Associations between polymorphisms of HOTAIR and risk of gastric cardia adenocarcinoma in a population of north China

Abstract

As an important long noncoding RNA, Hox transcript antisense intergenic RNA (HOTAIR) is involved in the development and progression of various carcinomas. However, the role and genetic alterations of HOTAIR in gastric cardia adenocarcinoma (GCA) occurrence and progression have not been elucidated. We performed a case-control study in a population of north China to evaluate the possible association between haplotype-tagging SNPs (htSNPs) of the whole HOTAIR sequence and the risk of GCA as well as functional effect of the susceptibility single nucleotide polymorphism (SNP) rs12826786 on gene expression. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to examine the genotype of htSNPs in 515 GCA patients and 654 control subjects, and the quantitative real-time reverse transcription PCR (RT-PCR) method was used to examine the expression of HOTAIR in 102 GCA patients. A family history of upper gastrointestinal cancer (UGIC) significantly increased the risk of developing GCA. Among three htSNPs of the HOTAIR gene (rs12826786 C>T, rs4759314 A>G, and rs10783618 C>T), only the T allele of rs12826786 was found to increase the risk of developing GCA and was associated with smoking habit and tumor-node-metastasis (TNM) stage. In addition, higher expression levels of HOTAIR were found in tumor tissues and rs12826786 SNP has a genotype-specific effect on HOTAIR expression. A high HOTAIR expression level was associated with poor GCA patients' survival. These results indicate that functional genotype alteration of rs12826786 SNP may influence the expression of HOTAIR, and HOTAIR may be a useful marker to predict the biological behavior of tumors and potentially a therapeutic target in GCA treatment.

Effects of the functional HOTAIR rs920778 and rs12826786 genetic variants in glioma susceptibility and patient prognosis

“…Previous studies on the contribution of rs920778 to gastric cancer in a Turkish population [25] also showed no differences between patients and cancer-free controls; however, studies in other tumor types testing the importance of rs920778 or rs12826786 in the Chinese population have shown different allele frequencies between patients and cancer-free controls [22][23][24]. It was also showed previously that rs920778 variants do not influence gastric cancer susceptibility [25], whereas others have showed statistically significant associations between these SNPs and risk to develop gastric cardia adenocarcinoma [22], esophageal squamous cell carcinoma (ESCC) [23], breast cancer [26][27][28] or gastric cancer [24]. Such discrepancies might be attributed to the different genetic backgrounds of the studied populations, different sample sizes, and/or to the variety of tumor types analyzed.…”

“…Indeed, the expression patterns, the regulatory mechanisms, and the functions of lncRNAs are highly tissue-specific [32]. Because SNPs differentially influence the regulation of lncRNAs [33], in particular the SNPs in this study [22][23][24], it is possible that these SNPs may present distinct relevance in the context of different tumor types. Since rs920778 and rs12826786 HOTAIR SNPs have been previously reported to be located in an intronic enhancer or in the promoter, respectively, we sought to understand if the different genotypes influence the expression levels of HOTAIR in glioma tissues.…”

“…No statistically significant associations were found between the TT and the CC genotypes (p-value = 0.866). Tick marks indicate censored data in cancer, but epidemiological studies evaluating tumor susceptibility conferred by genetic polymorphisms in its locus have not been extensively assessed [18][19][20][21][22]. Indeed, to the best of our knowledge, the current study is the first to evaluate associations between HOTAIR SNPs (rs920778 and rs12826786) and glioma susceptibility and prognosis.…”

“…Fifty ng of DNA were used for PCR amplification with KAPA Taq DNA Polymerase (Kapa Biosystems). Primers sequences (following previous publications [22,23]) and PCR conditions are listed in Supplementary Table 1. Ten μL of PCR product were enzymatically digested at 37 °C for 5 or 30 min with FastDigest MspI (Thermo Scientific, rs920778) or FastDigest BglII (Thermo Scientific, rs12826786), respectively.…”

“…Although HOTAIR expression has been reported as crucial in the carcinogenic process of many cancer types, and its abnormal expression was associated with patient poor prognosis, tumor grade, growth and invasion, and as a putative therapeutic target in glioma [19][20][21], few studies have focused on the significance of SNPs in HOTAIR affecting cancer risk [22][23][24][25][26][27][28]. Critically, no studies have evaluated the impact of HOTAIR SNPs in glioma risk and patient prognosis.…”