TY - JOUR
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
AU - Fuchs, Charles S.
AU - Ng, Kimmie
N1 - Funding Information:
Acknowledgments Grant support: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology), U10CA180790, U10CA180820 (ECOG-ACRIN), U10CA180838, U10CA180867, U10CA180888 (SWOG), and U24CA196171. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2019, Springer Nature Switzerland AG.
PY - 2019/7/1
Y1 - 2019/7/1
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).
KW - 25-hydroxyvitamin D
KW - Metastatic colorectal cancer
KW - Single-nucleotide polymorphisms
KW - Survival
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U2 - 10.1007/s10552-019-01183-1
DO - 10.1007/s10552-019-01183-1
M3 - Article
C2 - 31104167
AN - SCOPUS:85066077078
SN - 0957-5243
VL - 30
SP - 757
EP - 765
JO - Cancer Causes and Control
JF - Cancer Causes and Control
IS - 7
ER -