Abstract
The impact of HULC rs7763881 on colorectal cancer (CRC) susceptibility is not yet known. Also, the biological function of the cancer-related rs6983267 remains unclear. We investigated the association of these SNPs with the risk of CRC and adenomatous polyps (AP), their correlation with CCAT2 and HULC expression, and the potential of serum CCAT2 and HULC as biomarkers for CRC. 120 CRC patients, 30 AP patients, and 96 healthy controls were included. Genotyping and serum lncRNAs were assayed by qPCR. Studied SNPs were not associated with AP susceptibility. rs6983267 GG was associated with increased CRC risk, whereas rs7763881 AC was protective. rs7763881 and rs6983267 CT haplotype was protective. Serum CCAT2 and HULC were upregulated in CRC and AP patients versus controls and discriminated these groups by ROC analysis. rs6983267 GG and rs7763881 AA patients demonstrated higher serum CCAT2 and HULC compared with GT/TT and AC, respectively. rs6983267 and serum HULC predicted CRC diagnosis among non-CRC groups (AP + controls) by multivariate analysis. Studied SNPs or serum long noncoding RNAs weren’t correlated with nodal or distant metastasis. In conclusion, rs6983267 and rs7763881 are potential genetic markers of CRC predisposition and correlate with serum CCAT2 and HULC, two novel potential non-invasive diagnostic biomarkers for CRC.
Highlights
The genesis of colorectal cancer (CRC) involves complex multi-factorial steps in which an interplay exists between environmental factors, genetic background, represented by single nucleotide polymorphisms (SNPs), and abnormal gene expression[4], but knowledge of the full molecular basis of CRC is still limited[5]
In a stratification risk analysis by age and sex, the effects of rs7763881 Association of rs7763881 (A/C) and rs6983267 G/T genotypes on CRC risk were further investigated (Table 3). rs7763881 AC was a protective candidate for CRC risk among male patients and younger patients (≤50 years) (AC vs AA, OR = 0.31, 95% CI = 0.117–0.825, P = 0.018; OR = 0.259, 95% CI = 0.094–0.716, P = 0.011, respectively). rs6983267 GG genotype was associated with increased CRC susceptibility among male patients and older patients (>50 years) (GG vs GT/ TT, OR = 3.57, 95% CI = 1.53–8.33, P = 0.002; OR = 3.44, 95% CI = 1.25–10, P = 0.02, respectively)
We examined the joint effect of studied gene polymorphisms in patients with CRC compared to control group (Table 4)
Summary
The genesis of CRC involves complex multi-factorial steps in which an interplay exists between environmental factors, genetic background, represented by single nucleotide polymorphisms (SNPs), and abnormal gene expression[4], but knowledge of the full molecular basis of CRC is still limited[5]. Several cancer risk loci are transcribed into long noncoding RNAs (lncRNAs, >200 nucleotides)[6] These lncRNAs regulate various epigenetic, transcriptional, and post-transcriptional events, and potentially contribute to carcinogenesis as tumor suppressors or oncogenes[5,6]. Genome wide association studies have identified genetic variants in lncRNAs genomic regions as candidate risk factors for CRC7–9. These SNPs were postulated to alter lncRNA expression and/or structure, or affect lncRNA pathways. The SNP rs6983267, located in a gene desert in the MYC enhancer region, has been identified as being associated with increased CRC risk[7,8,10], and was functionally linked to enhanced WNT signaling in CRC12. The impact of rs7763881 on CRC susceptibility, its involvement in regulating HULC expression, and its relationship with tumor-related data are not yet known
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