Andreana N Holowatyj1,2,3, Jennifer Ose1,2, Biljana Gigic4, Tengda Lin1,2, Arve Ulvik5, Anne J M R Geijsen6, Stefanie Brezina7, Rama Kiblawi1,2,8, Eline H van Roekel9, Andreas Baierl10, Jürgen Böhm1,2, Martijn J L Bours9, Hermann Brenner11,12,13, Stéphanie O Breukink14, Jenny Chang-Claude15, Johannes H W de Wilt16, William M Grady17, Thomas Grünberger18, Tanja Gumpenberger7, Esther Herpel19, Michael Hoffmeister12, Eric T P Keulen20, Dieuwertje E Kok6, Janna L Koole9, Katharina Kosma18, Ewout A Kouwenhoven21, Gry Kvalheim5, Christopher I Li22, Peter Schirmacher19, Petra Schrotz-King11, Marie C Singer18, Fränzel J B van Duijnhoven6, Henk K van Halteren23, Kathy Vickers22, F Jeroen Vogelaar24, Christy A Warby1,2, Evertine Wesselink6, Per M Ueland5, Alexis B Ulrich4, Martin Schneider4, Nina Habermann25, Ellen Kampman6, Matty P Weijenberg9, Andrea Gsur7, Cornelia M Ulrich1,2. 1. Huntsman Cancer Institute, Salt Lake City, Utah, USA. 2. Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA. 3. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. 4. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Germany. 5. BEVITAL, Bergen, Norway. 6. Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands. 7. Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria. 8. Medical Faculty, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany. 9. Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, The Netherlands. 10. Department of Statistics and Operations Research, University of Vienna, Austria. 11. Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany. 12. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. 13. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 14. Department of Surgery, GROW School for Oncology and Development Biology, Maastricht University, The Netherlands. 15. Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg Germany. 16. Department of Surgery, Division of Surgical Oncology and Gastrointestinal Surgery, Radboud University Medical Center, The Netherlands. 17. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 18. Department of Surgery, Kaiser Franz Josef Hospital, Vienna, Austria. 19. Institute of Pathology, University of Heidelberg, Germany. 20. Department of Internal Medicine and Gastroenterology, Zuyderland Medical Center, Sittard, The Netherlands. 21. Department of Surgery, Hospital Group Twente ZGT, Almelo, The Netherlands. 22. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 23. Department of Internal Medicine, Admiraal de Ruyter Hospital, Goes, The Netherlands. 24. Department of Surgery, VieCuri Medical Center, Venlo, The Netherlands. 25. Genome Biology, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
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.
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.
Authors: Cornelia M Ulrich; Mary Playdon; Rama Kiblawi; Andreana N Holowatyj; Biljana Gigic; Stefanie Brezina; Anne J M R Geijsen; Jennifer Ose; Tengda Lin; Sheetal Hardikar; Caroline Himbert; Christy A Warby; Jürgen Böhm; Martijn J L Bours; Fränzel J B van Duijnhoven; Tanja Gumpenberger; Dieuwertje E Kok; Janna L Koole; Eline H van Roekel; Petra Schrotz-King; Arve Ulvik; Andrea Gsur; Nina Habermann; Matty P Weijenberg; Per Magne Ueland; Martin Schneider; Alexis Ulrich Journal: Br J Nutr Date: 2020-02-05 Impact factor: 3.718
Authors: Shumin M Zhang; Steven C Moore; Jennifer Lin; Nancy R Cook; JoAnn E Manson; I-Min Lee; Julie E Buring Journal: Am J Epidemiol Date: 2005-12-07 Impact factor: 4.897
Authors: Cornelia M Ulrich; Biljana Gigic; Graham A Colditz; Jane C Figueiredo; William M Grady; Christopher I Li; David Shibata; Erin M Siegel; Adetunji T Toriola; Alexis Ulrich; Jürgen Böhm; Jennifer Ose; Richard Viskochil; Martin Schneider Journal: Cancer Epidemiol Biomarkers Prev Date: 2018-12-06 Impact factor: 4.254
Authors: L Galluzzi; E Vacchelli; J Michels; P Garcia; O Kepp; L Senovilla; I Vitale; G Kroemer Journal: Oncogene Date: 2013-01-21 Impact factor: 9.867
Authors: 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 Journal: JNCI Cancer Spectr Date: 2020-07-07
Authors: Yun Zhu; Hao Wu; Peizhong Peter Wang; Sevtap Savas; Jennifer Woodrow; Tyler Wish; Rong Jin; Roger Green; Michael Woods; Barbara Roebothan; Sharon Buehler; Elizabeth Dicks; John R McLaughlin; Peter T Campbell; Patrick S Parfrey Journal: BMJ Open Date: 2013-02-07 Impact factor: 2.692