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

Abstract

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.

Expression of DGAT2 Gene and Its Associations With Intramuscular Fat Content and Breast Muscle Fiber Characteristics in Domestic Pigeons (Columba livia)

“…This result is consistent with previous studies reported on yaks, sheep, and chickens(1,2,28). DGAT2 is expressed widely in a variety of tissues in animals(1,29,30). The high expression level of DGAT2 in fat tissue indicates an important function in the synthesis and storage of triglycerides…”

Role of Dgat2 in Glucose Uptake and Fatty Acid Metabolism in C2C12 Skeletal Myotubes

“…So far, DGAT2 inhibition has not been attempted in a clinical setting but was reported as a well-tolerated therapeutic option for patients with nonalcoholic fatty liver disease [53]. In addition, DGAT2 mutations are associated with the phenotype of impaired muscle structure and function (e.g., Charcot-Marie-Tooth disease) in humans [54] and cellular transformation properties in several types of human cancer [55]. The findings of this study will add more insight in the application of DGAT inhibitor in risk prediction of several metabolic diseases and in phenotype identification according to their genotype match.…”

Integrated Analysis of Long Non-Coding RNA and mRNA to Reveal Putative Candidate Genes Associated with Backfat Quality in Beijing Black Pig

“…DGAT2, as a transmembrane protein, functions in lipid metabolism, especially in triacylglycerol (TG) synthesis. DGAT2 knocked out mice die after birth with a >90% reduction in TGs, which suggests that DGAT2 may act as the predominant enzyme for TG storage [ 58 , 59 ]. DGAT2 is also involved in the carotenoid synthesis, which may be important for yellow pigment deposition in yellow mutant rainbow trout [ 60 ].…”