Daily Endocrinology Research Analysis
Analyzed 102 papers and selected 3 impactful papers.
Summary
Gene editing, tumor genomics, and population-scale multi-omics lead today’s endocrinology-adjacent advances. In vivo base editing of HFE C282Y corrects hepatic iron overload in preclinical models, corticotroph adenomas are molecularly stratified with prognostic relevance, and whole-genome sequence colocalization links type 2 diabetes risk variants to tissue-specific gene regulation.
Research Themes
- Therapeutic genome editing for metabolic liver disease
- Molecular subtyping and risk stratification in pituitary tumors
- Integrative genomics for type 2 diabetes mechanisms
Selected Articles
1. In vivo base editing alleviates hepatic iron accumulation and fibrosis in models of HFE-related hereditary hemochromatosis.
LNP-delivered adenine base editing efficiently corrected the HFE C282Y variant in vivo, reducing hepatic iron overload and fibrosis/cancer-associated transcriptomic signatures, with no detectable off-target edits at high-risk sites. Parallel correction in patient-derived hepatocyte-like cells supports translational feasibility for non-viral gene correction in hereditary hemochromatosis.
Impact: Provides first robust preclinical evidence that base editing can durably correct the common HFE C282Y mutation and ameliorate hepatic pathology without detectable off-targets. This represents a substantial therapeutic step for a prevalent genetic iron overload disorder lacking causal treatments.
Clinical Implications: Although preclinical, these findings support development of LNP-mediated base editing as a potential one-time, disease-modifying therapy for hereditary hemochromatosis, with the prospect of reducing phlebotomy burden and preventing fibrosis/cirrhosis.
Key Findings
- In vivo adenine base editing corrected HFE C282Y in mouse liver up to ~67% with reduced hepatic iron despite continued iron challenge.
- No off-target edits detected at genomic sites with 1–2 mismatches by next-generation sequencing.
- Transcriptomics showed decreased fibrosis and cancer-associated signatures after editing.
- Patient-derived iPSC hepatocyte-like cells achieved ~64% correction using the same LNP-base editor system.
Methodological Strengths
- Dual-system validation in vivo (mouse) and in human iPSC-derived hepatocyte-like cells
- Rigorous off-target assessment by next-generation sequencing at predicted risk sites
Limitations
- Preclinical models with short-term follow-up; durability and long-term safety remain to be established
- Editing and efficacy assessed under controlled iron challenge; scalability and dose optimization in larger animals not reported
Future Directions: Long-term durability and safety studies in large animals, liver-wide editing quantification, immune response profiling, and translational dose-finding toward first-in-human trials.
BACKGROUND & AIMS: HFE-related hereditary hemochromatosis is caused by loss-of-function mutations in the HFE gene, leading to excessive intestinal iron absorption and hepatic deposition. The C282Y variant in homozygosity accounts for 80-90% of diagnosed cases. If untreated, iron accumulation can cause liver fibrosis, cirrhosis, and hepatocellular carcinoma. METHODS: We employed lipid nanoparticles (LNPs) to deliver base editor mRNA and sgRNA for in vivo correction of the HFE C282Y mutation in a murine model under iron challenge. Additionally, patient-derived induced pluripotent stem cells (iPSCs) and hepatocyte-like cells were edited using the same approach. RESULTS: Base editing achieved a conversion rate of 73.6 ± 4.9% in cultured murine hepatocytes and up to 67% in vivo. No off-target effects were detected at genomic sites with one or two mismatches, as confirmed by next-generation sequencing. Treated mice showed significantly reduced hepatic iron overload despite continued high dietary iron intake. Transcriptomic analysis revealed decreased signatures associated with fibrosis and cancer. For preclinical evaluation, iPSCs from C282Y homozygous patients were differentiated into hepatocyte-like cells. LNP-mediated base editing achieved up to 63.8 ± 0.8% correction in these cells, again without detectable off-target activity. CONCLUSIONS: These results provide proof of concept that base editing of the C282Y variant is both safe and efficient in vivo
2. Distinct Genetic Alterations Drive Cushing Disease Versus Silent Corticotroph Adenomas.
Integrated genomic/transcriptomic profiling of 38 corticotroph adenomas reveals low-CNV, USP8/USP48-mutant Cushing disease with favorable outcomes and a high-CNV, TP53/ATRX/DAXX-altered subgroup enriched for aggressive silent corticotroph adenomas. CNV burden strongly associates with invasion and recurrence, supporting mutation/CNV profiling for postoperative risk stratification.
Impact: Defines molecular subtypes with clear clinicopathologic correlates, including a novel ATRX fusion, and links CNV burden to aggressiveness—directly informing surveillance and management of corticotroph tumors.
Clinical Implications: Routine CNV/mutation profiling (USP8/USP48 vs TP53/ATRX/DAXX) can refine postoperative surveillance intensity and counsel patients on recurrence risk; low-CNV USP8/USP48-mutant CD may require less intensive follow-up.
