Elsevier

Gene

Volume 677, 30 November 2018, Pages 211-227
Gene

Research paper
Do genetic polymorphisms of the vitamin D receptor contribute to breast/ovarian cancer? A systematic review and network meta-analysis

https://doi.org/10.1016/j.gene.2018.07.070Get rights and content

Highlights

  • Vitamin D (VD) is responded to VD receptor (VDR) and exerts anti-proliferative efficiency.

  • Reveal the relationship between genetic polymorphisms of VDR and gynecological cancers

  • Identify the most suitable genetic model of VDR for detecting in a specific population

Abstract

Background

To identify the most suitable genetic model for detecting the risk of breast cancer (BC)/ovarian cancer (OC) in specific populations.

Methods

Databases were searched for related studies published up to October 2017. First, VDR genetic polymorphisms were compared in patients with and without cancer. Second, a network meta-analysis was used to reveal the relation between VDR genetic polymorphisms with disease outcomes. Subgroup analyses and a meta-regression were performed according to cancer types, ethnicity and genotypic method. The study is registered in PROSPERO with an ID: CRD42017075505.

Results

Forty-five studies were eligible, which included 65,754 patients and 55 clinical analyses. Of genetic models, results suggested that the recessive model with the CDX2 polymorphism predicted the risk of BC in all cases. The recessive polymorphism model with the rs2228570 (FokI) polymorphism seemed to the best predictor of BC in Caucasian patients, whereas the homozygote model with the CDX2 polymorphism appeared to best predict BC in African-American patients. The homozygote model with the rs2228570 (FokI) polymorphism model appeared to detect the risk of OC in all cases, whereas the heterozygote model with the rs1544410 (BsmI) polymorphism seemed to detect the risk of OC in Caucasian patients.

Conclusions

By detecting the risk of BC, the recessive model with the rs2228570 (FokI) polymorphism is likely the best genetic model in Caucasian patients, and the homozygote model with the CDX2 polymorphism appears to be best genetic model in African-American patients. Moreover, for detecting clinical risk of OC, heterozygote models with the rs1544410 (BsmI) polymorphism is likely the best genetic model for detecting the risk of OC in Caucasian patients.

Introduction

The incidence of breast cancer or ovarian cancer is increasing worldwide and constitutes a major public health problem for female health, and breast cancer (BC) has been one of the foremost major cause of morbidity and mortality (Wolff et al., 2018; Wang et al., 2018; Lambertini et al., 2018; Colombo et al., 2018; Sanhueza et al., 2016). According to statistics, BC is the second leading cause of cancer-related female deaths, second only to lung cancer (World Health Organization, 2012). It is responsible for 16% of all cancer cases and 22.9% of invasive malignancies in women (World Health Organization, 2012). It is reported that BC has estimated 252,710 new cases and 40,410 deaths reported in 2017 (Siegel et al., 2017). Moreover, in 2012, there were an estimated about 240,000 new cases of ovarian cancer (OC) diagnosed and about 150,000 OC-related deaths (Han et al., 2017; Kraus et al., 2017). Differences in early-onset cancer in females may be due to genetic and epigenetic differences between ethnic groups, as well as geographical factors.

Many researchers have examined cellular and molecular aspects of BC/OC, but the susceptible indicators or risk factors for BC are not well established (Fang et al., 2011; Yang et al., 2013; Zhang et al., 2012; Yang et al., 2018; Liu et al., 2018; Wang et al., 2018c). Higher levels of circulating vitamin D metabolites have been showed to consistently associate with a decreased risk of BC in several epidemiological studies (Bertone-Johnson et al., 2005; Crew et al., 2009). In contrast, epidemiological studies found no association between dietary vitamin D intake and the risk of BC/OC (Levi et al., 2001; McCullough et al., 2005; Robien et al., 2007). The nuclear receptor, vitamin D receptor (VDR), responses and transduces the pleiotropic response of the biologically active-hormonal form of vitamin D: 1α,25‑dihydroxyvitamin D3, also known as 1α,25(OH)2D3, in the endocrine system and plays important roles in physical processes, including calcium absorption, immunity, and proliferation (Uitterlinden et al., 2004; Wang et al., 2018b; Li et al., 2017; Vasile et al., 2017). Human vdr gene consists of a 4605 bp ORF (open read frame) and belongs to steroid-receptor (nuclear receptor) gene family (NR 1I1, nuclear receptor subfamily 1 group I member 1) (Baker et al., 1988; Chen et al., 2018; Pourcet et al., 2018; Ahmad et al., 2018; Sangkaew et al., 2018; Abdalla et al., 2018). Increasing evidence demonstrated that VDR expression decreased in BC tissues compared to normal breast tissues (Lopes et al., 2010; Rashid et al., 2015). Research also suggested that single nucleotide polymorphisms (SNPs) of VDR may serve as an OC's susceptibility marker (Lurie et al., 2007; Wang et al., 2018d).

