Inflammatory Bowel Disease Risk Variants Are Associated with an Increased Risk of Skin Cancer.

BACKGROUND: Inflammatory bowel disease is associated with an increased risk of skin cancer. The aims of this study were to determine whether IBD susceptibility variants are also associated with skin cancer susceptibility and if such risk is augmented by use of immune-suppressive therapy. METHODS: The discovery cohort included participants in the UK Biobank. The validation cohort included participants in the Michigan Genomics Initiative. The primary outcome of interest was skin cancer, subgrouped into nonmelanoma skin cancers (NMSC) and melanoma skin cancers (MSC). Multivariable logistic regression with matched controls (3 controls:1 case) was performed to identify genomic predictors of skin malignancy in the discovery cohort. Variants with P < .05 were tested for replication in the validation cohort. Validated Single nucleotide polymorphisms were then evaluated for effect modification by immune-suppressive medications. RESULTS: The discovery cohort included 10,247 cases of NMSC and 1883 cases of MSC. The validation cohort included 7334 cases of NMSC and 3304 cases of MSC. Twenty-nine variants were associated with risk of NMSC in the discovery cohort, of which 5 replicated in the validation cohort (increased risk, rs7773324-A [DUSP22; IRF4], rs2476601-G [PTPN22], rs1847472-C [BACH2], rs72810983-A [CPEB4]; decreased risk, rs6088765-G [PROCR; MMP24]). Twelve variants were associated with risk of MSC in the discovery cohort, of which 4 were replicated in the validation cohort (increased risk, rs61839660-T [IL2RA]; decreased risk, rs17391694-C [GIPC2; MGC27382], rs6088765-G [PROCR; MMP24], and rs1728785-C [ZFP90]). No effect modification was observed. CONCLUSIONS: The results of this study highlight shared genetic susceptibility across IBD and skin cancer, with increased risk of NMSC in those who carry risk variants in IRF4, PTPN22, CPEB4, and BACH2 and increased risk of MSC in those who carry a risk variant in IL2RA.

Single cell RNA sequencing of AML initiating cells reveals RNA-based evolution during disease progression.

The prognosis of most patients with AML is poor due to frequent disease relapse. The cause of relapse is thought to be from the persistence of leukemia initiating cells (LIC's) following treatment. Here we assessed RNA based changes in LICs from matched patient diagnosis and relapse samples using single-cell RNA sequencing. Previous studies on AML progression have focused on genetic changes at the DNA mutation level mostly in bulk AML cells and demonstrated the existence of DNA clonal evolution. Here we identified in LICs that the phenomenon of RNA clonal evolution occurs during AML progression. Despite the presence of vast transcriptional heterogeneity at the single cell level, pathway analysis identified common signaling networks involving metabolism, apoptosis and chemokine signaling that evolved during AML progression and become a signature of relapse samples. A subset of this gene signature was validated at the protein level in LICs by flow cytometry from an independent AML cohort and functional studies were performed to demonstrate co-targeting BCL2 and CXCR4 signaling may help overcome therapeutic challenges with AML heterogeneity. It is hoped this work will facilitate a greater understanding of AML relapse leading to improved prognostic biomarkers and therapeutic strategies to target LIC's.

A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction.

CONTEXT: Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation. OBJECTIVE: Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease. DESIGN: Genetics of Obesity-associated Liver Disease Consortium. SETTING: Population-based. MAIN OUTCOME: Computed tomography measured liver attenuation. RESULTS: Carriers of rs4841132-A (frequency 2%-19%) do not show increased hepatic steatosis; they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190 kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105-bp deletion including rs4841132-A in human hepatocarcinoma cells that increases PPP1R3B, decreases LOC157273, and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on electronic health record (EHR) data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides, and decreased acetoacetate and beta-hydroxybutyrate. CONCLUSIONS: These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI.

Gliomas display distinct sex-based differential methylation patterns based on molecular subtype.

