Higher vitamin B6 status is associated with improved survival among patients with stage I-III colorectal cancer

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

doi:10.1093/ajcn/nqac090

Higher vitamin B6 status is associated with improved survival among patients with stage I-III colorectal cancer

Andreana N Holowatyj, Jennifer Ose, Biljana Gigic, Tengda Lin, Arve Ulvik, Anne J M R Geijsen, Stefanie Brezina, Rama Kiblawi, Eline H van Roekel, Andreas Baierl, Jürgen Böhm, Martijn J L Bours, Hermann Brenner, Stéphanie O Breukink, Jenny Chang-Claude, Johannes H W de Wilt, William M Grady, Thomas Grünberger, Tanja Gumpenberger, Esther HerpelMichael Hoffmeister, Eric T P Keulen, Dieuwertje E Kok, Janna L Koole, Katharina Kosma, Ewout A Kouwenhoven, Gry Kvalheim, Christopher I Li, Peter Schirmacher, Petra Schrotz-King, Marie C Singer, Fränzel J B van Duijnhoven, Henk K van Halteren, Kathy Vickers, F Jeroen Vogelaar, Christy A Warby, Evertine Wesselink, Per M Ueland, Alexis B Ulrich, Martin Schneider, Nina Habermann, Ellen Kampman, Matty P Weijenberg, Andrea Gsur, Cornelia M Ulrich^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Background Folate-mediated 1-carbon metabolism requires several nutrients, including vitamin B6. Circulating biomarker concentrations indicating high vitamin B6 status are associated with a reduced risk of colorectal cancer (CRC). However, little is known about the effect of B6 status in relation to clinical outcomes in CRC patients. Objectives We investigated survival outcomes in relation to vitamin B6 status in prospectively followed CRC patients. Methods A total of 2031 patients with stage I-III CRC participated in 6 prospective patient cohorts in the international FOCUS (folate-dependent 1-carbon metabolism in colorectal cancer recurrence and survival) Consortium. Preoperative blood samples were used to measure vitamin B6 status by the direct marker pyridoxal 5 '-phosphate (PLP), as well as the functional marker HK-ratio (HKr)[3 '-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3 '-hydroxy anthranilic acid + anthranilic acid)]. Using Cox proportional hazards regression, we examined associations of vitamin B6 status with overall survival (OS), disease-free survival (DFS), and risk of recurrence, adjusted for patient age, sex, circulating creatinine concentrations, tumor site, stage, and cohort. Results After a median follow-up of 3.2 y for OS, higher preoperative vitamin B6 status as assessed by PLP and the functional marker HKr was associated with 16-32% higher all-cause and disease-free survival, although there was no significant association with disease recurrence (doubling in PLP concentration: HROS, 0.68; 95% CI: 0.59, 0.79; HRDFS, 0.84; 95% CI: 0.75, 0.94; HRRecurrence, 0.96; 95% CI: 0.84, 1.09; HKr: HROS, 2.04; 95% CI: 1.67, 2.49; HRDFS, 1.56; 95% CI: 1.31, 1.85; HRRecurrence, 1.21; 95% CI: 0.96,1. 52). The association of PLP with improved OS was consistent across colorectal tumor site (right-sided colon: HROS, 0.75; 95% CI: 0.59, 0.96; left-sided colon: HROS, 0.71; 95% CI: 0.55, 0.92; rectosigmoid junction and rectum: HROS, 0.61; 95% CI: 0.47, 0.78). Conclusion Higher preoperative vitamin B6 status is associated with improved OS among stage I-III CRC patients.

Original language	English
Pages (from-to)	303-313
Number of pages	11
Journal	American Journal of Clinical Nutrition
Volume	116
Issue number	2
Early online date	8 Apr 2022
DOIs	https://doi.org/10.1093/ajcn/nqac090
Publication status	Published - 4 Aug 2022

Keywords

B VITAMINS
BIOMARKERS
FOLATE
FOLIC-ACID
HEALTH
HKr
INFLAMMATION
MORTALITY
ONE-CARBON METABOLISM
PAR
PLP
QUALITY-OF-LIFE
RISK
colon cancer
colorectal cancer
one-carbon metabolism
rectal cancer
recurrence
survivorship
vitamin B6

