Vitamin D receptor polymorphisms and diseases.

The vitamin D receptor (VDR) is a ligand-activated transcription factor that mediates the genomic effects of 1,25dihydroxyvitamin D in a wide variety of tissues. The gene encoding the VDR is located on chromosome 12q and has several common allelic variants. The individual allelic variants and their haplotypes have been widely studied as markers of susceptibility to osteoporosis, a prevalent metabolic bone disease characterized by reduced bone mass and a resultant increased susceptibility to fracture. More recent attention has focused on the possible role of VDR gene variation in the development of other diseases, including breast and prostate cancer, osteoarthritis, atherosclerotic coronary artery disease, diabetes, primary hyperparathyroidism, susceptibility to infection, and psoriasis. In this paper, we review the evidence for a role of common molecular variation in the VDR gene in osteoporosis and other diseases and discuss areas in need of further investigation.

Molecular Epidemiology of Vitamin D Receptor Gene Variants

This review focuses on genes other than the high penetrance genes BRCA1 and BRCA2 that are involved in breast cancer susceptibility. The goal of this review is the discovery of polymorphisms that are either associated with breast cancer or that are in strong linkage disequilibrium with breast cancer causing variants. An association with breast cancer at a 5% significance level was found for 13 polymorphisms in 10 genes described in more than one breast cancer study. Our data will help focus on the further analysis of genetic polymorphisms in populations of appropriate size, and especially on the combinations of such polymorphisms. This will facilitate determination of population attributable risks, understanding of gene-gene interactions, and improving estimates of genetic cancer risks.

https://jmg.bmj.com/content/jmedgenet/39/4/225.full.pdf

Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility.

Plasma 25-hydroxy vitamin D concentrations, vitamin D receptor genotype and breast cancer risk in a UK Caucasian population.

Vitamin D and calcium are metabolically interrelated and highly correlated dietary factors. Experimental studies have shown their anticarcinogenic effects due to their participation in regulating cell proliferation, differentiation, and apoptosis in normal and malignant breast cells. Given the emerging interest in their potential roles in the etiology of breast cancer, we review the current epidemiologic literature on dietary and/or supplemental intakes of vitamin D, endogenous circulating levels of vitamin D, and dietary and/or supplemental intakes of calcium in relation to breast cancer risk. To place these studies in context, we also provide a brief review of other supporting epidemiologic evidence. Despite inconsistent results from the epidemiologic studies, several lines of evidence suggest that vitamin D and calcium may be involved in the development of breast cancer. Specifically, (a) there is some epidemiologic evidence for inverse associations between vitamin D and calcium intakes and breast cancer; (b) serum, plasma, and/or blood levels of vitamin D metabolites have been inversely associated with breast cancer risk in some studies; (c) high sunlight exposure, presumably reflecting vitamin D synthesis in the skin, has been associated with a reduced risk of breast cancer; (d) vitamin D and calcium intakes have been inversely related to breast density, an intermediate end point for breast cancer; (e) calcium has been associated with a reduced risk of benign proliferative epithelial disorders of the breast, putative precursors of breast cancer; and (f) certain polymorphisms of the vitamin D receptor might modify breast cancer susceptibility. To further confirm the potential protective effects of calcium and vitamin D on breast cancer, well-designed cohort studies and clinical trials are warranted.

