully acknowledged.
Further Information

Publication History

13 March 2018

05 June 2018

Publication Date:
11 July 2018 (online)


Sperm DNA is considered as the most vulnerable to oxidative stress-induced damage that also impairs global sperm DNA methylation leading to sperm-associated pathologies. C677T and A1298C polymorphisms of the methylene tetrahydrofolate reductase (MTHFR) gene affect MTHFR enzyme activity. This study was planned as a case–control study to determine the MTHFR gene polymorphisms in the fathers of children affected with sporadic nonfamilial heritable retinoblastoma in an Indian population. MTHFR polymorphisms for single nucleotide polymorphisms 677 and 1298 were also determined in sporadic nonfamilial heritable retinoblastoma patients to estimate the risk for retinoblastoma development and to evaluate the role of MTHFR in retinoblastoma pathogenesis.

  • References

  • 1 Dimaras H, Kimani K, Dimba EA. , et al. Retinoblastoma. Lancet 2012; 379 (9824): 1436-1446
  • 2 Kivelä T. The Epidemiological Challenge of the Most Frequent Eye Cancer: Retinoblastoma, an Issue of Birth and Death. London: BMJ Publishing Group Ltd; 2009
  • 3 Knudson Jr AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 1971; 68 (04) 820-823
  • 4 Friend SH, Bernards R, Rogelj S. , et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986; 323 (6089): 643-646
  • 5 Cavenee WK, Hansen MF, Nordenskjold M. , et al. Genetic origin of mutations predisposing to retinoblastoma. Science 1985; 228 (4698): 501-503
  • 6 Lohmann DR, Gallie BL. Retinoblastoma: revisiting the model prototype of inherited cancer. Am J Med Genet C Semin Med Genet 2004; ; Aug 15; 129C (01) 23-28
  • 7 Thériault BL, Dimaras H, Gallie BL, Corson TW. The genomic landscape of retinoblastoma: a review. Clin Experiment Ophthalmol 2014; 42 (01) 33-52
  • 8 Shifa JZ, Gezmu AM. Presenting signs of retinoblastoma at a tertiary level teaching hospital in Ethiopia. Pan Afr Med J 2017; 28: 66
  • 9 Zhu XP, Dunn JM, Phillips RA. , et al. Preferential germline mutation of the paternal allele in retinoblastoma. Nature 1989; 340 (6231): 312-313
  • 10 Dryja TP, Mukai S, Petersen R, Rapaport JM, Walton D, Yandell DW. Parental origin of mutations of the retinoblastoma gene. Nature 1989; 339 (6225): 556-558
  • 11 Selhub J. Folate, vitamin B12 and vitamin B6 and one carbon metabolism. J Nutr Health Aging 2002; 6 (01) 39-42
  • 12 Stuppia L, Franzago M, Ballerini P, Gatta V, Antonucci I. Epigenetics and male reproduction: the consequences of paternal lifestyle on fertility, embryo development, and children lifetime health. Clin Epigenetics 2015; 7 (01) 120
  • 13 Gupta N, Sarkar S, David A. , et al. Significant impact of the MTHFR polymorphisms and haplotypes on male infertility risk. PLoS One 2013; 8 (07) e69180
  • 14 Frosst P, Blom HJ, Milos R. , et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10 (01) 111-113
  • 15 Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 1998; 64 (03) 169-172
  • 16 Kelly TL, Neaga OR, Schwahn BC, Rozen R, Trasler JM. Infertility in 5,10-methylenetetrahydrofolate reductase (MTHFR)-deficient male mice is partially alleviated by lifetime dietary betaine supplementation. Biol Reprod 2005; 72 (03) 667-677
  • 17 Mastrangelo D, Loré C, Grasso G. Retinoblastoma as an epigenetic disease: a proposal. J Cancer Ther 2011; 2 (03) 362
  • 18 Urhoj SK, Raaschou-Nielsen O, Hansen AV, Mortensen LH, Andersen PK, Nybo Andersen AM. Advanced paternal age and childhood cancer in offspring: a nationwide register-based cohort study. Int J Cancer 2017; 140 (11) 2461-2472
  • 19 Lambrot R, Xu C, Saint-Phar S. , et al. Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes. Nat Commun 2013; 4: 2889
  • 20 Kumar SB, Chawla B, Bisht S, Yadav RK, Dada R. Tobacco use increases oxidative DNA damage in sperm-possible etiology of childhood cancer. Asian Pac J Cancer Prev 2015; 16 (16) 6967-6972
  • 21 Hoffman M. Hypothesis: hyperhomocysteinemia is an indicator of oxidant stress. Med Hypotheses 2011; 77 (06) 1088-1093
  • 22 Blount BC, Mack MM, Wehr CM. , et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci U S A 1997; 94 (07) 3290-3295
  • 23 Alonso-Aperte E, González MP, Póo-Prieto R, Varela-Moreiras G. Folate status and S-adenosylmethionine/S-adenosylhomocysteine ratio in colorectal adenocarcinoma in humans. Eur J Clin Nutr 2008; 62 (02) 295-298
  • 24 Newman AC, Maddocks ODK. One-carbon metabolism in cancer. Br J Cancer 2017; 116 (12) 1499-1504
  • 25 To KF, Leung WK, Lee TL. , et al. Promoter hypermethylation of tumor-related genes in gastric intestinal metaplasia of patients with and without gastric cancer. Int J Cancer 2002; 102 (06) 623-628
  • 26 Van Tongelen A, Loriot A, De Smet C. Oncogenic roles of DNA hypomethylation through the activation of cancer-germline genes. Cancer Lett 2017; 396: 130-137
