Ghesquière, Bart

Inherited metabolic disorders (IMDs) are genetic disorders that occur in as many as 1:2500 births worldwide. Nevertheless, they are quite rare individually and even more rare is the co-occurrence of two IMDs in one individual. To better understand the metabolic cross-talk between glycosylation changes and deficient energy metabolism, and its potential effect on outcomes, we evaluated patient fibroblasts with likely pathogenic variants in PGM1 and pathogenic variants in NDUFA13 derived from a patient who passed away at 16 years of age. The patient presented with characteristic of PGM1-CDG including bifid uvula, muscle involvement, abnormal glycosylation in blood, and elevated liver transaminases. In addition, hearing loss, seizures, elevated plasma and CSF lactate and a Leigh-like MRI brain pattern were present, which are commonly associated with Leigh syndrome. PGM1-CDG has been reported in about 70 individuals, while NDUFA13 deficiency has so far only been reported in 13 patients. As abundant energy is essential for glycosylation, and both PGM1 and NDUFA13 are linked to energy metabolism, we sought to better understand the underlying biochemical cause of the patient’s clinical presentation. To do so, we performed extensive investigations including tracer metabolomics, lipidomics and enzymatic studies on the patient’s fibroblasts. We found a profound depletion of UDP-hexoses, consistent with PGM1-CDG. Complex I enzyme activity and mitochondrial function were also impaired, corroborating complex I deficiency and Leigh syndrome. Further, lipidomics analysis showed similarities with both PGM1-CDG and OXPHOS-deficient patients. Based on our results, the patient was diagnosed with both PGM1-CDG and Leigh syndrome. In summary, we present the first case of combined CDG and Leigh syndrome, caused by (likely) pathogenic variants in PGM1 and NDUFA13, and underline the importance of considering the synergistic effects of multiple disease-causing variants in patients with complex clinical presentation, leading to the patient’s early demise.

Abstract Molecular drivers of metastasis in patients with high-risk localized prostate cancer are poorly understood. Therefore, we aim to study molecular drivers of metastatic progression in patients with high-risk prostate cancer. A retrospective matched case-control study of two clinico-pathologically identical groups of patients with high-risk prostate cancer was undertaken. One group developed metastatic recurrence (n = 19) while the other did not (n = 25). The primary index tumor was identified by a uro-pathologist, followed by DNA and RNA extraction for somatic copy-number aberration (SCNA) analysis and whole-transcriptome gene expression analysis. In vitro and in vivo studies included cell line manipulation and xenograft models. The integrative CNA and gene expression analyses identified an increase in Antizyme Inhibitor 1 (AZIN1) gene expression within a focal amplification of 8q22.3, which was associated with metastatic recurrence of patients with high-risk prostate cancer in four independent cohorts. The effects of AZIN1 knockdown were evaluated, due to its therapeutic potential. AZIN1 knockdown effected proliferation and metastatic potential of prostate cancer cells and xenograft models. RNA sequencing after AZIN1 knockdown in prostate cancer cells revealed upregulation of genes coding for collagen subunits. The observed effect on cell migration after AZIN1 knockdown was mimicked when exposing prostate cancer cells to bio-active molecules deriving from COL4A1 and COL4A2. Our integrated CNA and gene expression analysis of primary high-risk prostate cancer identified the AZIN1 gene as a novel driver of metastatic progression, by altering collagen subunit expression. Future research should further investigate its therapeutic potential in preventing metastatic recurrence. Implications: AZIN1 was identified as driver of metastatic progression in high-risk prostate cancer through matrikine regulation.