development-of-mouse-models-for-mntrier-s-disease

Development of Mouse Models for M&#233;n&#233;trier's Disease

M&#233;n&#233;trier&#39;s disease (MD) is a rare acquired premalignant gastric disorder characterized by giant rugal folds, decreased acid secretion, and ...

Yale School of Medicine

To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, had a high rate of significantly mutated genes in important immune-modulating pathways and in the antigen presentation machinery, including biallelic losses of  and  genes due to copy-number alterations and copy-neutral loss of heterozygosity. WNT/β-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of colorectal cancer demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration and, furthermore, that colorectal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion. This multi-omic analysis of 1,211 colorectal cancer primary tumors reveals that it should be possible to better monitor resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not. .

Genetic Mechanisms of Immune Evasion in Colorectal Cancer.

To identify causes of the autosomal-recessive malformation, diencephalic-mesencephalic junction dysplasia (DMJD) syndrome.

Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome.

Large-scale, population-based biobanks integrating health records and genomic profiles may provide a platform to identify individuals with disease-predisposing genetic variants. Here, we recall probands carrying familial hypercholesterolemia (FH)-associated variants, perform cascade screening of family members, and describe health outcomes affected by such a strategy.

Recall by genotype and cascade screening for familial hypercholesterolemia in a population-based biobank from Estonia.

Lipid droplets (LDs) store lipids for energy and are central to cellular lipid homeostasis. The mechanisms coordinating lipid storage in LDs with cellular metabolism are unclear but relevant to obesity-related diseases. Here we utilized genome-wide screening to identify genes that modulate lipid storage in macrophages, a cell type involved in metabolic diseases. Among ∼550 identified screen hits is MLX, a basic helix-loop-helix leucine-zipper transcription factor that regulates metabolic processes. We show that MLX and glucose-sensing family members MLXIP/MondoA and MLXIPL/ChREBP bind LDs via C-terminal amphipathic helices. When LDs accumulate in cells, these transcription factors bind to LDs, reducing their availability for transcriptional activity and attenuating the response to glucose. Conversely, the absence of LDs results in hyperactivation of MLX target genes. Our findings uncover a paradigm for a lipid storage response in which binding of MLX transcription factors to LD surfaces adjusts the expression of metabolic genes to lipid storage levels.

Partitioning of MLX-Family Transcription Factors to Lipid Droplets Regulates Metabolic Gene Expression.

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes. Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.

The mutational constraint spectrum quantified from variation in 141,456 humans.

Adipose tissue contains a complex immune environment and is a central contributor to heightened systemic inflammation in obese persons. Epoxyeicosatrienoic acids (EETs) are lipid signaling molecules that decrease inflammation in obese animals, but their effect on inflammation in humans is unknown. The enzyme soluble epoxide hydrolase (sEH) hydrolyzes EETs to less active diols, and we hypothesized that pharmacologic sEH inhibition would decrease adipose inflammation in obese individuals. We treated obese prediabetic adults with the sEH inhibitor GSK2256294 versus placebo in a crossover design, collected subcutaneous abdominal adipose tissue via lipoaspiration and characterized the tissue T cell profile. Treatment with GSK2256294 decreased the percentage of pro-inflammatory T cells producing interferon-gamma (IFNγ), but not interleukin (IL)-17A, and decreased the amount of secreted tumor necrosis factor-alpha (TNFα). Understanding the contribution of the EET/sEH pathway to inflammation in obesity could lead to new strategies to modulate adipose and systemic inflammation.

The soluble epoxide hydrolase inhibitor GSK2256294 decreases the proportion of adipose pro-inflammatory T cells.

The SARS-CoV-2 Delta variant rose to dominance in mid-2021, likely propelled by an estimated 40%-80% increased transmissibility over Alpha. To investigate if this ostensible difference in transmissibility is uniform across populations, we partner with public health programs from all six states in New England in the United States. We compare logistic growth rates during each variant's respective emergence period, finding that Delta emerged 1.37-2.63 times faster than Alpha (range across states). We compute variant-specific effective reproductive numbers, estimating that Delta is 63%-167% more transmissible than Alpha (range across states). Finally, we estimate that Delta infections generate on average 6.2 (95% CI 3.1-10.9) times more viral RNA copies per milliliter than Alpha infections during their respective emergence. Overall, our evidence suggests that Delta's enhanced transmissibility can be attributed to its innate ability to increase infectiousness, but its epidemiological dynamics may vary depending on underlying population attributes and sequencing data availability.

