Circulating folate and folic acid concentrations: Associations with colorectal cancer recurrence and survival

Anne J.M.R. Geijsen; Arve Ulvik; Biljana Gigic; Dieuwertje E. Kok; Fränzel J.B. Van Duijnhoven; Andreana N. Holowatyj; Stefanie Brezina; Eline H. Van Roekel; Andreas Baierl; Michael M. Bergmann; Jürgen Böhm; Martijn J.L. Bours; Hermann Brenner; Stéphanie O. Breukink; Mary P. Bronner; Jenny Chang-Claude; Johannes H.W. De Wilt; William M. Grady; Thomas Grünberger; Tanja Gumpenberger; Esther Herpel; Michael Hoffmeister; Lyen C. Huang; Jolanta D. Jedrzkiewicz; Eric T.P. Keulen; Rama Kiblawi; Torsten Kölsch; Janna L. Koole; Katharina Kosma; Ewout A. Kouwenhoven; Flip M. Kruyt; Gry Kvalheim; Christopher I. Li; Tengda Lin; Jennifer Ose; T. Bartley Pickron; Courtney L. Scaife; Peter Schirmacher; Martin A. Schneider; Petra Schrotz-King; Marie C. Singer; Eric R. Swanson; Peter Van Duijvendijk; Henk K. Van Halteren; Moniek Van Zutphen; Kathy Vickers; F. Jeroen Vogelaar; Evertine Wesselink; Nina Habermann; Alexis B. Ulrich; Per M. Ueland; Matty P. Weijenberg; Andrea Gsur; Cornelia M. Ulrich; Ellen Kampman

doi:10.1093/JNCICS/PKAA051

Circulating folate and folic acid concentrations: Associations with colorectal cancer recurrence and survival

Anne J.M.R. Geijsen, Arve Ulvik, Biljana Gigic, Dieuwertje E. Kok, Fränzel J.B. Van Duijnhoven, Andreana N. Holowatyj, Stefanie Brezina, Eline H. Van Roekel, Andreas Baierl, Michael M. Bergmann, Jürgen Böhm, Martijn J.L. Bours, Hermann Brenner, Stéphanie O. Breukink, Mary P. Bronner, Jenny Chang-Claude, Johannes H.W. De Wilt, William M. Grady, Thomas Grünberger, Tanja GumpenbergerEsther Herpel, Michael Hoffmeister, Lyen C. Huang, Jolanta D. Jedrzkiewicz, Eric T.P. Keulen, Rama Kiblawi, Torsten Kölsch, Janna L. Koole, Katharina Kosma, Ewout A. Kouwenhoven, Flip M. Kruyt, Gry Kvalheim, Christopher I. Li, Tengda Lin, Jennifer Ose, T. Bartley Pickron, Courtney L. Scaife, Peter Schirmacher, Martin A. Schneider, Petra Schrotz-King, Marie C. Singer, Eric R. Swanson, Peter Van Duijvendijk, Henk K. Van Halteren, Moniek Van Zutphen, Kathy Vickers, F. Jeroen Vogelaar, Evertine Wesselink, Nina Habermann, Alexis B. Ulrich, Per M. Ueland, Matty P. Weijenberg, Andrea Gsur, Cornelia M. Ulrich, Ellen Kampman

Research output: Contribution to Journal › Review article › Academic › peer-review

Abstract

Background: Folates, including folic acid, may play a dual role in colorectal cancer development. Folate is suggested to be protective in early carcinogenesis but could accelerate growth of premalignant lesions or micrometastases. Whether circulating concentrations of folate and folic acid, measured around time of diagnosis, are associated with recurrence and survival in colorectal cancer patients is largely unknown. Methods: Circulating concentrations of folate, folic acid, and folate catabolites p-aminobenzoylglutamate and p-acetamidobenzoylglutamate were measured by liquid chromatography-tandem mass spectrometry at diagnosis in 2024 stage I-III colorectal cancer patients from European and US patient cohort studies. Multivariable-adjusted Cox proportional hazard models were used to assess associations between folate, folic acid, and folate catabolites concentrations with recurrence, overall survival, and disease-free survival. Results: No statistically significant associations were observed between folate, p-aminobenzoylglutamate, and p-acetamidobenzoylglutamate concentrations and recurrence, overall survival, and disease-free survival, with hazard ratios ranging from 0.92 to 1.16. The detection of folic acid in the circulation (yes or no) was not associated with any outcome. However, among patients with detectable folic acid concentrations (n=296), a higher risk of recurrence was observed for each twofold increase in folic acid (hazard ratio = 1.31, 95% confidence interval = 1.02 to 1.58). No statistically significant associations were found between folic acid concentrations and overall and disease-free survival. Conclusions: Circulating folate and folate catabolite concentrations at colorectal cancer diagnosis were not associated with recurrence and survival. However, caution is warranted for high blood concentrations of folic acid because they may increase the risk of colorectal cancer recurrence.

