Vitamin D receptor and calcium-sensing receptor polymorphisms and colorectal cancer survival in the Newfoundland population

Abstract

Background:Increased serum levels of vitamin D and calcium have been associated with lower risks of colorectal cancer (CRC) incidence and mortality. These inverse associations may be mediated by the vitamin D receptor (VDR) and the calcium-sensing receptor (CASR). We investigated genetic variants in VDR and CASR for their relevance to CRC prognosis.Methods:A population-based cohort of 531 CRC patients diagnosed from 1999 to 2003 in Newfoundland and Labrador, Canada, was followed for mortality and cancer recurrence until April 2010. Germline DNA samples were genotyped with the Illumina Omni-Quad 1 Million chip. Multivariate Cox models assessed 41 tag single-nucleotide polymorphisms and relative haplotypes on VDR and CASR in relation to all-cause mortality (overall survival, OS) and disease-free survival (DFS).Results:Gene-level associations were observed between VDR and the DFS of rectal cancer patients (P=0.037) as well as between CASR and the OS of colon cancer patients (P=0.014). Haplotype analysis within linkage blocks of CASR revealed the G-G-G-G-G-A-C haplotype (rs10222633-rs10934578-rs3804592-rs17250717-A986S-R990G-rs1802757) to be associated with a decreased OS of colon cancer (HR, 3.15; 95% CI, 1.66–5.96). Potential interactions were seen among prediagnostic dietary calcium intake with the CASR R990G (Pint=0.040) and the CASR G-T-G-G-G-G-C haplotype for rs10222633-rs10934578-rs3804592-rs17250717-A986S-R990G-rs1802757 (Pint=0.017), with decreased OS time associated with these variants limited to patients consuming dietary calcium below the median, although the stratified results were not statistically significant after correction for multiple testing.Conclusions:Polymorphic variations in VDR and CASR may be associated with survival after a diagnosis of CRC.

Comparative Study of Organoids from Patient-Derived Normal and Tumor Colon and Rectal Tissue

“…In addition, differences in the effect of calcitriol on the transcriptome of normal rectum and rectal tumor organoids were mainly on the level of gene expression. These findings appear to conflict with the reported links between genomic variation/polymorphisms in several vitamin D system genes ( VDR , GC , CYP24A1 , CYP2R1, and DHCR7/NADSYN1 ) and differences in the response to vitamin D compounds in studies involving CRC patients [ 68 , 69 , 70 , 71 , 72 , 73 ]. However, this discrepancy may again reflect differences between the in vivo and in vitro situations, since some vitamin D system genes play no role in cultured organoids; for example, the GC gene encodes the vitamin D binding protein, which is responsible for the blood transport of 25-hydroxyvitamin D/calcidiol and calcitriol.…”

Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment

“…Polymorphisms in genes related with vitamin D metabolism, including VDR , CYP27A1 , CYP27B1 , CYP24A1 and GC , have been associated with cancer risk and progression, and may function as a valuable factor in cancer prognosis. Here, we summarized the epidemiological and genetic studies performed in recent years depicting the association of gene polymorphisms with cancer risk, progression and prognosis in Table 257, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119.…”

Vitamin D Receptor (VDR) Gene Polymorphism in Patients Diagnosed with Colorectal Cancer

“…These findings are similar to ours; for single polymorphisms, the results are mixed or not statistically significant, but there are valuable findings after the haplotypes analysis presents the most important haplotypes. A study based on the Newfoundland population investigated TaqI and BsmI polymorphism in one block for CRC survival and found no relevant association [ 33 ]. Ashmore et al determined null results with CRC for both sole SNPs in VDR gene and haplotypes [ 34 ].…”