👤 Kord Kober

Biological age acceleration and disruptions in neurotrophin pathway signaling may significantly contribute to cancer-related cognitive impairment (CRCI) etiology. In this study, we evaluated the relationship of epigenetic age acceleration with cognitive function measures and circulating BDNF levels. Furthermore, we evaluated DNA methylation (DNAm) patterns to explore neurotrophin pathway associations with CRCI symptoms. In a longitudinal study, 51 newly diagnosed Adolescent and Young adult cancer patients and 8 age-matched healthy controls provided blood samples for DNAm and BDNF measurements with concurrent clinical assessments (#NCT03476070). We evaluated the relationship of epigenetic ageing with cancer status, circulating BDNF levels, and measured cognitive function. Next, we identified significant differentially methylated positions (DMPs), regions (DMRs), and significantly enriched pathways associated with BDNF and cognitive function outcomes. PhenoAge and GrimAge demonstrated significant age acceleration relative to non-cancer controls and worsening cognitive function symptoms, with accelerated GrimAge associated with decreasing BDNF levels. DMPs associated with 5 different cognitive function outcomes (FactCog Score, Response, Memory, Executive Function, Multi-Tasking) were mapped to genes within KEGG pathway HSA:04722 (Neurotrophin Signaling Pathway). Key enriched pathways relative to both subjective cognitive function and multiple objective cognitive measurement domains were also enriched with respect to BDNF levels, including Synapse (GO:0045202), Glutamatergic Synapse (GO:0098978), and Neuron Projection (GO:0043005). Cancer and cancer treatment lead to significant epigenetic age acceleration, which can influence neuronal health and CRCI symptom onset. Furthermore, DNAm patterns corroborate BDNF as a potential biomarker for CRCI and suggest neurotrophin pathways play a meaningful role in CRCI etiology. Show less

Growth hormone secretion by sporadic somatotroph neuroendocrine pituitary tumors (PitNETs) is a major cause of acromegaly. These tumors are relatively heterogenous in terms of histopathological and molecular features. Our previous transcriptomic profiling of somatotroph tumors revealed three distinct molecular subtypes. This study aimed to investigate the difference in DNA methylation patterns in subtypes of somatotroph PitNETs and its role in distinctive gene expression. Genome-wide DNA methylation was investigated in 48 somatotroph PitNETs with EPIC microarrays. Gene expression was assessed with RNAseq. Bisulfite pyrosequencing and qRT-PCR were used for verifying the results of DNA methylation and gene expression. Clustering tumor samples based on methylation data reflected the transcriptome-related classification. Subtype 1 tumors are densely granulated without GNAS mutation, characterized by high expression of NR5A1 (SF-1) and GIPR. The expression of both genes is correlated with specific methylation of the gene body and promoter. This subtype has a lower methylation level of 5' gene regions and CpG islands than the remaining tumors. Subtype 2 PitNETs are densely granulated and frequently GNAS-mutated, while those in subtype 3 are mainly sparsely granulated. Methylation/expression analysis indicates that ∼50% genes located in differentially methylated regions are those differentially expressed between tumor subtypes. Correlation analysis revealed DNA methylation-controlled genes, including CDKN1B, CCND2, EBF3, CDH4, CDH12, MGMT, STAT5A, PLXND1, PTPRE, and MMP16, and genes encoding ion channels and semaphorins. DNA methylation profiling confirmed the existence of three molecular subtypes of somatotroph PitNETs. High expression of NR5A1 and GIPR in subtype 1 tumors is correlated with specific methylation of both genes. Show less

Acromegaly results from growth hormone hypersecretion, predominantly caused by a somatotroph pituitary neuroendocrine tumor (PitNET). Acromegaly-causing tumors are histologically diverse. Our aim was to determine transcriptomic profiles of various somatotroph PitNETs and to evaluate clinical implication of differential gene expression. A total of 48 tumors were subjected to RNA sequencing, while expression of selected genes was assessed in 134 tumors with qRT-PCR. Whole-transcriptome analysis revealed three transcriptomic groups of somatotroph PitNETs. They differ in expression of numerous genes including those involved in growth hormone secretion and known prognostic genes. Transcriptomic subgroups can be distinguished by determining the expression of marker genes. Analysis of the entire cohort of patients confirmed differences between molecular subtypes of tumors. Transcriptomic group 1 includes ~20% of acromegaly patients with Show less

Hypertrophic cardiomyopathy (HCM) related myocardial vascular remodelling may lead to the reduction of myocardial blood supply and a subsequent progressive loss of cardiac function. This process has been difficult to observe and thus their connection remains unclear. Here we used non-invasive myocardial blood flow sensitive CMR to show an impairment of resting myocardial perfusion in a mouse model of naturally occurring HCM. We used a mouse model (DBA/2 J; D2 mouse strain) that spontaneously carries variants in the two most susceptible HCM genes-Mybpc3 and Myh7 and bears the key features of human HCM. The C57BL/6 J (B6) was used as a reference strain. Mice with either B6 or D2 backgrounds (male: n = 4, female: n = 4) underwent cine-CMR for functional assessment at 9.4 T. Left ventricular (LV) wall thickness was measured in end diastolic phase by cine-CMR. Quantitative myocardial perfusion maps (male: n = 5, female: n = 5 in each group) were acquired from arterial spin labelling (cine ASL-CMR) at rest. Myocardial perfusion values were measured by delineating different regions of interest based on the LV segmentation model in the mid ventricle of the LV myocardium. Directly after the CMR, the mouse hearts were removed for histological assessments to confirm the incidence of myocardial interstitial fibrosis (n = 8 in each group) and small vessel remodelling such as vessel density (n = 6 in each group) and perivascular fibrosis (n = 8 in each group). LV hypertrophy was more pronounced in D2 than in B6 mice (male: D2 LV wall thickness = 1.3 ± 0.1 mm vs B6 LV wall thickness = 1.0 ± 0.0 mm, p < 0.001; female: D2 LV wall thickness = 1.0 ± 0.1 mm vs B6 LV wall thickness = 0.8 ± 0.1 mm, p < 0.01). The resting global myocardial perfusion (myocardial blood flow; MBF) was lower in D2 than in B6 mice (end-diastole: D2 MBF Our work describes an imaging marker using cine ASL-CMR with a potential to monitor vascular and myocardial remodelling in HCM. Show less