Multiple polymorphisms of the vdr gene have been described, with four important and common SNPs found in the exon 2 or 3′UTR regions (Nejentsev et al., 2004). One of these SNPs, rs2228570 (FokI), is located within exon 2 region (Arai et al., 1997; Nejentsev et al., 2004). Other three SNPs, rs1544410 (BsmI), rs731236 (TaqI) or rs7975232 (ApaI) are located in intron 8, exon 9 or intron 9, respectively (Arai et al., 1997; Nejentsev et al., 2004). CDX2 is a gut-specific nuclear transcription factor that is a key regulator of intestinal epithelial formation and differentiation. The CDX2rs11568820 (CDX2) polymorphism has been reported to lead to decreased transcriptional activity of the VDR promoter (Arai et al., 2001). A previous study also reported that variety in the length of rs17878969 [poly(A)] may affect vdr gene's expression by influencing post-transcription regulation (Whitfield et al., 2001) (Supplementary Table S1).

Numerous systematic reviews focused on the involvement of vdr polymorphisms, such as rs1544410 (BsmI) and rs2228570 (FokI), in tumorigenesis of breast/ovarian cancer (Mun et al., 2015; Rai et al., 2017). However, inconsistent results and a lack of studies of some types of cancer warrant additional research (Li et al., 2016; Lin et al., 2017; Lu et al., 2016). In addition, previous studies considered only direct evidence, and whether vdr polymorphisms are a risk factor for susceptibility to breast/ovarian cancer has not been investigated. Furthermore, no previous reviews of the role of vdr's SNPs in the risk of cancer among different patient populations have included a network meta-analysis and meta-regressions.

Section snippets

Methods

This systematic review was based on a previously defined protocol (PROSPERO, CRD 42017075505) (PROSPERO, 2009) and was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) extension statement for systematic reviews incorporating network meta-analyses for health care treatments and the recommendations of the Cochrane Collaboration (Cochrane Handbook for Systematic Reviews of Interventions, 2011; Hutton et al., 2015; Moher et al., 2009).

Description of the patients

In total, 634 publications were retrieved from databases. After removing duplicates, 410 publications were screened based on their titles and abstracts, and 107 were excluded. In total, 45 studies (Abbas et al., 2008; Abd-Elsalam et al., 2015; Amadori et al., 2017; Anderson et al., 2011; Bretherton-Watt et al., 2001; Buyru et al., 2003; Chakraborty et al., 2009; Chen et al., 2005; Clendenen et al., 2008; Colagar et al., 2015; Curran et al., 1999; Dalessandri et al., 2012; Dunning et al., 1999;

Discussion

The present network meta-analysis represents the most comprehensive synthesis of currently available data on vdr polymorphisms and the risk of BC/OC. We reviewed the findings of direct and indirect analyses of the risk of BC/OC associated with VDR polymorphisms (N = 65,754 subjects) in homozygote, heterozygote, dominant model, recessive, and allele contrast models.

Results revealed that compared with the controls (noncancer patients), heterozygote and dominant models with the rs1544410 (BsmI)

Competing of interest

The authors declare no conflict of interest.

Funding

The study was funded by Chinese government: (1) Special Project for Capital Health Development Research (No. 2014-2-5031) and (2) Dean Innovation Fund (YNKT2014039) from the 302nd Hospital of Chinese PLA, Beijing 100039, PR China. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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