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Methylenetetrahydrofolate reductase (MTHFR) and breast cancer risk: a nested-case-control study and a pooled meta-analysis

  • Epidemiology
  • Published:
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Abstract

Background

A reduced activity of methylenetetrahydrofolate reductase (MTHFR) due to frequent C677T polymorphism affects DNA synthesis, repair and methylation and may be implicated in breast cancer risk.

Methods

We conducted a nested case-control study within a phase III prevention trial of tamoxifen. After a median follow-up of 81.2 months, 79 of the 5,408 hysterectomised women aged 35–70 years, who had received either tamoxifen 20 mg/day or placebo for 5 years, developed breast cancer. A total of 46 breast cancer cases and 80 unaffected controls matched to treatment allocation, years from randomization (±2 years) and age at randomization (±5 years), underwent genotyping for MTHFR C677T polymorphism using real time PCR.

Results

The MTHFR 677 genotype frequencies for CC, CT, TT in breast cancer cases were 30%, 44% and 26%, respectively, and 35%, 51%, 14% in controls. We observed a borderline significant odds ratio of 2.51 (95% CI, 0.96–6.55) of breast cancer in subjects with 677TT genotype, with no further association after stratifying for age and treatment group. A meta-analysis of 18 studies, including our own, showed an increased risk of breast cancer in premenopausal women with 677TT genotype, with an odds ratio of 1.42 (95% CI, 1.02–1.98).

Conclusions

Our study lends support to a positive association between the MTHFR variant homozygous allele 677TT and breast cancer risk. Additional studies are warranted to provide further insight into the role of folate metabolism deficiency and breast cancer.

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Acknowledgements

We acknowledge the support of a FIRC (Fondazione Italiana Ricerca sul Cancro) fellowship to Debora Macis, grants from AICF (American Italian Cancer Foundation), AIRC (Associazione Italiana Ricerca sul Cancro) and LILT (Lega Italiana Lotta Tumori).

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Authors and Affiliations

  1. Division of Chemoprevention, European Institute of Oncology, Milan, Italy

    Debora Macis, Harriet Johansson, Bernardo Bonanni & Andrea Decensi

  2. Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy

    Patrick Maisonneuve, Edoardo Botteri, Simona Iodice & Barbara Santillo

  3. Niguarda Hospital, Milan, Italy

    Silvana Penco

  4. Ospedale San Camillo Forlanini, Rome, Italy

    Giacomo Gucciardo

  5. Istituto per lo Studio e la Cura dei Tumori “Fondazione Pascale”, Naples, Italy

    Giuseppe D’Aiuto

  6. Centro per lo Studio e la Prevenzione Oncologica, Florence, Italy

    Marco Rosselli del Turco

  7. Ospedale G.B. Morgani, Forli, Italy

    Marinella Amadori

  8. Fondazione Maugeri, Pavia, Italy

    Alberto Costa

  9. SC Oncologia Medica e Preventiva, E.O. Ospedali Galliera, Mura delle Cappuccine 14, 16128, Genoa, Italy

    Andrea Decensi

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  1. Debora Macis
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  2. Patrick Maisonneuve
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Corresponding author

Correspondence to Andrea Decensi.

Appendix

Appendix

The Italian Tamoxifen Study Group also includes the following physicians and scientists who contributed to this trial:

Ambulatorio Raphael, Calcinato: A. Ferrari

Associazione Life per la prevenzione e la cura dei Tumori, Vigevano: E. Chiesa; P. Gallotti

Azienda Ospedaliera San Paolo, Milano: S. Bruno; G. Pardi; M. Podda

Casa di Cura “Villa Igea”, Acqui Terme: G. Bocchiotti

Casa di Cura “La Vialarda”, Biella: M. Valentini; P. Vallivero

Casa di Cura Citta’ di Bra, Bra: F. Monasterolo

Centro de Referencia da Saude da Mulher, Sao Paulo: A. Barros; F. Laginha

Centro Diagnostico Italiano, Milano: R. Agresti

Centro Oncologico, Trieste: S. Milani

Centro per lo Studio e la Prevenzione Oncologica, Firenze: MG. Muraca; M. Rosselli del Turco

