Influence of genetic variation in the vitamin D pathway on plasma 25-hydroxyvitamin D3 levels and survival among patients with metastatic colorectal cancer

Chen Yuan, Lindsay Renfro, Pratibha B. Ambadwar, Fang-Shu Ou, Howard L. McLeod, Federico Innocenti, Jeffrey A. Meyerhardt, Brian M. Wolpin, Richard M. Goldberg, Axel F Grothey, Charles S. Fuchs, Kimmie Ng

Research output: Contribution to journalArticle

Abstract

Purpose: The relationships of genetic variation in the vitamin D pathway with circulating 25-hydroxyvitamin D3 [25(OH)D] levels and survival remain largely unknown for patients with metastatic colorectal cancer (mCRC). Methods: Among 535 patients participating in a randomized trial of chemotherapy for mCRC, we prospectively measured baseline plasma 25(OH)D and examined 124 tagging single-nucleotide polymorphisms (SNPs) within seven genes in the vitamin D pathway, including five SNPs associated with circulating 25(OH)D levels in previous genome-wide association studies (GWAS). We evaluated whether these SNPs were associated with plasma 25(OH)D levels and patient outcome (overall survival, time to progression, and tumor response), using linear, logistic, and Cox proportional hazards regression. Results: We observed a significant association between 25(OH)D levels and an additive genetic risk score determined by the five GWAS-identified SNPs (p = 0.0009). We did not observe any direct association between 25(OH)D-associated SNPs, individually or as a genetic risk score, and patient outcome. However, we found a significant interaction between 25(OH)D levels and rs12785878 genotype in DHCR7 on overall survival (pinteraction = 0.02). Conclusion: Germline genetic variation in the vitamin D pathway informs baseline 25(OH)D levels among patients with mCRC. The association between 25(OH)D levels and overall survival may vary by DHCR7 genotype. ClinicalTrials.gov Identifier: NCT00003594 (https://clinicaltrials.gov/ct2/show/NCT00003594).

Original languageEnglish (US)
Pages (from-to)757-765
Number of pages9
JournalCancer Causes and Control
Volume30
Issue number7
DOIs
StatePublished - Jul 1 2019

Fingerprint

Calcifediol
Vitamin D
Single Nucleotide Polymorphism
Colorectal Neoplasms
Survival
Genome-Wide Association Study
Genotype
Drug Therapy
Genes
Neoplasms

Keywords

  • 25-hydroxyvitamin D
  • Metastatic colorectal cancer
  • Single-nucleotide polymorphisms
  • Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Influence of genetic variation in the vitamin D pathway on plasma 25-hydroxyvitamin D3 levels and survival among patients with metastatic colorectal cancer. / Yuan, Chen; Renfro, Lindsay; Ambadwar, Pratibha B.; Ou, Fang-Shu; McLeod, Howard L.; Innocenti, Federico; Meyerhardt, Jeffrey A.; Wolpin, Brian M.; Goldberg, Richard M.; Grothey, Axel F; Fuchs, Charles S.; Ng, Kimmie.

In: Cancer Causes and Control, Vol. 30, No. 7, 01.07.2019, p. 757-765.

Research output: Contribution to journalArticle

Yuan, C, Renfro, L, Ambadwar, PB, Ou, F-S, McLeod, HL, Innocenti, F, Meyerhardt, JA, Wolpin, BM, Goldberg, RM, Grothey, AF, Fuchs, CS & Ng, K 2019, 'Influence of genetic variation in the vitamin D pathway on plasma 25-hydroxyvitamin D3 levels and survival among patients with metastatic colorectal cancer', Cancer Causes and Control, vol. 30, no. 7, pp. 757-765. https://doi.org/10.1007/s10552-019-01183-1
Yuan, Chen ; Renfro, Lindsay ; Ambadwar, Pratibha B. ; Ou, Fang-Shu ; McLeod, Howard L. ; Innocenti, Federico ; Meyerhardt, Jeffrey A. ; Wolpin, Brian M. ; Goldberg, Richard M. ; Grothey, Axel F ; Fuchs, Charles S. ; Ng, Kimmie. / Influence of genetic variation in the vitamin D pathway on plasma 25-hydroxyvitamin D3 levels and survival among patients with metastatic colorectal cancer. In: Cancer Causes and Control. 2019 ; Vol. 30, No. 7. pp. 757-765.
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abstract = "Purpose: The relationships of genetic variation in the vitamin D pathway with circulating 25-hydroxyvitamin D3 [25(OH)D] levels and survival remain largely unknown for patients with metastatic colorectal cancer (mCRC). Methods: Among 535 patients participating in a randomized trial of chemotherapy for mCRC, we prospectively measured baseline plasma 25(OH)D and examined 124 tagging single-nucleotide polymorphisms (SNPs) within seven genes in the vitamin D pathway, including five SNPs associated with circulating 25(OH)D levels in previous genome-wide association studies (GWAS). We evaluated whether these SNPs were associated with plasma 25(OH)D levels and patient outcome (overall survival, time to progression, and tumor response), using linear, logistic, and Cox proportional hazards regression. Results: We observed a significant association between 25(OH)D levels and an additive genetic risk score determined by the five GWAS-identified SNPs (p = 0.0009). We did not observe any direct association between 25(OH)D-associated SNPs, individually or as a genetic risk score, and patient outcome. However, we found a significant interaction between 25(OH)D levels and rs12785878 genotype in DHCR7 on overall survival (pinteraction = 0.02). Conclusion: Germline genetic variation in the vitamin D pathway informs baseline 25(OH)D levels among patients with mCRC. The association between 25(OH)D levels and overall survival may vary by DHCR7 genotype. ClinicalTrials.gov Identifier: NCT00003594 (https://clinicaltrials.gov/ct2/show/NCT00003594).",
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T1 - Influence of genetic variation in the vitamin D pathway on plasma 25-hydroxyvitamin D3 levels and survival among patients with metastatic colorectal cancer

