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

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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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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.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Ave, Boston, MA, 02215, USA

    Chen Yuan, Jeffrey A. Meyerhardt, Brian M. Wolpin & Kimmie Ng

  2. Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA

    Lindsay Renfro & Pratibha B. Ambadwar

  3. Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA

    Fang-Shu Ou

  4. DeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center, Tampa, FL, USA

    Howard L. McLeod

  5. Eshelman School of Pharmacy and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Federico Innocenti

  6. West Virginia University Cancer Institute, Morgantown, WV, USA

    Richard M. Goldberg

  7. Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA

    Axel Grothey

  8. Yale Cancer Center and Smilow Cancer Hospital, New Haven, CT, USA

    Charles S. Fuchs

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  1. Chen Yuan
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Correspondence to Chen Yuan.

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Conflict of interest

Charles S. Fuchs declares consulting for Agios, Bain Capital, Bayer, Celgene, Dicerna, Eli Lilly, Entrinsic Health, Five Prime Therapeutics, Genentech, Gilead Sciences, KEW, Merck, Merrimack Pharmaceuticals, Pfizer, Sanofi, Taiho, and Unum Therapeutics. He also serves as a Director for CytomX Therapeutics and owns unexercised stock options for CytomX Therapeutics and Entrinsic Health. Other authors declare that they have no conflict of interest.

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Yuan, C., Renfro, L., Ambadwar, P.B. et al. 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 Control 30, 757–765 (2019). https://doi.org/10.1007/s10552-019-01183-1

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  • DOI: https://doi.org/10.1007/s10552-019-01183-1

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