Effects of glutamate and aspartate on prostate cancer and breast cancer: a Mendelian randomization study.

Background: Respectively, prostate cancer (PCa) and breast cancer (BC) are the second most and most commonly diagnosed cancer in men and women, and they account for a majority of cancer-related deaths world-wide. Cancer cells typically exhibit much-facilitated growth that necessitates upregulated glycolysis and augmented amino acid metabolism, that of glutamine and aspartate in particular, which is tightly coupled with an increased flux of the tricarboxylic acid (TCA) cycle. Epidemiological studies have exploited metabolomics to explore the etiology and found potentially effective biomarkers for early detection or progression of prostate and breast cancers. However, large randomized controlled trials (RCTs) to establish causal associations between amino acid metabolism and prostate and breast cancers have not been reported.

Objective: Utilizing two-sample Mendelian randomization (MR), we aimed to estimate how genetically predicted glutamate and aspartate levels could impact upon prostate and breast cancers development.

Methods: Single nucleotide polymorphisms (SNPs) as instrumental variables (IVs), associated with the serum levels of glutamate and aspartate were extracted from the publicly available genome-wide association studies (GWASs), which were conducted to associate genetic variations with blood metabolite levels using comprehensive metabolite profiling in 1,960 adults; and the glutamate and aspartate we have chosen were two of 644 metabolites. The summary statistics for the largest and latest GWAS datasets for prostate cancer (61,106 controls and 79,148 cases) were from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium, and datasets for breast cancer (113,789 controls and 133,384 cases) were from Breast Cancer Association Consortium (BCAC). The study was performed through two-sample MR method.

Results: Causal estimates were expressed as odds ratios (OR) and 95% confidence interval (CI) per standard deviation increment in serum level of aspartate or glutamate. Aspartate was positively associated with prostate cancer (Effect = 1.043; 95% confidence interval, 1.003 to 1.084; P = 0.034) and breast cancer (Effect = 1.033; 95% confidence interval, 1.004 to 1.063; P = 0.028); however, glutamate was neither associated with prostate cancer nor with breast cancer. The potential causal associations were robust to the sensitivity analysis.

Conclusions: Our study found that the level of serum aspartate could serve as a risk factor that contributed to the development of prostate and breast cancers. Efforts on a detailed description of the underlying biochemical mechanisms would be extremely valuable in early assessment and/or diagnosis, and strategizing clinical intervention, of both cancers.