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Holowatyj, A. N., Ose, J., Gigic, B., Lin, T., Ulvik, A., Geijsen, A. J. M. R., Brezina, S., Kiblawi, R., van Roekel, E. H., Baierl, A., Böhm, J., Bours, M. J. L., Brenner, H., Breukink, S. O., Chang-Claude, J., de Wilt, J. H. W., Grady, W. M., Grünberger, T., Gumpenberger, T., ... Ulrich, C. M. (2022). Higher vitamin B6 status is associated with improved survival among patients with stage I-III colorectal cancer. American Journal of Clinical Nutrition, 116(2), 303-313. https://doi.org/10.1093/ajcn/nqac090

@article{539de96718fb4aa4a712533d797b4064,

title = "Higher vitamin B6 status is associated with improved survival among patients with stage I-III colorectal cancer",

abstract = "Background Folate-mediated 1-carbon metabolism requires several nutrients, including vitamin B6. Circulating biomarker concentrations indicating high vitamin B6 status are associated with a reduced risk of colorectal cancer (CRC). However, little is known about the effect of B6 status in relation to clinical outcomes in CRC patients. Objectives We investigated survival outcomes in relation to vitamin B6 status in prospectively followed CRC patients. Methods A total of 2031 patients with stage I-III CRC participated in 6 prospective patient cohorts in the international FOCUS (folate-dependent 1-carbon metabolism in colorectal cancer recurrence and survival) Consortium. Preoperative blood samples were used to measure vitamin B6 status by the direct marker pyridoxal 5 '-phosphate (PLP), as well as the functional marker HK-ratio (HKr)[3 '-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3 '-hydroxy anthranilic acid + anthranilic acid)]. Using Cox proportional hazards regression, we examined associations of vitamin B6 status with overall survival (OS), disease-free survival (DFS), and risk of recurrence, adjusted for patient age, sex, circulating creatinine concentrations, tumor site, stage, and cohort. Results After a median follow-up of 3.2 y for OS, higher preoperative vitamin B6 status as assessed by PLP and the functional marker HKr was associated with 16-32% higher all-cause and disease-free survival, although there was no significant association with disease recurrence (doubling in PLP concentration: HROS, 0.68; 95% CI: 0.59, 0.79; HRDFS, 0.84; 95% CI: 0.75, 0.94; HRRecurrence, 0.96; 95% CI: 0.84, 1.09; HKr: HROS, 2.04; 95% CI: 1.67, 2.49; HRDFS, 1.56; 95% CI: 1.31, 1.85; HRRecurrence, 1.21; 95% CI: 0.96,1. 52). The association of PLP with improved OS was consistent across colorectal tumor site (right-sided colon: HROS, 0.75; 95% CI: 0.59, 0.96; left-sided colon: HROS, 0.71; 95% CI: 0.55, 0.92; rectosigmoid junction and rectum: HROS, 0.61; 95% CI: 0.47, 0.78). Conclusion Higher preoperative vitamin B6 status is associated with improved OS among stage I-III CRC patients.",

keywords = "B VITAMINS, BIOMARKERS, FOLATE, FOLIC-ACID, HEALTH, HKr, INFLAMMATION, MORTALITY, ONE-CARBON METABOLISM, PAR, PLP, QUALITY-OF-LIFE, RISK, colon cancer, colorectal cancer, one-carbon metabolism, rectal cancer, recurrence, survivorship, vitamin B6",

author = "Holowatyj, {Andreana N} and Jennifer Ose and Biljana Gigic and Tengda Lin and Arve Ulvik and Geijsen, {Anne J M R} and Stefanie Brezina and Rama Kiblawi and {van Roekel}, {Eline H} and Andreas Baierl and J{\"u}rgen B{\"o}hm and Bours, {Martijn J L} and Hermann Brenner and Breukink, {St{\'e}phanie O} 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 Keulen, {Eric T P} and Kok, {Dieuwertje E} and Koole, {Janna L} and Katharina Kosma and Kouwenhoven, {Ewout A} and Gry Kvalheim and Li, {Christopher I} and Peter Schirmacher and Petra Schrotz-King and Singer, {Marie C} and {van Duijnhoven}, {Fr{\"a}nzel J B} and {van Halteren}, {Henk K} and Kathy Vickers and Vogelaar, {F Jeroen} and Warby, {Christy A} and Evertine Wesselink and Ueland, {Per M} and Ulrich, {Alexis B} and Martin Schneider and Nina Habermann and Ellen Kampman and Weijenberg, {Matty P} and Andrea Gsur and Ulrich, {Cornelia M}",

