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Brainstem gliomas are a heterogeneous group of tumors that encompass both benign tumors cured with surgical resection and highly lethal cancers with no efficacious therapies. We perform a comprehensive study incorporating epigenetic and genomic analyses on a large cohort of brainstem gliomas, including Diffuse Intrinsic Pontine Gliomas. Here we report, from DNA methylation data, distinct clusters termed H3-Pons, H3-Medulla, IDH, and PA-like, each associated with unique genomic and clinical profiles. The majority of tumors within H3-Pons and-H3-Medulla harbors H3F3A mutations but shows distinct methylation patterns that correlate with anatomical localization within the pons or medulla, respectively. Clinical data show significantly different overall survival between these clusters, and pathway analysis demonstrates different oncogenic mechanisms in these samples. Our findings indicate that the integration of genetic and epigenetic data can facilitate better understanding of brainstem gliomagenesis and classification, and guide future studies for the development of novel treatments for this disease., Brainstem gliomas are heterogenous in terms of clinical outcome and disease etiology. Here, the authors present a genetic and epigenetic landscape of brainstem gliomas, finding distinct epigenetic clusters associated with unique genetic and clinical profiles.

Obesity-related insulin resistance represents the core component of the metabolic syndrome, promoting glucose intolerance, pancreatic beta cell failure and type 2 diabetes. Efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications Here, we identify transforming growth factor beta-like stimulated clone (TSC) 22 D4 as a molecular determinant of insulin signalling and glucose handling. Hepatic TSC22D4 inhibition both prevents and reverses hyperglycaemia, glucose intolerance and insulin resistance in diabetes mouse models. TSC22D4 exerts its effects on systemic glucose homeostasis—at least in part—through the direct transcriptional regulation of the small secretory protein lipocalin 13 (LCN13). Human diabetic patients display elevated hepatic TSC22D4 expression, which correlates with decreased insulin sensitivity, hyperglycaemia and LCN13 serum levels. Our results establish TSC22D4 as a checkpoint in systemic glucose metabolism in both mice and humans, and propose TSC22D4 inhibition as an insulin sensitizing option in diabetes therapy., TSC22D4 regulates hepatic lipoprotein production, but has so far mainly been studied in the context of cancer cachexia. Here, the authors show TSC22D4 inhibition improves insulin sensitivity in several mouse models of diabetes, which they attribute at least in part to the induction of secreted LCN13.

Quantitative genetic epistasis has been hypothesized to be an important factor in the development and progression of complex diseases. Cancers in particular are driven by the accumulation of mutations that may act epistatically during the course of the disease. However, as cancer mutations are uncovered at an unprecedented rate, determining which combinations of genetic alterations interact to produce cancer phenotypes remains a challenge. Here we show that by using combinatorial RNAi screening in cell culture, dense and often previously undetermined interactions among cancer genes were revealed by assessing gene pairs that are frequently co-altered in primary breast cancers. These interacting gene pairs are significantly associated with survival time when co-altered in patients, indicating that genetic interaction mapping may be leveraged to improve risk assessment. As many of these interacting gene pairs involve known drug targets, personalized treatment regimens may be improved by overlaying genetic interactions with mutational profiling.