Comparative transmissibility of SARS-CoV-2 variants Delta and Alpha in New England, USA.

Pathogenic germline  alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer is the most common cancer in LFS females. We performed first of its kind multimodal analysis of LFS breast cancer (LFS-BC) compared to sporadic premenopausal BC. Nearly all LFS-BC underwent biallelic loss of  with no recurrent oncogenic variants except  (HER2) amplification. Compared to sporadic BC,  and invasive LFS-BC exhibited a high burden of short amplified aneuploid segments (SAAS). Pro-apoptotic p53 target genes  and  failed to be up-regulated in LFS-BC as was seen in sporadic BC compared to normal breast tissue. LFS-BC had lower CD8+ T-cell infiltration compared to sporadic BC yet higher levels of proliferating cytotoxic T-cells. Within LFS-BC, progression from  to invasive BC was marked by an increase in chromosomal instability with a decrease in proliferating cytotoxic T-cells. Our study uncovers critical events in mutant p53-driven tumorigenesis in breast tissue.

Distinct genomic and immunologic tumor evolution in germline -driven breast cancers.

The objective of this study was to identify the transcriptional landscape of insulin resistance (IR) in subcutaneous adipose tissue (SAT) in humans across the spectrum of obesity.

The subcutaneous adipose transcriptome identifies a molecular signature of insulin resistance shared with visceral adipose.

Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens. However, whether such responses can target cancer driver mutations, lead to immune recognition of a patient's tumour and result in clinical activity are largely unknown. These questions are of particular interest for patients who have tumours with a low mutational burden. Here we conducted a phase I trial (ClinicalTrials.gov identifier NCT02950766) to test a neoantigen-targeting PCV in patients with high-risk, fully resected clear cell renal cell carcinoma (RCC; stage III or IV) with or without ipilimumab administered adjacent to the vaccine. At a median follow-up of 40.2 months after surgery, none of the 9 participants enrolled in the study had a recurrence of RCC. No dose-limiting toxicities were observed. All patients generated T cell immune responses against the PCV antigens, including to RCC driver mutations in VHL, PBRM1, BAP1, KDM5C and PIK3CA. Following vaccination, there was a durable expansion of peripheral T cell clones. Moreover, T cell reactivity against autologous tumours was detected in seven out of nine patients. Our results demonstrate that neoantigen-targeting PCVs in high-risk RCC are highly immunogenic, capable of targeting key driver mutations and can induce antitumour immunity. These observations, in conjunction with the absence of recurrence in all nine vaccinated patients, highlights the promise of PCVs as effective adjuvant therapy in RCC.

Article	Year
Genetic Mechanisms of Immune Evasion in Colorectal Cancer. Cancer discovery\| PubMed ID: 29510987	2018
Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome. Annals of neurology\| PubMed ID: 30178464	2018
Recall by genotype and cascade screening for familial hypercholesterolemia in a population-based biobank from Estonia. Genetics in medicine : official journal of the American College of Medical Genetics\| PubMed ID: 30270359	2019
Partitioning of MLX-Family Transcription Factors to Lipid Droplets Regulates Metabolic Gene Expression. Molecular cell\| PubMed ID: 32023484	2020
The mutational constraint spectrum quantified from variation in 141,456 humans. Nature\| PubMed ID: 32461654	2020
The soluble epoxide hydrolase inhibitor GSK2256294 decreases the proportion of adipose pro-inflammatory T cells. Prostaglandins & other lipid mediators\| PubMed ID: 34922004	2022
Comparative transmissibility of SARS-CoV-2 variants Delta and Alpha in New England, USA. Cell reports. Medicine\| PubMed ID: 35480627	2022
Distinct genomic and immunologic tumor evolution in germline -driven breast cancers. bioRxiv : the preprint server for biology\| PubMed ID: 38617260	2024
The subcutaneous adipose transcriptome identifies a molecular signature of insulin resistance shared with visceral adipose. Obesity (Silver Spring, Md.)\| PubMed ID: 38967296	2024
A neoantigen vaccine generates antitumour immunity in renal cell carcinoma. Nature\| PubMed ID: 39910301	2025

Tryston T. Gabriel

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