Comprehensive Genetic Analysis of DGAT2 Mutations and Gene Expression Patterns in Human Cancers

Simple Summary Cellular metabolism including lipid metabolism is often altered in cancer cells. To keep up with the high energetic demand of cancer cells lipid metabolism is increased. Thus, mutations, changes in gene expression or other alterations of lipid metabolism genes are often seen in cancer cells. In this report we characterized DGAT2, a gene required for triacylglycerol synthesis and cell membrane structure using the Catalogue of Somatic Mutations in Cancers (COSMIC). We identified a hotspot mutation at D222V that may affect enzyme activity in cancer cells. Additionally, we find that DGAT2 mutations in cancer cells are distinguishable from a conserved mutation that is linked to Axonal Charcot-Marie-Tooth disease, an inherited condition leading to muscle degeneration. This suggests that DGAT2 mutations and alterations in cancer cells are specific to drive cellular transformation and immortalization. DGAT2 is a transmembrane protein encoded by the DGAT2 gene that functions in lipid metabolism, triacylglycerol synthesis, and lipid droplet regulation. Cancer cells exhibit altered lipid metabolism and mutations in DGAT2 may contribute to this state. Using data from the Catalogue of Somatic Mutations in Cancer (COSMIC), we analyzed all cancer genetic DGAT2 alterations, including mutations, copy number variations and gene expression. We find that several DGAT2 mutations fall within the catalytic site of the enzyme. Using the Variant Effect Scoring Tool (VEST), we identify multiple mutations with a high likelihood of contributing to cellular transformation. We also found that D222V is a mutation hotspot neighboring a previously discovered Y223H mutation that causes Axonal Charcot-Marie-Tooth disease. Remarkably, Y223H has not been detected in cancers, suggesting that it is inhibitory to cancer progression. We also identify several single nucleotide polymorphisms (SNP) with high VEST scores, indicating that certain alleles in human populations have a pathogenic predisposition. Most mutations do not correlate with a change in gene expression, nor is gene expression dependent on high allele copy number. However, we did identify eight alleles with high expression levels, suggesting that at least in certain cases, the excess DGAT2 gene product is not inhibitory to cellular proliferation. This work uncovers unknown functions of DGAT2 in cancers and suggests that its role may be more complex than previously appreciated.