Integrative analysis of genomic and transcriptomic alterations of AGR2 and AGR3 in cancer

The AGR2 and AGR3 genes have been shown by numerous groups to be functionally associated with adenocarcinoma progression and metastasis. In this paper, we explore the data available in databases concerning genomic and transcriptomic features of these two genes: the NCBI dbSNP database was used to explore the presence and roles of constitutional SNPs, and the NCI, Cancer Cell Line Encyclopedia (CCLE) and TCGA databases were used to explore somatic mutations and copy number variations (CNVs), as well as mRNA expression of these genes in human cancer cell lines and tumours. Relationships of AGR2/3 expression with whole-genome mRNA expression and cancer features (i.e. mutations and CNVs of oncogenes and tumour suppressor genes (TSG)) were established using the CCLE and TCGA databases. In addition, the CCLE data concerning CRISPR gene extinction screens (Achilles project) of these two genes and a panel of oncogenes and TSG were explored. We observed that no functional polymorphism or recurrent mutation could be detected in AGR2 or AGR3. The expression of these genes was positively correlated with the expression of epithelial genes and inversely correlated with that of mesenchymal genes. It was also significantly associated with several cancer features, such as TP53 or SMAD4 mutations, depending on the gene and the cancer type. In addition, the CRISPR screens revealed the absence of cell fitness modification upon gene extinction, in contrast with oncogenes (cell fitness decrease) and TSG (cell fitness increase). Overall, these explorations revealed that AGR2 and AGR3 proteins appear as common non-genetic evolutionary factors in the process of human tumorigenesis.