Rare variants confer shared susceptibility to gastrointestinal tract cancer risk.

Background: Cancers arising within the gastrointestinal tract are complex disorders involving genetic events that cause the conversion of normal tissue to premalignant lesions and malignancy. Shared genetic features are reported in epithelial-based gastrointestinal cancers which indicate common susceptibility among this group of malignancies. In addition, the contribution of rare variants may constitute parts of genetic susceptibility. Methods: A cross-cancer analysis of 38,171 shared rare genetic variants from genome-wide association assays was conducted, which included data from 3,194 cases and 1,455 controls across three cancer sites (esophageal, gastric and colorectal). The SNP-level association was performed by multivariate logistic regression analyses for single cancer, followed by association analysis for SubSETs (ASSET) to adjust the bias of overlapping controls. Gene-level analyses were conducted by SKAT-O, with multiple comparison adjustments by false discovery rate (FDR). Based on the significant genes indicated by SKATO analysis, pathways analysis was conducted using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases. Results: Meta-analysis in three gastrointestinal (GI) cancers identified 13 novel susceptibility loci that reached genome-wide significance (P ASSET< 5×10-8). SKAT-O analysis revealed EXOC6, LRP5L and MIR1263/LINC01324 to be significant genes shared by GI cancers (P adj<0.05, P FDR<0.05). Furthermore, GO pathway analysis identified significant enrichment of synaptic transmission and neuron development pathways shared by all three cancer types. Conclusion: Rare variants and the corresponding genes potentially contribute to shared susceptibility in different GI cancer types. The discovery of these novel variants and genes offers new insights for the carcinogenic mechanisms and missing heritability of GI cancers.