/pdf/vitamin-d-calcium-and-breast-cancer-risk-a-review-2omn0zdu09.pdf

Vitamin D, Calcium, and Breast Cancer Risk: A Review

a case‐control association study: the androgen receptor elements in the promotors of the downstream genes. Both (AR) and the vitamin D receptor (VDR). We have used receptors are expressed in breast tissue and are known to two series of Caucasian female breast cancer cases, one moderate rates of cell division. incident and one prevalent, and compared both with two sets of matched controls from the East Anglian region of Missense mutations in the AR have been shown to cause Britain. Since the results are similar in the two series we partial androgen insensitivity (leading to feminization, includhave combined them. The AR poly[Gly]n and poly[Gln]n ing gynaecomastia) together with familial male breast cancer tracts were genotyped in a total of 508 female breast cancer in a few families (3,4). Two of the amino acid substitutions cases and 426 controls. The VDR TaqI polymorphism was implicated, Arg607Gln and Arg608Lys in the DNA-binding analysed in 951 cases and 627 controls drawn from the same domain, reduce the affinity of these mutant ARs for their population series. There were no significant differences response elements and thus their transactivation efficiencies between cases and controls for either the AR or VDR (5). The AR is expressed in female breast epithelium and polymorphisms. Compared with individuals with two short androgens binding to these receptors inhibit breast cell prolifalleles (<22 repeats) of the AR poly[Gln]n tract, the odds eration (6,7), although AR status in breast tumours is not so ratios and 95% confidence intervals (95% CI) for indi- strongly correlated with prognosis as oestrogen receptor and viduals with one or two long alleles were 0.82 (95% progesterone receptor status (8). CI 0.62‐1.09) and 1.31 (95% CI 0.87‐1.97), respectively. Exon 1 of the AR encodes two expressed polymorphic Heterozygotes and homozygotes for the VDR TaqI cutting repeats, a poly[Gly]n and a poly[Gln]n tract. Expansion of the site had odds ratios of 1.01 (95% CI 0.81‐1.27) and 0.97 poly[Gln]n tract beyond the normal range of 11‐35 repeats (95% CI 0.71‐1.32), respectively. None of the AR or VDR causes X-linked spinal-bulbar muscular atrophy (Kennedy’s polymorphisms investigated has a major effect on risk of disease) and frequently also mild androgen insensitivity (9). breast cancer in the British population. The length of the poly[Gln]n tract has been shown to be inversely related to transactivation efficiency and rate of sperm production (10,11). Recently, some studies have suggested an

No association between androgen or vitamin D receptor gene polymorphisms and risk of breast cancer.

To date, microarray analyses have led to the discovery of numerous individual 'molecular signatures' associated with specific cancers. However, there are serious limitations for the adoption of these multi-gene signatures in the clinical environment for diagnostic or prognostic testing as studies with more power need to be carried out. This may involve larger richer cohorts and more advanced analyses. In this study, we conduct analyses-based on gene regulatory network-to reveal distinct and common biomarkers across cancer types. Using microarray data of triple-negative and medullary breast, ovarian and lung cancers applied to a combination of glasso and Bayesian networks (BNs), we derived a unique network-containing genes that are uniquely involved: small proline-rich protein 1A (SPRR1A), follistatin like 1 (FSTL1), collagen type XII alpha 1 (COL12A1) and RAD51 associated protein 1 (RAD51AP1). RAD51AP1 and FSTL1 are significantly overexpressed in ovarian cancer patients but only RAD51AP1 is upregulated in lung cancer patients compared with healthy controls. The upregulation of RAD51AP1 was mirrored in the bloods of both ovarian and lung cancer patients, and Kaplan-Meier (KM) plots predicted poorer overall survival (OS) in patients with high expression of RAD51AP1. Suppression of RAD51AP1 by RNA interference reduced cell proliferation in vitro in ovarian (SKOV3) and lung (A549) cancer cells. This effect appears to be modulated by a decrease in the expression of mTOR-related genes and pro-metastatic candidate genes. Our data describe how an initial in silico approach can generate novel biomarkers that could potentially support current clinical practice and improve long-term outcomes.

/pdf/identification-of-cancer-biomarkers-of-prognostic-value-dj1o82j722.pdf

Identification of cancer biomarkers of prognostic value using specific gene regulatory networks (GRN): A novel role of RAD51AP1 for ovarian and lung cancers

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No association between androgen or vitamin D receptor gene polymorphisms and risk of breast cancer.

Identification of cancer biomarkers of prognostic value using specific gene regulatory networks (GRN): A novel role of RAD51AP1 for ovarian and lung cancers