In the present study, for the first time, we provided evidence that SNPs (i.e., rs13252298, rs7007694, rs16901946, and rs1456315) in the lncRNA PRNCR1 at the “gene-desert” region in 8q24 might be associated with CRC susceptibility. We identified the rs13252298 and rs1456315 were associated with significantly decreased risks of CRC. In stratification analyses, we found that the rs1456315 was related to the tumor size of CRC. Moreover, patients with the rs7007694C allele and rs16901946G allele had decreased risks to develop poorly differentiated CRC, whereas patients with the rs1456315G allele had an increased risk to develop poorly differentiated CRC. These findings indicate that the polymorphisms in the lncRNA PRNCR1 may be related to the development of CRC, offering a novel and potential strategy for functional analysis of susceptibility loci to human diseases.
It has been shown that lncRNAs have developmental and tissue specific expression patterns, with an aberrant regulation in various diseases, including cancer [24, 36–44]. LncRNAs have been reported to be involved in cancer development in three different ways: Firstly, some lncRNAs take part in the process as oncogene or oncogene regulator, for example, MALAT1 gene in non-small cell lung cancer  and H19 in colon cancer . The expression of MALAT1 was up-regulated in many kinds of human cancers such as breast cancer, prostate cancer, colon cancer, liver cancer, and uterus cancer [44, 47–49]. Mice lacking H19 presented an increased polyp count which is related to CRC . Secondly, lncRNA may be related to cancer metastasis or prognosis. Gupta et al. reported a lncRNA HOTAIR which was associated with cancer metastasis and poor survival . Thirdly, lncRNAs appear as tumor suppressor gene: MEG3 is the first lncRNA proposed to function as a tumor suppressor and also a top level regulatory RNA because of its ability stimulating both p53-dependent and p53-independent pathways [32, 51]. Recurring chromosomal aberrations can influence the expression of many lncRNAs, such as disrupted in schizophrenia 1 and 2 (DISC1 and DISC2), which were involved in the development of various diseases [52, 53]. For instance, a large number of SNPs in the DISC1 genomic sequence have been reported to be associated with schizophrenia spectrum disorder [54, 55].
Emerging evidence has demonstrated that SNPs located in non-coding regions may be used as susceptibility factors to several diseases. Scott et al. reported that SNPs adjacent to the lncRNA ANRIL were associated with increased risks of type 2 diabetes . The viewpoint was also confirmed by a separate study, which reported that distinct SNPs in the lncRNA ANRIL locus were associated with susceptibility to coronary artery disease and atherosclerosis . Further characterization of the identified polymorphisms showed that SNPs can disrupt ANRIL splicing, leading to a circular transcript that is resistant to RNase digestion . The circularized transcripts have effect on ANRIL normal function and influence INK4/ARF expression. Other evidence is from the recent study of leukemia and CRC which identified both germline and somatic mutations in lncRNA genes . Recently, a novel lncRNA, named PRNCR1, has been discovered and was reported to be up-regulated in prostate cancer . SNPs in the lncRNA PRNCR1 gene might influence the predicted secondary structure of PRNCR1 mRNA, alter the stability of the lncRNA PRNCR1 or the mRNA conformation, and result in the modification of its interacting partners . Since the lncRNA PRNCR1 located in 8q24 which was a susceptibility locus to CRC [2–17, 59], we hypothesized that SNPs in this region may have roles in the development of CRC. Our findings confirmed our hypothesis. We found that tag SNPs in the lncRNA PRNCR1 may be a protective factor against CRC, suggesting that SNPs in lncRNA may be involved in the tumorigenesis of CRC. Although Chung and colleague’s report suggested that the lncRNA PRNCR1 was associated with prostate carcinogenesis and may play a role through the regulation of androgen receptor (AR) transactivation activity , no report investigated the relationship between the region 2 of 8q24 and CRC risk. Moreover, there were reports suggested that AR also participated in the pathologic process of CRC through TGFβ pathway [60, 61]. In this study, we found that the rs1456315 was also associated with clinical features of CRC, which was consistent with the report by Chung et al. .
Although we detected the association between SNPs in lncRNA and CRC, there were limitations needed to be mentioned in our study. One is that the follow-up information is blank, which limited our further analysis on the association between SNPs in lncRNA and CRC prognosis. Another is that the study subjects are all ethnic Han Chinese, and the sample size is moderate. Further large-scale studies in different populations, therefore, still need to be done.