Original language	English
Article number	pkaa051
Journal	JNCI Cancer Spectrum
Volume	4
Issue number	5
DOIs	https://doi.org/10.1093/JNCICS/PKAA051
Publication status	Published - 2021
Externally published	Yes

Funding

This work was supported by Wereld Kanker Onderzoek Fonds (WKOF) and World Cancer Research Fund International (WCRF International); the World Cancer Research Fund International Regular Grant Programme (WKOF/WCRF, the Netherlands, project no. 2014/1179); Alpe d’Huzes/Dutch Cancer Society (KWF Kankerbestrijding, the Netherlands, project no. UM 2010-4867, UM 2012-5653, UW 2013-5927, UW 2015-7946); ERA-NET on Translational Cancer Research (TRANSCAN/Dutch Cancer Society, the Netherlands, project no. UW 2013-6397, UM 2014-6877); the Netherlands Organization for Health Research and Development (ZonMw, the Netherlands); the Austrian Science Fund (FWF, Austria; project no. I 2104-B26); the Federal Ministry of Education and Research (BMBF, Germany; project no. 01KT1503); The Research Council of Norway (RCN, Norway; project no. 246402/H10); the National Cancer Institute (NCI, United States; project no. R01 CA189184, U01 CA206110, R01 CA207371); the Huntsman Cancer Foundation (HCI, U.S.); the National Institutes of Health (NIH, United States; grant no. P30 CA015704, P30 CA042014, U01 CA152756, R01 CA194663, and R01 CA220004) coordinated by the ERA-NET, JTC 2013 call on Translational Cancer Research (TRANSCAN). In addition, D. E. Kok is supported by a Veni grant (grant no. 016.Veni.188.082) of the Netherlands Organisation for Scientific Research. W. M. Grady is funded by the Fred Hutchinson Cancer Research Center, the Seattle Translational Tumor Research Program, and the Cottrell Family. A. N. Holowatyj was supported by the National Institutes of Health under Ruth L. Kirschstein National Research Service Award from the National Human Genome Research Institute (grant no. T32 HG008962). E. H. van Roekel was financially supported by Wereld Kanker Onderzoek Fonds (WKOF) as part of the World Cancer Research Fund International grant program (grant no. 2016/ 1620). J. L. Koole and M. J. L. Bours were financially This work was supported by Wereld Kanker Onderzoek Fonds (WKOF) and World Cancer Research Fund International (WCRF International); the World Cancer Research Fund International Regular Grant Programme (WKOF/WCRF, the Netherlands, project no. 2014/1179); Alpe d'Huzes/Dutch Cancer Society (KWF Kankerbestrijding, the Netherlands, project no. UM 2010-4867, UM 2012-5653, UW 2013-5927, UW 2015-7946); ERA-NET on Translational Cancer Research (TRANSCAN/Dutch Cancer Society, the Netherlands, project no. UW 2013-6397, UM 2014-6877); the Netherlands Organization for Health Research and Development (ZonMw, the Netherlands); the Austrian Science Fund (FWF, Austria; project no. I 2104-B26); the Federal Ministry of Education and Research (BMBF, Germany; project no. 01KT1503); The Research Council of Norway (RCN, Norway; project no. 246402/H10); the National Cancer Institute (NCI, United States; project no. R01 CA189184, U01 CA206110, R01 CA207371); the Huntsman Cancer Foundation (HCI, U.S.); the National Institutes of Health (NIH, United States; grant no. P30 CA015704, P30 CA042014, U01 CA152756, R01 CA194663, and R01 CA220004) coordinated by the ERA-NET, JTC 2013 call on Translational Cancer Research (TRANSCAN). In addition, D. E. Kok is supported by a Veni grant (grant no. 016.Veni.188.082) of the Netherlands Organisation for Scientific Research. W. M. Grady is funded by the Fred Hutchinson Cancer Research Center, the Seattle Translational Tumor Research Program, and the Cottrell Family. A. N. Holowatyj was supported by the National Institutes of Health under Ruth L. Kirschstein National Research Service Award from the National Human Genome Research Institute (grant no. T32 HG008962). E. H. van Roekel was financially supported by Wereld Kanker Onderzoek Fonds (WKOF) as part of the World Cancer Research Fund International grant program (grant no. 2016/ 1620). J. L. Koole and M. J. L. Bours were financially supported by Kankeronderzoekfonds Limburg as part of Health Foundation Limburg (grant no. 00005739). supported by Kankeronderzoekfonds Limburg as part of Health Foundation Limburg (grant no. 00005739).