note = "{\textcopyright} The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.",

year = "2022",

month = aug,

day = "4",

doi = "10.1093/ajcn/nqac090",

language = "English",

volume = "116",

pages = "303--313",

journal = "American Journal of Clinical Nutrition",

issn = "0002-9165",

publisher = "Elsevier Inc.",

number = "2",

}

Holowatyj, AN, Ose, J, Gigic, B, Lin, T, Ulvik, A, Geijsen, AJMR, Brezina, S, Kiblawi, R, van Roekel, EH, Baierl, A, Böhm, J, Bours, MJL, Brenner, H, Breukink, SO, Chang-Claude, J, de Wilt, JHW, Grady, WM, Grünberger, T, Gumpenberger, T, Herpel, E, Hoffmeister, M, Keulen, ETP, Kok, DE, Koole, JL, Kosma, K, Kouwenhoven, EA, Kvalheim, G, Li, CI, Schirmacher, P, Schrotz-King, P, Singer, MC, van Duijnhoven, FJB, van Halteren, HK, Vickers, K, Vogelaar, FJ, Warby, CA, Wesselink, E, Ueland, PM, Ulrich, AB, Schneider, M, Habermann, N, Kampman, E, Weijenberg, MP, Gsur, A & Ulrich, CM 2022, 'Higher vitamin B6 status is associated with improved survival among patients with stage I-III colorectal cancer', American Journal of Clinical Nutrition, vol. 116, no. 2, pp. 303-313. https://doi.org/10.1093/ajcn/nqac090

TY - JOUR

T1 - Higher vitamin B6 status is associated with improved survival among patients with stage I-III colorectal cancer