  • 27 Ehrlich M. DNA methylation in cancer: too much, but also too little. Oncogene 2002; 21 (35) 5400-5413
  • 28 Chen D, Zhang XR, Zhang Y. , et al. Hypomethylation of repetitive elements in blood leukocyte DNA and risk of gastric lesions in a Chinese population. Cancer Epidemiol 2016; 41: 122-128
  • 29 Aitken RJ, Smith TB, Jobling MS, Baker MA, De Iuliis GN. Oxidative stress and male reproductive health. Asian J Androl 2014; 16 (01) 31-38
  • 30 Valavanidis A, Vlachogianni T, Fiotakis C. 8-hydroxy-2′ -deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesis. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2009; 27 (02) 120-139
  • 31 World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Sperm. Geneva, Switzerland: WHO; 2010
  • 32 Suguna S, Nandal D, Kamble S, Bharatha A, Kunkulol R. Genomic DNA isolation from human whole blood samples by non enzymatic salting out method. Int J Pharm Pharm Sci 2014; 6: 198-199
  • 33 Venkatesh S, Shamsi MB, Dudeja S, Kumar R, Dada R. Reactive oxygen species measurement in neat and washed semen: comparative analysis and its significance in male infertility assessment. Arch Gynecol Obstet 2011; 283 (01) 121-126
  • 34 Evenson DP. Sperm chromatin structure assay (SCSA®). Methods Mol Biol 2013; 927: 147-164
  • 35 Arora RS, Eden TO, Kapoor G. Epidemiology of childhood cancer in India. Indian J Cancer 2009; 46 (04) 264-273
  • 36 Bisht S, Faiq M, Tolahunase M, Dada R. Oxidative stress and male infertility. Nat Rev Urol 2017; 14 (08) 470-485
  • 37 Dada R, Kumar M, Jesudasan R, Fernández JL, Gosálvez J, Agarwal A. Epigenetics and its role in male infertility. J Assist Reprod Genet 2012; 29 (03) 213-223
  • 38 Sharma R, Biedenharn KR, Fedor JM, Agarwal A. Lifestyle factors and reproductive health: taking control of your fertility. Reprod Biol Endocrinol 2013; 11 (01) 66
  • 39 Baccarelli A, Bollati V. Epigenetics and environmental chemicals. Curr Opin Pediatr 2009; 21 (02) 243-251
  • 40 Bunin GR, Li Y, Ganguly A, Meadows AT, Tseng M. Parental nutrient intake and risk of retinoblastoma resulting from new germline RB1 mutation. Cancer Causes Control 2013; 24 (02) 343-355
  • 41 Kumar K, Venkatesh S, Sharma PR, Tiwari PK, Dada R. DAZL 260A > G and MTHFR 677C > T variants in sperm DNA of infertile Indian men. Indian J Biochem Biophys 2011; 48 (06) 422-426
  • 42 Rezgoune M, Chellat D, Abadi N, Satta D. MTHFR A1298C gene polymorphism and the risk of male infertility in Algerian population. Int J Pharm Sci Rev Res 2016; 36 (01) 73-76
  • 43 Bennett-Baker PE, Wilkowski J, Burke DT. Age-associated activation of epigenetically repressed genes in the mouse. Genetics 2003; 165 (04) 2055-2062
  • 44 Sharma R, Agarwal A, Rohra VK, Assidi M, Abu-Elmagd M, Turki RF. Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring. Reprod Biol Endocrinol 2015; 13 (01) 35
  • 45 Conti SL, Eisenberg ML. Paternal aging and increased risk of congenital disease, psychiatric disorders, and cancer. Asian J Androl 2016; 18 (03) 420-424
  • 46 Duthie SJ. Folic acid deficiency and cancer: mechanisms of DNA instability. Br Med Bull 1999; 55 (03) 578-592
  • 47 Fenech MF. Dietary reference values of individual micronutrients and nutriomes for genome damage prevention: current status and a road map to the future. Am J Clin Nutr 2010; 91 (05) 1438S-1454S
  • 48 Heijmans BT, Boer JM, Suchiman HE. , et al. A common variant of the methylenetetrahydrofolate reductase gene (1p36) is associated with an increased risk of cancer. Cancer Res 2003; 63 (06) 1249-1253
  • 49 Xu X, Chen J. One-carbon metabolism and breast cancer: an epidemiological perspective. J Genet Genomics 2009; 36 (04) 203-214
  • 50 Lissowska J, Gaudet MM, Brinton LA. , et al. Genetic polymorphisms in the one-carbon metabolism pathway and breast cancer risk: a population-based case-control study and meta-analyses. Int J Cancer 2007; 120 (12) 2696-2703
  • 51 Stern LL, Mason JB, Selhub J, Choi SW. Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene. Cancer Epidemiol Biomarkers Prev 2000; 9 (08) 849-853
  • 52 de Lima ELS, da Silva VC, da Silva HDA. , et al. MTR polymorphic variant A2756G and retinoblastoma risk in Brazilian children. Pediatr Blood Cancer 2010; 54 (07) 904-908
  • 53 Soleimani E, Saliminejad K, Akbari MT, Kamali K, Ahani A. Association study of the common polymorphisms in the folate-methionine pathway with retinoblastoma. Ophthalmic Genet 2016; 37 (04) 384-387
  • 54 Mostowska A, Hozyasz KK, Wojcicki P, Dziegelewska M, Jagodzinski PP. Associations of folate and choline metabolism gene polymorphisms with orofacial clefts. J Med Genet 2010; 47 (12) 809-815
  • 55 Friedman G, Goldschmidt N, Friedlander Y. , et al. A common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocysteine and folate concentrations. J Nutr 1999; 129 (09) 1656-1661