Vitamin D binding protein genetic isoforms, serum vitamin D, and cancer risk in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial

Sep 21, 2026

Associations between vitamin D biochemical status and cancer may be modified by vitamin D binding protein isoforms encoded by GC. Serum 25-hydroxyvitamin D [25(OH)D] levels were analyzed with Gc isoforms Gc1-1, Gc1-2, and Gc2-2 for cancer risk in the PLCO Cancer Screening Trial cohort (3,795 cases, 3,856 controls). Multivariable-adjusted logistic regression estimated odds ratios across 25(OH)D quantiles stratified by Gc isoform, and proportional hazards models assessed GC-cancer associations in individuals with genetic data. Overall cancer risk was not modified by GC genotype for most cancers.

LanguageEnglish

CategoryResearch & Report

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Pages16

Reading Time40 min

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Abstract

Methods and study cohorts

Key findings on cancer risk modification

Additional analyses beyond 25(OH)D

Introduction

PLOS ONE OPEN ACCESS Citation: Weinstein SJ, Parisi D, Mondul AM, Layne TM, Huang J, Stolzenberg-Solomon RZ, et al. (2024) Vitamin D binding protein genetic isoforms, serum vitamin D, and cancer risk in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. PLoS ONE 19(12): e0315252 . [https://doi.org/10.1371/journal](https://doi.org/10.1371/journal). pone.0315252 Editor: Michal Zmijewski, Medical University of Gdańsk, POLAND Received: July 15, 2024 Accepted: November 21, 2024 Published: December 20, 2024 Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Data Availability Statement: To protect the personal health information of participants within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), data are only available through the PLCO Cancer Data Access System. PLCO data can be shared via this proposal submission and approval process system and after an appropriate Data Transfer Agreement is in place. Instructions to request access to PLCO data and specimens can be found here: [https://cdas.cancer](https://cdas.cancer). RESEARCH ARTICLE Vitamin D binding protein genetic isoforms, serum vitamin D, and cancer risk in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial Stephanie J. Weinstein1 *, Dominick Parisi2, Alison M. Mondul3, Tracy M. Layne4, Jiaqi Huang5, Rachael Z. Stolzenberg-Solomon1, Regina G. Ziegler1, Mark P. Purdue1, Wen-Yi Huang1, Christian C. Abnet1, Neal D. Freedman6, Kai Yu1, Demetrius Albanes1 1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, United States of America, 2 Information Management Services, Inc. , Calverton, Maryland, United States of America, 3 Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan, United States of America, 4 Icahn School of Medicine at Mount Sinai, New York, New York, United States of America, 5 Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China, 6 Division of Cancer Control and Population Sciences, National Cancer Institute, NIH, Bethesda, Maryland, United States of America * [weinstes@mail.nih.gov](weinstes@mail.nih.gov) Abstract Associations between vitamin D biochemical status and cancer may be modified by vitamin D binding protein isoforms which are encoded by GC (group-specific component) . We examined interactions between serum 25-hydroxyvitamin D [25(OH)D], the Gc isoforms Gc1-1, Gc1-2, and Gc2-2, and cancer risk within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort based on 3,795 cases and 3,856 controls. Multivariableadjusted logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer risk according to 25(OH)D quantiles, stratified by Gc isoform. Separately, the GC-cancer risk association was examined using proportional hazards regression among 109,746 individuals with genetic data and 26,713 diagnosed with cancer. Specific vitamin D binding protein isoform subtypes were delineated and analyzed, including Gc1-1 subtypes (Gc1s-Gc1s, Gc1f-Gc1s, and Gc1f-Gc1f) and Gc2 subtypes (Gc1s-Gc2, Gc1fGc2, and Gc2-Gc2) . For most cancers, the GC genotype did not modify the risk associations for 25(OH)D; e.g. , the OR for high vs. low vitamin D quintile was 1.09 (0 .89–1.33) for overall cancer risk among individuals with the Gc1-1 isoform and 1.04 (0 .83–1.31) among those with either the Gc1-2 or Gc2-2 isoforms. ORs for high compared to low vitamin D tertile for colorectal, lung, breast, and prostate cancer among those with the Gc1-1 vs. any Gc2 isoforms were, respectively, 0.60 vs. 0.73, 1.96 vs. 1.03, 1.30 vs. 1. 18, and 1.19 vs.

FAQs

How were vitamin D and GC isoforms evaluated in relation to cancer risk?

The study assessed serum 25-hydroxyvitamin D [25(OH)D] together with GC-encoded vitamin D binding protein isoforms (Gc1-1, Gc1-2, and Gc2-2) to examine interactions with cancer risk in the PLCO cohort.

Did GC genotype modify the association between 25(OH)D and overall cancer risk?

For most cancers, GC genotype did not modify 25(OH)D risk associations, with similar odds ratios for high versus low vitamin D across Gc isoform groups.

Was there any exception where GC qualitatively modified vitamin D-related cancer risk?

Yes. The GC genotype qualitatively modified the association for bladder cancer risk, showing different odds ratios depending on whether individuals carried Gc1-1 versus Gc2-related isoforms, with a reported interaction p value of 0.03.

Sep 21, 2026

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