Leucine-rich glioma inactivated 3: Integrative analyses reveal its potential prognostic role in cancer.

Leucine-rich glioma inactivated 3 (LGI3) is a secreted protein in vertebrates, which belongs to the LGI family. In our previous study, LGI3 was found to be expressed in brain, adipose tissues and the skin, where it functions as a multifunctional cytokine. In the present study, we used bioinformatic tools to perform data mining, phylogenetics and prognostic association analysis to investigate the prognostic role of LGI3 in cancers. The sequences of LGI3 orthologues were analyzed from various species, and it was found that LGI3 was highly conserved in mammals and that the subsets of amino acid residues were phylogenetically coevolved in four major clusters. Single nucleotide polymorphisms (SNPs) of the human LGI3 gene included 228 functionally relevant variants (missense, nonsense and frameshift) in a total of 1,042 SNPs. Four missense SNPs had a global minor allele frequency ≥0.001. Somatic mutations in cancer with functional relevance were found in various types of cancer, including uterine, stomach and lung cancer. In addition, five amino acid residues with cancer mutations were shown to be coevolved in the vertebrate phylogeny, suggesting their importance in protein dysfunctions in cancer. One conserved amino acid and three SNPs were found to be mutated in stomach cancer and melanoma. Analysis of expression microarray data demonstrated that the expression of LGI3 was significantly associated with the prognosis of brain, colorectal and lung cancer. Taken together, these results suggested that the genetic variations and expression levels of LGI3 have potential value in cancer prognosis.