The Discovery And Functional Characterization Of Pancreatic Cancer Susceptibility Gene LINC00673

Genome-wide association studies (GWAS) developed in the recent years have assisted biomedical researchers to identify a number of genes or genetic loci that are associated with pancreatic cancer risk. However, genetic factors influencing the development of sporadic pancreatic cancer remain largely unknown. In the present study, we report the discovery of new loci associated with susceptibility to pancreatic cancer by using genome-wide association analysis, and the functional and phenotypic relevance of the SNP and gene was examined by biochemical assays.We have recently reported a GWAS of pancreatic cancer in Chinese population, in which 666,141 SNPs were scanned in 981 pancreatic cancer cases and 1,991 controls followed by replicating 33 SNPs with P≤10-6 in independent sample sets consisting of 2,869 cases and 3,207 controls and five susceptibility loci were identified. However, it was proposed and has been demonstrated in several studies that the use of very stringent P-value threshold for selection of loci for replication in GWAS may overlook some true susceptibility loci. Therefore, it is warranted to perform further replication study with SNPs having less stringent P-value to identify more susceptibility loci for pancreatic cancer.By using a two-stage replication of 46 promising SNPs with 10-6<P<10-5 identified in our previous genome-wide scan, we found rs11655237G>A SNP in the fourth exon of LINC00673 associated with susceptibility to pancreatic cancer in the same direction as discovered in the genome-wide scan stage. Combined analysis of scan and replication data showed that this association was far beyond the genome-wide significance (P= 3.95×10-11), with the odds ratio of the minor A allele for pancreatic cancer risk being 1.26 (95% CI= 1.15-1.38).Biochemical analysis demonstrated that the germline variation in the LINC00673 exon (rs11655237) creates a target site for miRNA-1231 binding, which diminishes the effect of LINC00673 and thus confers susceptibility to oncogenesis. By using the LINC00673 knockdown and overexpression, combined with RNA pull-down and immunoprecipitation, we demonstrate that LINC00673 interacts with protein tyrosine phosphatase SHP2 and provokes its ubiquitin-mediated degradation, which causes diminished SRC/ERK oncogenic signaling and enhanced activation of signal transducers and activators of transcription 1-dependent anti-tumor response. In addition, knockdown of LINC00673 in pancreatic cancer cell lines promotes their proliferation, ability to form colonies, and xenograft tumor growth, whereas overexpression of LINC00673 obtains the opposite result.In conclusion, these findings shed new light on the importance role of LINC00673 in maintaining cell homeostasis and functional germline variation might confer susceptibility to pancreatic cancer. Our findings are of importance in better understanding the development of pancreatic cancer and may have potential utility in personalized prevention, and clinical care of this malignancy.