Key Findings
- USP8/USP48 mutations in 48% of Cushing disease tumors associate with low CNV, minimal invasion, and favorable remission.
- Silent corticotroph adenomas are enriched for TP53/ATRX/DAXX alterations with markedly elevated CNV and aggressive features.
- An ATRX-FAM138A mRNA fusion was identified, causing ATRX loss in an aggressive tumor.
- Across 38 tumors, higher CNV burden correlates with invasion, persistence, and recurrence/progression.
Methodological Strengths
- Integrated whole-exome, CNV, and RNA-seq with clinicopathologic correlation
- Unsupervised transcriptome clustering defining biologically and clinically meaningful subgroups
Limitations
- Modest sample size from specialized centers may limit generalizability
- Observational design without prospective validation of risk-stratified management
Future Directions: Prospective validation of CNV/mutation-guided surveillance, multi-institutional cohorts, and functional studies of ATRX/TP53/DAXX-driven corticotroph tumorigenesis.
BACKGROUND: Corticotroph adenomas include functioning tumors causing Cushing disease (CD) and silent corticotroph adenomas (SCA), which differ markedly in size, clinical presentation, and aggressiveness. The molecular basis for these differences remains incompletely understood. OBJECTIVE: To characterize genomic and transcriptomic alterations underlying the divergent clinical behavior of CD and SCA. METHODS: Thirty-eight tumors from 34 patients underwent whole-exome sequencing, copy-number variation (CNV) analysis, and mRNA sequencing. Molecular findings were integrated with clinical, radiological, and pathological data. RESULTS: USP8/USP48 mutations were present in 10 of 21 CD tumors (48%) and were associated with low CNV levels, minimal invasion, and favorable post-operative remission. In contrast, five of 13 SCAs harbored TP53/ATRX/DAXX mutations, all had markedly elevated CNV, and aggressive clinical features. Transcriptomic analysis identified an ATRX-FAM138A mRNA fusion, resulting in loss of ATRX expression in an aggressive tumor. Unsupervised transcriptome analyses defined four clusters. All USP8/USP48-mutant CD clustered together had low CNV and low recurrence rates. Cluster 2 consisted of a mixture of CD and SCA, with intermediate CNV and non-aggressive behavior. Cluster 3 included USP8-wildtype CD with heterogeneous yet generally non-aggressive courses. Cluster 4 represented high-CNV tumors enriched for TP53/ATRX/DAXX alterations, with the highest rates of radiological invasion, persistent disease, and recurrence or progression. Across the cohort, higher CNV was significantly associated with parameters of aggressiveness. CONCLUSION: Corticotroph adenomas comprise distinct molecular subtypes. USP8/USP48-mutant CD represents a low-CNV, low-risk group, whereas tumors harboring TP53/ATRX/DAXX mutations exhibit high CNV and aggressive clinical behavior. CNV and mutation profiling may assist in postoperative risk stratification.
3. Colocalization of eQTLs With Type 2 Diabetes and Glycemic Traits Using Whole-Genome Sequences in Diverse Populations From the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program.
Using TOPMed whole-genome sequencing in diverse cohorts, the study fine-mapped T2D/glycemic trait loci and identified 80 eQTL colocalizations in disease-relevant tissues, linking genetic risk to gene regulation. Results provide a functional roadmap to prioritize causal variants and target genes for precision medicine.
Impact: Connects population genetics to tissue-specific gene regulation at scale, advancing causal inference for T2D loci and accelerating target discovery beyond association signals.
Clinical Implications: While not directly clinical, the colocalized regulatory signals can guide functional validation and therapeutic target prioritization, informing precision risk prediction and drug development.
Key Findings
- Identified novel T2D/glycemic trait variants and improved fine-mapping resolution using whole-genome sequencing in diverse populations.
- Discovered 80 colocalization signals between GWAS loci and eQTLs in diabetes-relevant tissues, linking variants to gene regulation.
- Provided a resource to prioritize causal variants and effector genes for functional follow-up and target discovery.
Methodological Strengths
- Whole-genome sequencing enables comprehensive variant discovery and fine-mapping
- Integration with eQTL data across relevant tissues for regulatory colocalization
Limitations
- Functional validation of implicated genes/mechanisms is pending
- Abstract does not specify exact sample size or tissue panels; external generalizability requires replication
Future Directions: Experimental validation of prioritized variants/genes, single-cell multi-omic colocalization, and integration with perturbational datasets to nominate druggable pathways.
We aimed to improve understanding of the genetic architecture of type 2 diabetes and glycemic traits by leveraging whole-genome sequencing in diverse populations. Our goal was to identify novel variants, refine known loci, and link genetic signals to regulatory mechanisms through colocalization with expression quantitative trait loci. We discovered novel variants, significantly improved fine-mapping resolution, and identified 80 regulatory colocalization signals in diabetes-relevant tissues. These findings support precision medicine approaches by connecting genetic variation to functional biology in type 2 diabetes.