Thomas Fleischer

Aberrant DNA methylation is a hallmark of many cancer types. Despite our knowledge of epigenetic and transcriptomic alterations in lung adenocarcinoma (LUAD), we lack robust multi‐modal molecular classifications for patient stratification. This is partly because the impact of epigenetic alterations on lung cancer development and progression is still not fully understood. To that end, we identified disease‐associated processes under epigenetic regulation in LUAD. We performed a genome‐wide expression‐methylation Quantitative Trait Loci (emQTL) analysis by integrating DNA methylation and gene expression data from 453 patients in the TCGA cohort. Using a community detection algorithm, we identified distinct communities of CpG‐gene associations with diverse biological processes. Interestingly, we identified a community linked to hormone response and lipid metabolism; the identified CpGs in this community were enriched in enhancer regions and binding regions of transcription factors such as FOXA1/2, GRHL2, HNF1B, AR, and ESR1. Furthermore, the CpGs were connected to their associated genes through chromatin interaction loops. These findings suggest that the expression of genes involved in hormone response and lipid metabolism in LUAD is epigenetically regulated through DNA methylation and enhancer‐promoter interactions. By applying consensus clustering on the integrated expression‐methylation pattern of the emQTL‐genes and CpGs linked to hormone response and lipid metabolism, we further identified subclasses of patients with distinct prognoses. This novel patient stratification was validated in an independent patient cohort of 135 patients and showed increased prognostic significance compared to previously defined molecular subtypes.

Anti-VEGF (vascular endothelial growth factor) treatment improves response rates, but not progression-free or overall survival in advanced breast cancer. It has been suggested that subgroups of patients may benefit from this treatment; however, the effects of adding anti-VEGF treatment to a standard chemotherapy regimen in breast cancer patients are not well studied. Understanding the effects of the anti-vascular treatment on tumor vasculature may provide a selection of patients that can benefit. The aim of this study was to study the vascular effect of bevacizumab using clinical dynamic contrast-enhanced MRI (DCE-MRI). A total of 70 women were randomized to receive either chemotherapy alone or chemotherapy with bevacizumab for 25 weeks. DCE-MRI was performed at baseline and at 12 and 25 weeks, and in addition 25 of 70 patients agreed to participate in an early MRI after one week. Voxel-wise pharmacokinetic analysis was performed using semi-quantitative methods and the extended Tofts model. Vascular architecture was assessed by calculating the fractal dimension of the contrast-enhanced images. Changes during treatment were compared with baseline and between the treatment groups. There was no significant difference in tumor volume at any point; however, DCE-MRI parameters revealed differences in vascular function and vessel architecture. Adding bevacizumab to chemotherapy led to a pronounced reduction in vascular DCE-MRI parameters, indicating decreased vascularity. At 12 and 25 weeks, the difference between the treatment groups is severely reduced.