AU - Holowatyj, Andreana N

AU - Ose, Jennifer

AU - Gigic, Biljana

AU - Lin, Tengda

AU - Ulvik, Arve

AU - Geijsen, Anne J M R

AU - Brezina, Stefanie

AU - Kiblawi, Rama

AU - van Roekel, Eline H

AU - Baierl, Andreas

AU - Böhm, Jürgen

AU - Bours, Martijn J L

AU - Brenner, Hermann

AU - Breukink, Stéphanie O

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 - Keulen, Eric T P

AU - Kok, Dieuwertje E

AU - Koole, Janna L

AU - Kosma, Katharina

AU - Kouwenhoven, Ewout A

AU - Kvalheim, Gry

AU - Li, Christopher I

AU - Schirmacher, Peter

AU - Schrotz-King, Petra

AU - Singer, Marie C

AU - van Duijnhoven, Fränzel J B

AU - van Halteren, Henk K

AU - Vickers, Kathy

AU - Vogelaar, F Jeroen

AU - Warby, Christy A

AU - Wesselink, Evertine

AU - Ueland, Per M

AU - Ulrich, Alexis B

AU - Schneider, Martin

AU - Habermann, Nina

AU - Kampman, Ellen

AU - Weijenberg, Matty P

AU - Gsur, Andrea

AU - Ulrich, Cornelia M

PY - 2022/8/4

Y1 - 2022/8/4

N2 - Background Folate-mediated 1-carbon metabolism requires several nutrients, including vitamin B6. Circulating biomarker concentrations indicating high vitamin B6 status are associated with a reduced risk of colorectal cancer (CRC). However, little is known about the effect of B6 status in relation to clinical outcomes in CRC patients. Objectives We investigated survival outcomes in relation to vitamin B6 status in prospectively followed CRC patients. Methods A total of 2031 patients with stage I-III CRC participated in 6 prospective patient cohorts in the international FOCUS (folate-dependent 1-carbon metabolism in colorectal cancer recurrence and survival) Consortium. Preoperative blood samples were used to measure vitamin B6 status by the direct marker pyridoxal 5 '-phosphate (PLP), as well as the functional marker HK-ratio (HKr)[3 '-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3 '-hydroxy anthranilic acid + anthranilic acid)]. Using Cox proportional hazards regression, we examined associations of vitamin B6 status with overall survival (OS), disease-free survival (DFS), and risk of recurrence, adjusted for patient age, sex, circulating creatinine concentrations, tumor site, stage, and cohort. Results After a median follow-up of 3.2 y for OS, higher preoperative vitamin B6 status as assessed by PLP and the functional marker HKr was associated with 16-32% higher all-cause and disease-free survival, although there was no significant association with disease recurrence (doubling in PLP concentration: HROS, 0.68; 95% CI: 0.59, 0.79; HRDFS, 0.84; 95% CI: 0.75, 0.94; HRRecurrence, 0.96; 95% CI: 0.84, 1.09; HKr: HROS, 2.04; 95% CI: 1.67, 2.49; HRDFS, 1.56; 95% CI: 1.31, 1.85; HRRecurrence, 1.21; 95% CI: 0.96,1. 52). The association of PLP with improved OS was consistent across colorectal tumor site (right-sided colon: HROS, 0.75; 95% CI: 0.59, 0.96; left-sided colon: HROS, 0.71; 95% CI: 0.55, 0.92; rectosigmoid junction and rectum: HROS, 0.61; 95% CI: 0.47, 0.78). Conclusion Higher preoperative vitamin B6 status is associated with improved OS among stage I-III CRC patients.

AB - Background Folate-mediated 1-carbon metabolism requires several nutrients, including vitamin B6. Circulating biomarker concentrations indicating high vitamin B6 status are associated with a reduced risk of colorectal cancer (CRC). However, little is known about the effect of B6 status in relation to clinical outcomes in CRC patients. Objectives We investigated survival outcomes in relation to vitamin B6 status in prospectively followed CRC patients. Methods A total of 2031 patients with stage I-III CRC participated in 6 prospective patient cohorts in the international FOCUS (folate-dependent 1-carbon metabolism in colorectal cancer recurrence and survival) Consortium. Preoperative blood samples were used to measure vitamin B6 status by the direct marker pyridoxal 5 '-phosphate (PLP), as well as the functional marker HK-ratio (HKr)[3 '-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3 '-hydroxy anthranilic acid + anthranilic acid)]. Using Cox proportional hazards regression, we examined associations of vitamin B6 status with overall survival (OS), disease-free survival (DFS), and risk of recurrence, adjusted for patient age, sex, circulating creatinine concentrations, tumor site, stage, and cohort. Results After a median follow-up of 3.2 y for OS, higher preoperative vitamin B6 status as assessed by PLP and the functional marker HKr was associated with 16-32% higher all-cause and disease-free survival, although there was no significant association with disease recurrence (doubling in PLP concentration: HROS, 0.68; 95% CI: 0.59, 0.79; HRDFS, 0.84; 95% CI: 0.75, 0.94; HRRecurrence, 0.96; 95% CI: 0.84, 1.09; HKr: HROS, 2.04; 95% CI: 1.67, 2.49; HRDFS, 1.56; 95% CI: 1.31, 1.85; HRRecurrence, 1.21; 95% CI: 0.96,1. 52). The association of PLP with improved OS was consistent across colorectal tumor site (right-sided colon: HROS, 0.75; 95% CI: 0.59, 0.96; left-sided colon: HROS, 0.71; 95% CI: 0.55, 0.92; rectosigmoid junction and rectum: HROS, 0.61; 95% CI: 0.47, 0.78). Conclusion Higher preoperative vitamin B6 status is associated with improved OS among stage I-III CRC patients.

KW - B VITAMINS

KW - BIOMARKERS

KW - FOLATE

KW - FOLIC-ACID

KW - HEALTH

KW - HKr

KW - INFLAMMATION

KW - MORTALITY

KW - ONE-CARBON METABOLISM

KW - PAR

KW - PLP

KW - QUALITY-OF-LIFE

KW - RISK

KW - colon cancer

KW - colorectal cancer

KW - one-carbon metabolism

KW - rectal cancer

KW - recurrence

KW - survivorship

KW - vitamin B6

U2 - 10.1093/ajcn/nqac090

DO - 10.1093/ajcn/nqac090

M3 - Article

C2 - 35394006

SN - 0002-9165

VL - 116

SP - 303

EP - 313

JO - American Journal of Clinical Nutrition

JF - American Journal of Clinical Nutrition

IS - 2

ER -