Funders	Funder number
ERA-NET on Translational Cancer Research
Seattle Translational Tumor Research Program
TRANSCAN	UM 2014-6877, UW 2013-6397
National Institutes of Health	P30 CA042014, R01 CA194663, P30 CA015704, R01 CA220004, U01 CA152756
National Human Genome Research Institute	00005739, 2016/ 1620, T32 HG008962
National Cancer Institute	R01 CA189184, R01 CA207371, U01 CA206110
Huntsman Cancer Foundation
World Cancer Research Fund International
World Cancer Research Fund	2014/1179
ZonMw
Bundesministerium für Bildung und Forschung	01KT1503
Austrian Science Fund	2104-B26
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
KWF Kankerbestrijding	UM 2012-5653, UM 2010-4867, UW 2013-5927, UW 2015-7946
Norges forskningsråd	246402/H10
Wereld Kanker Onderzoek Fonds

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Geijsen, A. J. M. R., Ulvik, A., Gigic, B., Kok, D. E., Van Duijnhoven, F. J. B., Holowatyj, A. N., Brezina, S., Van Roekel, E. H., Baierl, A., Bergmann, M. M., Böhm, J., Bours, M. J. L., Brenner, H., Breukink, S. O., Bronner, M. P., Chang-Claude, J., De Wilt, J. H. W., Grady, W. M., Grünberger, T., ... Kampman, E. (2021). Circulating folate and folic acid concentrations: Associations with colorectal cancer recurrence and survival. JNCI Cancer Spectrum, 4(5), Article pkaa051. https://doi.org/10.1093/JNCICS/PKAA051

@article{9145b9d9d9ac494b9350052b6367d38b,

title = "Circulating folate and folic acid concentrations: Associations with colorectal cancer recurrence and survival",

abstract = "Background: Folates, including folic acid, may play a dual role in colorectal cancer development. Folate is suggested to be protective in early carcinogenesis but could accelerate growth of premalignant lesions or micrometastases. Whether circulating concentrations of folate and folic acid, measured around time of diagnosis, are associated with recurrence and survival in colorectal cancer patients is largely unknown. Methods: Circulating concentrations of folate, folic acid, and folate catabolites p-aminobenzoylglutamate and p-acetamidobenzoylglutamate were measured by liquid chromatography-tandem mass spectrometry at diagnosis in 2024 stage I-III colorectal cancer patients from European and US patient cohort studies. Multivariable-adjusted Cox proportional hazard models were used to assess associations between folate, folic acid, and folate catabolites concentrations with recurrence, overall survival, and disease-free survival. Results: No statistically significant associations were observed between folate, p-aminobenzoylglutamate, and p-acetamidobenzoylglutamate concentrations and recurrence, overall survival, and disease-free survival, with hazard ratios ranging from 0.92 to 1.16. The detection of folic acid in the circulation (yes or no) was not associated with any outcome. However, among patients with detectable folic acid concentrations (n=296), a higher risk of recurrence was observed for each twofold increase in folic acid (hazard ratio = 1.31, 95% confidence interval = 1.02 to 1.58). No statistically significant associations were found between folic acid concentrations and overall and disease-free survival. Conclusions: Circulating folate and folate catabolite concentrations at colorectal cancer diagnosis were not associated with recurrence and survival. However, caution is warranted for high blood concentrations of folic acid because they may increase the risk of colorectal cancer recurrence.",