BACKGROUND: Gliomas are the most common type of primary brain tumor and one of many cancers where males are diagnosed with greater frequency than females. However, little is known about the sex-based molecular differences in glioblastomas (GBMs) or lower grade glioma (non-GBM) subtypes. DNA methylation is an epigenetic mechanism involved in regulating gene transcription. In glioma and other cancers, hypermethylation of specific gene promoters downregulates transcription and may have a profound effect on patient outcome. The purpose of this study was to determine if sex-based methylation differences exist in different glioma subtypes. METHODS: Molecular and clinical data from glioma patients were obtained from The Cancer Genome Atlas and grouped according to tumor grade and molecular subtype (IDH1/2 mutation and 1p/19q chromosomal deletion). Sex-specific differentially methylated probes (DMPs) were identified in each subtype and further analyzed to determine if they were part of differentially methylated regions (DMRs) or associated with differentially methylated DNA transcription regulatory binding motifs. RESULTS: Analysis of methylation data in 4 glioma subtypes revealed unique sets of both sex-specific DMPs and DMRs in each subtype. Motif analysis based on DMP position also identified distinct sex-based sets of DNA-binding motifs that varied according to glioma subtype. Downstream targets of 2 of the GBM-specific transcription binding sites, NFAT5 and KLF6, showed differential gene expression consistent with increased methylation mediating downregulation. CONCLUSION: DNA methylation differences between males and females in 4 glioma molecular subtypes suggest an important, sex-specific role for DNA methylation in epigenetic regulation of gliomagenesis.

Proteins inform survival-based differences in patients with glioblastoma.

BACKGROUND: Improving the care of patients with glioblastoma (GB) requires accurate and reliable predictors of patient prognosis. Unfortunately, while protein markers are an effective readout of cellular function, proteomics has been underutilized in GB prognostic marker discovery. METHODS: For this study, GB patients were prospectively recruited and proteomics discovery using liquid chromatography-mass spectrometry analysis (LC-MS/MS) was performed for 27 patients including 13 short-term survivors (STS) (≤10 months) and 14 long-term survivors (LTS) (≥18 months). RESULTS: Proteomics discovery identified 11 941 peptides in 2495 unique proteins, with 469 proteins exhibiting significant dysregulation when comparing STS to LTS. We verified the differential abundance of 67 out of these 469 proteins in a small previously published independent dataset. Proteins involved in axon guidance were upregulated in STS compared to LTS, while those involved in p53 signaling were upregulated in LTS. We also assessed the correlation between LS MS/MS data with RNAseq data from the same discovery patients and found a low correlation between protein abundance and mRNA expression. Finally, using LC-MS/MS on a set of 18 samples from 6 patients, we quantified the intratumoral heterogeneity of more than 2256 proteins in the multisample dataset. CONCLUSIONS: These proteomic datasets and noted protein variations present a beneficial resource for better predicting patient outcome and investigating potential therapeutic targets.

Sex is an important prognostic factor for glioblastoma but not for nonglioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common and most malignant glioma. Nonglioblastoma (non-GBM) gliomas (WHO Grades II and III) are invasive and also often fatal. The goal of this study is to determine whether sex differences exist in glioma survival. METHODS: Data were obtained from the National Cancer Database (NCDB) for years 2010 to 2014. GBM (WHO Grade IV; N = 2073) and non-GBM (WHO Grades II and III; N = 2963) were defined using the histology grouping of the Central Brain Tumor Registry of the United States. Non-GBM was divided into oligodendrogliomas/mixed gliomas and astrocytomas. Sex differences in survival were analyzed using Kaplan-Meier and multivariable Cox proportional hazards models adjusted for known prognostic variables. RESULTS: There was a female survival advantage in patients with GBM both in the unadjusted (P = .048) and adjusted (P = .003) models. Unadjusted, median survival was 20.1 months (95% CI: 18.7-21.3 months) for women and 17.8 months (95% CI: 16.9-18.7 months) for men. Adjusted, median survival was 20.4 months (95% CI: 18.9-21.6 months) for women and 17.5 months (95% CI: 16.7-18.3 months) for men. When stratifying by age group (18-55 vs 56+ years at diagnosis), this female survival advantage appeared only in the older group, adjusting for covariates (P = .017). Women (44.1%) had a higher proportion of methylated MGMT (O6-methylguanine-DNA methyltransferase) than men (38.4%). No sex differences were found for non-GBM. CONCLUSIONS: Using the NCDB data, there was a statistically significant female survival advantage in GBM, but not in non-GBM.