Centro Regionale di Riferimento Oncologico, Aviano: MA. Pizzichetta; A. Veronesi

Centro Tumori, Roma: P. Pagni

Clinica “Mater Domini”, Castellanza: P. Carnaghi; E. Giorgetti

Clinica Ortopedica, Monza: G. Peretti

Comitato Prevenzione Tumori al Seno, Milano: G. Scaltrini; B. Sorrentino R. Travaglini

Consultorio familiare Mirandola, Mirandola: R. Guidetti

Ematologia Clinica e del Lavoro, Milano: P.M. Mannucci

Fondazione Maugeri, Pavia: G. Bernardo; A. Costa

Fondazione Monzino, Milano: M. Guazzi; A. Salvioni

Fundacion de la ESO, Buenos Aires: A. Rancati

Hospital da PUCRS, Porto Alegre: A. Frasson

Istituto di Oncologia “F. Addarii”, Bologna: A. Fini; C. Maltoni

Istituto Europeo di Oncologia, Milano: B. Bazolli; B. Bonanni; P. Boyle; E. Cassano; A. Decensi; G. Farante; A. Guerrieri-Gonzaga; A. Luini; P. Maisonneuve; C. Robertson; N. Rotmensz; B. Santillo; P. Veronesi; U. Veronesi; G. Viale

Istituto Oncologico, Bari/Bisceglie: M. De Liso; F. Schittuli

Istituto per lo Studio e la Cura dei Tumori, Napoli: G. D’Aiuto; J. Bryce; P. Oliviero

Istituto Provinciale per la Maternita’, Milano: R. Rocci

Lega Italiana per la Lotta contro i Tumori, Como: L. Bombelli

Lega Italiana per la Lotta contro i Tumori, Milano: G. Ravasi

Lega Italiana per la Lotta contro i Tumori, Vicenza: M. Gulisano; F. Lovison; P. Maggi

Mario Negri Sud, Chietti: E. Mari

Memorial Sloan Kettering, New York: V. Sacchini

Ospedale “Caduti Bollatesi”, Bollate: G. Dossena

Ospedale “Mariano Santo”, Cosenza: S. Conforti; P. Pellegrino

Ospedale Civile di Gorizia, Gorizia: M. Zottar

Ospedale Civile Maggiore, Verona: S. Modena; A.M. Molino

Ospedale Civile, Portomagiore: B. Lenzi

Ospedale di Arezzo, Arezzo: P. Ghezzi

Ospedale di Cernusco sul Naviglio, Cernusco sul Naviglio: G. Luvaro; E. Schiatti

Ospedale di Circolo, Varese: N. Donadello

Ospedale di Gravedona e Sondrio, Gravedona: G. Baratelli; D. Bettega

Ospedale di Legnago, Legnago: F. Lonardi

Ospedale di Lodi, Lodi: M. Luerti

Ospedale di Morbegno, Morbegno: L. Della Torre; L. Tabacchi

Ospedale G. Fornaroli, Magenta: G. Zandonini

Ospedale G.B Morgani, Forli’: M. Amadori; D. Casadei

Ospedale Infermi, Rimini: F. Desiderio; A. Ravaioli; M. Scarpellini

Ospedale Oncologico “M. Ascoli”, Palermo: G. Brignone; M. Gugliuzza

Ospedale Regionale di Torrette, Ancona: M. Bonsignori

Ospedale San Camillo-Forlanini, Roma: G. Gucciardo; T. Silipo

Ospedale San Martino, Genova: P. Lorenzi; N. Ragni; M. Valenzano

Ospedale San Timoteo, Termoli: N. Zizza

Ospedale Santa Chiara, Pisa: F. Raia

Ospedale Universitario di Patrasso, Patrasso: E. Cardamakis

Ospedale Val d’Arda, Cortemaggiore: E. Scolari

Policlinico Gemelli, Roma: G. Scambia

Policlinico Monteluce Clinica Chirurgica, Perugia: L. Carli; A. Rulli

Presidio Ospedaliero Macedonio Melloni, Milano: L. Canigiula; A. Magro; A. Zocca

Università degli studi di Padova, Padova: C. Di Maggio; A. Pluchinotta

Università degli studi di Roma “La Sapienza”, Roma: L. D’Amore

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Macis, D., Maisonneuve, P., Johansson, H. et al. Methylenetetrahydrofolate reductase (MTHFR) and breast cancer risk: a nested-case-control study and a pooled meta-analysis. Breast Cancer Res Treat 106, 263–271 (2007). https://doi.org/10.1007/s10549-006-9491-6

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