author = "Geijsen, {Anne J.M.R.} and Arve Ulvik and Biljana Gigic and Kok, {Dieuwertje E.} and {Van Duijnhoven}, {Fr{\"a}nzel J.B.} and Holowatyj, {Andreana N.} and Stefanie Brezina and {Van Roekel}, {Eline H.} and Andreas Baierl and Bergmann, {Michael M.} and J{\"u}rgen B{\"o}hm and Bours, {Martijn J.L.} and Hermann Brenner and Breukink, {St{\'e}phanie O.} and Bronner, {Mary P.} and Jenny Chang-Claude and {De Wilt}, {Johannes H.W.} and Grady, {William M.} and Thomas Gr{\"u}nberger and Tanja Gumpenberger and Esther Herpel and Michael Hoffmeister and Huang, {Lyen C.} and Jedrzkiewicz, {Jolanta D.} and Keulen, {Eric T.P.} and Rama Kiblawi and Torsten K{\"o}lsch and Koole, {Janna L.} and Katharina Kosma and Kouwenhoven, {Ewout A.} and Kruyt, {Flip M.} and Gry Kvalheim and Li, {Christopher I.} and Tengda Lin and Jennifer Ose and Pickron, {T. Bartley} and Scaife, {Courtney L.} and Peter Schirmacher and Schneider, {Martin A.} and Petra Schrotz-King and Singer, {Marie C.} and Swanson, {Eric R.} and {Van Duijvendijk}, Peter and {Van Halteren}, {Henk K.} and {Van Zutphen}, Moniek and Kathy Vickers and Vogelaar, {F. Jeroen} and Evertine Wesselink and Nina Habermann and Ulrich, {Alexis B.} and Ueland, {Per M.} and Weijenberg, {Matty P.} and Andrea Gsur and Ulrich, {Cornelia M.} and Ellen Kampman",

year = "2021",

doi = "10.1093/JNCICS/PKAA051",

language = "English",

volume = "4",

journal = "JNCI Cancer Spectrum",

issn = "2515-5091",

publisher = "24150509",

number = "5",

}

Geijsen, AJMR, Ulvik, A, Gigic, B, Kok, DE, Van Duijnhoven, FJB, Holowatyj, AN, Brezina, S, Van Roekel, EH, Baierl, A, Bergmann, MM, Böhm, J, Bours, MJL, Brenner, H, Breukink, SO, Bronner, MP, Chang-Claude, J, De Wilt, JHW, Grady, WM, Grünberger, T, Gumpenberger, T, Herpel, E, Hoffmeister, M, Huang, LC, Jedrzkiewicz, JD, Keulen, ETP, Kiblawi, R, Kölsch, T, Koole, JL, Kosma, K, Kouwenhoven, EA, Kruyt, FM, Kvalheim, G, Li, CI, Lin, T, Ose, J, Pickron, TB, Scaife, CL, Schirmacher, P, Schneider, MA, Schrotz-King, P, Singer, MC, Swanson, ER, Van Duijvendijk, P, Van Halteren, HK, Van Zutphen, M, Vickers, K, Vogelaar, FJ, Wesselink, E, Habermann, N, Ulrich, AB, Ueland, PM, Weijenberg, MP, Gsur, A, Ulrich, CM & Kampman, E 2021, 'Circulating folate and folic acid concentrations: Associations with colorectal cancer recurrence and survival', JNCI Cancer Spectrum, vol. 4, no. 5, pkaa051. https://doi.org/10.1093/JNCICS/PKAA051

TY - JOUR

T1 - Circulating folate and folic acid concentrations

T2 - Associations with colorectal cancer recurrence and survival

AU - Geijsen, Anne J.M.R.

AU - Ulvik, Arve

AU - Gigic, Biljana

AU - Kok, Dieuwertje E.

AU - Van Duijnhoven, Fränzel J.B.

AU - Holowatyj, Andreana N.

AU - Brezina, Stefanie

AU - Van Roekel, Eline H.

AU - Baierl, Andreas

AU - Bergmann, Michael M.

AU - Böhm, Jürgen

AU - Bours, Martijn J.L.

AU - Brenner, Hermann

AU - Breukink, Stéphanie O.

AU - Bronner, Mary P.

AU - Chang-Claude, Jenny

AU - De Wilt, Johannes H.W.

AU - Grady, William M.

AU - Grünberger, Thomas

AU - Gumpenberger, Tanja

AU - Herpel, Esther

AU - Hoffmeister, Michael

AU - Huang, Lyen C.

AU - Jedrzkiewicz, Jolanta D.

AU - Keulen, Eric T.P.

AU - Kiblawi, Rama

AU - Kölsch, Torsten

AU - Koole, Janna L.

AU - Kosma, Katharina

AU - Kouwenhoven, Ewout A.

AU - Kruyt, Flip M.

AU - Kvalheim, Gry

AU - Li, Christopher I.

AU - Lin, Tengda

AU - Ose, Jennifer

AU - Pickron, T. Bartley

AU - Scaife, Courtney L.

