Tumor heterogeneity and tumor-microglia interactions in primary and recurrent IDH1-mutant gliomas

The isocitrate dehydrogenase (IDH) gene is recurrently mutated in adult diffuse gliomas. IDH-mutant gliomas are categorized into oligodendrogliomas and astrocytomas, each with unique pathological features. Here, we use single-nucleus RNA and ATAC sequencing to compare the molecular heterogeneity of these glioma subtypes. In addition to astrocyte-like, oligodendrocyte progenitor-like, and cycling tumor subpopulations, a tumor population enriched for ribosomal genes and translation elongation factors is primarily present in oligodendrogliomas. Longitudinal analysis of astrocytomas indicates that the proportion of tumor subpopulations remains stable in recurrent tumors. Analysis of tumor-associated microglia/macrophages (TAMs) reveals significant differences between oligodendrogliomas, with astrocytomas harboring inflammatory TAMs expressing phosphorylated STAT1, as confirmed by immunohistochemistry. Furthermore, inferred receptor-ligand interactions between tumor subpopulations and TAMs may contribute to TAM state diversity. Overall, our study sheds light on distinct tumor populations, TAM heterogeneity, TAM-tumor interactions in IDH-mutant glioma subtypes, and the relative stability of tumor subpopulations in recurrent astrocytomas

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Impacts of forest conversion and agriculture practices on water pathways in Southern Brazil

© 2018 John Wiley & Sons, Ltd. Land-use/cover change (LUCC), and more specifically deforestation and multidecadal agriculture, is one of the various controlling factors of water fluxes at the hillslope or catchment scale. We investigated the impact of LUCC on water pathways and stream stormflow generation processes in a subtropical region in southern Brazil. We monitored, sampled and analysed stream water, pore water, subsurface water, and rainwater for dissolved silicon concentration (DSi) and 18O/16O (δ18O) signature to identify contributing sources to the streamflow under forest and under agriculture. Both forested and agricultural catchments were highly responsive to rainfall events in terms of discharge and shallow groundwater level. DSi versus δ18O scatter plots indicated that for both land-use types, two run-off components contributed to the stream discharge. The presence of a dense macropore network, combined with the presence of a compact and impeding B-horizon, led to rapid subsurface flow in the forested catchment. In the agricultural catchment, the rapid response to rainfall was mostly due to surface run-off. A 2-component isotopic hydrograph separation indicated a larger contribution of rainfall water to run-off during rainfall event in the agricultural catchments. We attributed this higher contribution to a decrease in topsoil hydraulic conductivity associated with agricultural practices. The chemical signature of the old water component in the forested catchment was very similar to that of the shallow groundwater and the pore soil water: It is therefore likely that the shallow groundwater was the main source of old water. This is not the case in the agricultural catchments where the old water component had a much higher DSi concentration than the shallow groundwater and the soil pore water. As the agricultural catchments were larger, this may to some extent simply be a scale effect. However, the higher water yields under agriculture and the high DSi concentration observed in the old water under agriculture suggest a significant contribution of deep groundwater to catchment run-off under agriculture, suggesting that LUCC may have significant effects on weathering rates and patterns.status: publishe

Defective homologous recombination DNA repair as therapeutic target in advanced chordoma

Chordomas are rare bone tumors with limited therapeutic options. Here, the authors identify molecular alterations associated with defective homologous recombination DNA repair in advanced chordomas and report prolonged response in a patient treated with a PARP inhibitor, which later acquired resistance due to a newly gained PARP1 mutation

Integrative genomic and transcriptomic analysis of leiomyosarcoma

The molecular genetic landscape of leiomyosarcoma (LMS) is largely unknown. Here, the authors identify frequent DNA copy number alterations, whole-genome duplication, TP53 and RB1 inactivation, alternative telomere lengthening, and genomic imprints of defective DNA repair via homologous recombination as a potential therapeutic target in LMS patients

Pheno-seq - linking visual features and gene expression in 3D cell culture systems

Patient-derived 3D cell culture systems are currently advancing cancer research since they potentiate the molecular analysis of tissue-like properties and drug response under well-defined conditions. However, our understanding of the relationship between the heterogeneity of morphological phenotypes and the underlying transcriptome is still limited. To address this issue, we here introduce "pheno-seq" to directly link visual features of 3D cell culture systems with profiling their transcriptome. As prototypic applications breast and colorectal cancer (CRC) spheroids were analyzed by pheno-seq. We identified characteristic gene expression signatures of epithelial-to-mesenchymal transition that are associated with invasive growth behavior of clonal breast cancer spheroids. Furthermore, we linked long-term proliferative capacity in a patient-derived model of CRC to a lowly abundant PROX1-positive cancer stem cell subtype. We anticipate that the ability to integrate transcriptome analysis and morphological patho-phenotypes of cancer cells will provide novel insight on the molecular origins of intratumor heterogeneity

Pheno-seq - linking visual features and gene expression in 3D cell culture systems

Patient-derived 3D cell culture systems are currently advancing cancer research since they potentiate the molecular analysis of tissue-like properties and drug response under well-defined conditions. However, our understanding of the relationship between the heterogeneity of morphological phenotypes and the underlying transcriptome is still limited. To address this issue, we here introduce "pheno-seq" to directly link visual features of 3D cell culture systems with profiling their transcriptome. As prototypic applications breast and colorectal cancer (CRC) spheroids were analyzed by pheno-seq. We identified characteristic gene expression signatures of epithelial-to-mesenchymal transition that are associated with invasive growth behavior of clonal breast cancer spheroids. Furthermore, we linked long-term proliferative capacity in a patient-derived model of CRC to a lowly abundant PROX1-positive cancer stem cell subtype. We anticipate that the ability to integrate transcriptome analysis and morphological patho-phenotypes of cancer cells will provide novel insight on the molecular origins of intratumor heterogeneity