AU - Yuan, Chen

AU - Renfro, Lindsay

AU - Ambadwar, Pratibha B.

AU - Ou, Fang-Shu

AU - McLeod, Howard L.

AU - Innocenti, Federico

AU - Meyerhardt, Jeffrey A.

AU - Wolpin, Brian M.

AU - Goldberg, Richard M.

AU - Grothey, Axel F

AU - Fuchs, Charles S.

AU - Ng, Kimmie

PY - 2019/7/1

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N2 - Purpose: The relationships of genetic variation in the vitamin D pathway with circulating 25-hydroxyvitamin D3 [25(OH)D] levels and survival remain largely unknown for patients with metastatic colorectal cancer (mCRC). Methods: Among 535 patients participating in a randomized trial of chemotherapy for mCRC, we prospectively measured baseline plasma 25(OH)D and examined 124 tagging single-nucleotide polymorphisms (SNPs) within seven genes in the vitamin D pathway, including five SNPs associated with circulating 25(OH)D levels in previous genome-wide association studies (GWAS). We evaluated whether these SNPs were associated with plasma 25(OH)D levels and patient outcome (overall survival, time to progression, and tumor response), using linear, logistic, and Cox proportional hazards regression. Results: We observed a significant association between 25(OH)D levels and an additive genetic risk score determined by the five GWAS-identified SNPs (p = 0.0009). We did not observe any direct association between 25(OH)D-associated SNPs, individually or as a genetic risk score, and patient outcome. However, we found a significant interaction between 25(OH)D levels and rs12785878 genotype in DHCR7 on overall survival (pinteraction = 0.02). Conclusion: Germline genetic variation in the vitamin D pathway informs baseline 25(OH)D levels among patients with mCRC. The association between 25(OH)D levels and overall survival may vary by DHCR7 genotype. ClinicalTrials.gov Identifier: NCT00003594 (https://clinicaltrials.gov/ct2/show/NCT00003594).

AB - Purpose: The relationships of genetic variation in the vitamin D pathway with circulating 25-hydroxyvitamin D3 [25(OH)D] levels and survival remain largely unknown for patients with metastatic colorectal cancer (mCRC). Methods: Among 535 patients participating in a randomized trial of chemotherapy for mCRC, we prospectively measured baseline plasma 25(OH)D and examined 124 tagging single-nucleotide polymorphisms (SNPs) within seven genes in the vitamin D pathway, including five SNPs associated with circulating 25(OH)D levels in previous genome-wide association studies (GWAS). We evaluated whether these SNPs were associated with plasma 25(OH)D levels and patient outcome (overall survival, time to progression, and tumor response), using linear, logistic, and Cox proportional hazards regression. Results: We observed a significant association between 25(OH)D levels and an additive genetic risk score determined by the five GWAS-identified SNPs (p = 0.0009). We did not observe any direct association between 25(OH)D-associated SNPs, individually or as a genetic risk score, and patient outcome. However, we found a significant interaction between 25(OH)D levels and rs12785878 genotype in DHCR7 on overall survival (pinteraction = 0.02). Conclusion: Germline genetic variation in the vitamin D pathway informs baseline 25(OH)D levels among patients with mCRC. The association between 25(OH)D levels and overall survival may vary by DHCR7 genotype. ClinicalTrials.gov Identifier: NCT00003594 (https://clinicaltrials.gov/ct2/show/NCT00003594).

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