AU - Schirmacher, Peter

AU - Schneider, Martin A.

AU - Schrotz-King, Petra

AU - Singer, Marie C.

AU - Swanson, Eric R.

AU - Van Duijvendijk, Peter

AU - Van Halteren, Henk K.

AU - Van Zutphen, Moniek

AU - Vickers, Kathy

AU - Vogelaar, F. Jeroen

AU - Wesselink, Evertine

AU - Habermann, Nina

AU - Ulrich, Alexis B.

AU - Ueland, Per M.

AU - Weijenberg, Matty P.

AU - Gsur, Andrea

AU - Ulrich, Cornelia M.

AU - Kampman, Ellen

PY - 2021

Y1 - 2021

N2 - Background: Folates, including folic acid, may play a dual role in colorectal cancer development. Folate is suggested to be protective in early carcinogenesis but could accelerate growth of premalignant lesions or micrometastases. Whether circulating concentrations of folate and folic acid, measured around time of diagnosis, are associated with recurrence and survival in colorectal cancer patients is largely unknown. Methods: Circulating concentrations of folate, folic acid, and folate catabolites p-aminobenzoylglutamate and p-acetamidobenzoylglutamate were measured by liquid chromatography-tandem mass spectrometry at diagnosis in 2024 stage I-III colorectal cancer patients from European and US patient cohort studies. Multivariable-adjusted Cox proportional hazard models were used to assess associations between folate, folic acid, and folate catabolites concentrations with recurrence, overall survival, and disease-free survival. Results: No statistically significant associations were observed between folate, p-aminobenzoylglutamate, and p-acetamidobenzoylglutamate concentrations and recurrence, overall survival, and disease-free survival, with hazard ratios ranging from 0.92 to 1.16. The detection of folic acid in the circulation (yes or no) was not associated with any outcome. However, among patients with detectable folic acid concentrations (n=296), a higher risk of recurrence was observed for each twofold increase in folic acid (hazard ratio = 1.31, 95% confidence interval = 1.02 to 1.58). No statistically significant associations were found between folic acid concentrations and overall and disease-free survival. Conclusions: Circulating folate and folate catabolite concentrations at colorectal cancer diagnosis were not associated with recurrence and survival. However, caution is warranted for high blood concentrations of folic acid because they may increase the risk of colorectal cancer recurrence.

AB - Background: Folates, including folic acid, may play a dual role in colorectal cancer development. Folate is suggested to be protective in early carcinogenesis but could accelerate growth of premalignant lesions or micrometastases. Whether circulating concentrations of folate and folic acid, measured around time of diagnosis, are associated with recurrence and survival in colorectal cancer patients is largely unknown. Methods: Circulating concentrations of folate, folic acid, and folate catabolites p-aminobenzoylglutamate and p-acetamidobenzoylglutamate were measured by liquid chromatography-tandem mass spectrometry at diagnosis in 2024 stage I-III colorectal cancer patients from European and US patient cohort studies. Multivariable-adjusted Cox proportional hazard models were used to assess associations between folate, folic acid, and folate catabolites concentrations with recurrence, overall survival, and disease-free survival. Results: No statistically significant associations were observed between folate, p-aminobenzoylglutamate, and p-acetamidobenzoylglutamate concentrations and recurrence, overall survival, and disease-free survival, with hazard ratios ranging from 0.92 to 1.16. The detection of folic acid in the circulation (yes or no) was not associated with any outcome. However, among patients with detectable folic acid concentrations (n=296), a higher risk of recurrence was observed for each twofold increase in folic acid (hazard ratio = 1.31, 95% confidence interval = 1.02 to 1.58). No statistically significant associations were found between folic acid concentrations and overall and disease-free survival. Conclusions: Circulating folate and folate catabolite concentrations at colorectal cancer diagnosis were not associated with recurrence and survival. However, caution is warranted for high blood concentrations of folic acid because they may increase the risk of colorectal cancer recurrence.

UR - http://www.scopus.com/inward/record.url?scp=85100601722&partnerID=8YFLogxK

U2 - 10.1093/JNCICS/PKAA051

DO - 10.1093/JNCICS/PKAA051

M3 - Review article

SN - 2515-5091

VL - 4

JO - JNCI Cancer Spectrum

JF - JNCI Cancer Spectrum

IS - 5

M1 - pkaa051

ER -

Circulating folate and folic acid concentrations: Associations with colorectal cancer recurrence and survival

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