Association of estrogen receptor betavariants and serum levels of estradiol with risk of colorectal cancer: a case control study

Abstract

BackgroundEndogenous estrogens may play a vital role in colorectal tumorigenesis. Estrogen receptor beta is the predominant subtype which mediates the biological effect of estrogens, while loss of expression of estrogen receptor beta has been indicated as a common step in the development of colorectal cancer (CRC). Epidemiological studies have revealed several functional polymorphisms of estrogen receptor beta (ESR2) for cancer risk, but relevant study in CRC is limited, particularly in men. This study aimed to investigate the association of circulating estradiol and variations of ESR2 with CRC risk in men.MethodsWe initiated a case–control study consisting of 390 patients with CRC and 445 healthy controls in men only. We genotyped ESR2 single nucleotide polymorphisms (SNPs) rs1256049 and rs4986938 and measured serum estradiol concentration using chemilluminescence immunoassay. Multivariable logistic regression model was performed to evaluate the associations between these variables and CRC risk.ResultsESR2 rs1256049 CT/TT genotypes were associated with reduced risk of CRC (odds ratio [OR], 0.7, 95% confidence interval [CI], 0.5–1.0), while rs4986938 CT/TT genotypes were associated with increased risk of CRC (OR, 1.5, 95% CI, 1.0–2.1). In addition, the CRC risk increased with the number of risk genotypes of these two SNPs in a dose–response manner (Ptrend, 0.003). Specifically, subjects carrying risk genotypes of both SNPs had the highest risk of CRC (OR, 2.0, 95% CI, 1.3–3.3.). Moreover, serum estradiol concentration alone was associated with risk of CRC in men (OR, 1.2, 95% CI, 1.0–1.3). However, individuals presenting both rs4986938 CT/TT genotypes and high level of serum estradiol had a high risk of CRC (OR, 2.3, 95% CI, 1.4–3.9), compared with those presenting CC genotype and low level of serum estradiol. The similar joint results were not observed for SNP rs1256049.ConclusionsThese results suggest that endogenous estrogen and genetic variations in ESR2 may individually, or more likely jointly, affect CRC risk in male Han Chinese population, while larger studies are needed to validate our findings.

Helicobacter pylori Infection Synergizes with Three Inflammation-Related Genetic Variants in the GWASs to Increase Risk of Gastric Cancer in a Chinese Population

“…Genomic DNA was extracted from peripheral blood using a Fuji whole blood DNA kit (Fujifilm Corporation, Tokyo, Japan) following the manufacturer’s instructions and stored at -80°C until use. Three SNPs (rs4072037, rs13361707 and rs2274223) were all genotyped using TaqMan assay with ABI 7900HT real-time PCR System (Applied Biosystems, Foster City, CA, USA) as previously described [17]. The call rate for each SNP was >95%.…”

Molecular Pathways: Estrogen Pathway in Colorectal Cancer

“…10,11,39 In a recent study, Level of E2 was higher in cohort of Chinese men with colon cancer compared to controls, in this population combination of genetic variations in the ESR2 and E2 level was predictive of the risk of colon cancer, where in the group with high E2 level and CT/TT genotypes of ESR2 risk of colon cancer was 2.3 (95% CI, 1.4–3.9) compared to those with low level of E2 and CC genotype. 40 …”

A Possible Link of Genetic Variations in ER/IGF1R Pathway and Risk of Melanoma

“…ESR2 was also found to be related to various cancer types. For instance, rs1255998 and rs1256061 were linked to lung tumors [40], and rs1256049 was correlated with increased risks of colorectal cancer [41] and prostate cancer [42]. SNPs rs1520220, rs2946834, and rs5742694 in IGF1 had continuously been linked to cancer prognosis [43], as well as coronary artery disease [44].…”