Stephanie Weinstein

Ph.D

NCI

Staff Scientist

PLCO (Learn more about this study)

PLCO-846

Oct 29, 2021

Vitamin D Binding Protein Genetic Isoforms and Cancer Incidence in PLCO

We and others have conducted extensive studies of circulating 25-hydroxyvitamin D [25(OH)D, the accepted biomarker of vitamin D status], and vitamin D binding protein (DBP, the primary carrier of vitamin D in circulation), in relation to cancer incidence and mortality in PLCO.1-13 The recent genome-wide scanning of all PLCO participants with available germline DNA enables closer examination of these phenotype associations considering the influence of genotypes, including DBP isoforms.

There are three common isoforms of DBP (also known as ‘‘group-specific component’’ or “Gc”), denoted as Gc1f, Gc1s, and Gc2 and defined based on two SNPs (rs7041 and rs4588) in the DBP gene, Gc. One study reported that the Gc1f/Gc1f phenotype was associated with a reduced risk of overall cancer14 and another reported that Gc2 was associated with reduced risk of breast cancer.15 Three studies found that associations between circulating vitamin D and risk of colorectal adenoma, colorectal cancer, and colorectal cancer mortality differed based on DBP isoform.16-18 Specifically, in all three studies, inverse associations with circulating vitamin D were limited to those with the Gc2 DBP isoform.

We have recently completed an analysis of pre-diagnostic vitamin D status and total and site-specific cancer survival in PLCO and found that 25(OH)D was associated with reduced overall cancer mortality and lung cancer mortality. Furthermore, the vitamin D/survival associations were limited to cases with the Gc2 DBP isoform (Submitted 9/2021).

We propose to examine the association between DBP isoforms (i.e., Gc1f, Gc1s, and Gc2) and total and site-specific cancer incidence in the full PLCO cohort with genome-wide scan data. We will also examine effect modification by DBP isoform of the circulating 25(OH)D-cancer risk associations in the existing nested case-control sets (~4,038 total cases and matched controls). This study should help elucidate mechanisms for vitamin D-cancer associations and could have implications for cancer etiology and prevention.

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15. Abbas S, et al. Cancer Epidemiol Biomarkers Prev. 2008;17(6):1339-1343.
16. Gibbs DC, et al. Int J Cancer. 2020;147(10):2725-2734.
17. Gibbs DC, et al. Am J Epidemiol. 2018;187(9):1923-1930.
18. Gibbs DC, et al. JNCI Cancer Spectr. 2020;4(1):pkz083.

1. To examine the association between DBP genetic isoforms Gc1f, Gc1s, and Gc2 and total and site-specific cancer incidence.

2. To examine effect modification by DBP genetic isoform of the pre-diagnostic circulating 25(OH)D associations with total and site-specific cancer risk.