HMGA2 Research Articles

Novel Approaches to Possible Targeted Therapies and Prophylaxis of Uterine Fibroids.

Uterine leiomyomas are the most common benign tumors in women of childbearing age. They may lead to problems of conception or complications during the gestational period. The methods of treatment include surgical (myomectomy and hysterectomy, embolization of arteries) and therapeutic treatment (ulipristal acetate, leuprolide acetate, cetrorelix, goserelin, mifepristone). Both approaches are efficient but incompatible with pregnancy planning. Therefore, there is a call for medical practice to develop therapeutical means of preventing leiomyoma onset in patients planning on becoming pregnant. Based on the analysis of GWAS data on the search for mononucleotide polymorphisms associated with the risk of leiomyoma, in meta-transcriptomic and meta-methylomic studies, target proteins have been proposed. Prospective therapeutic treatments of leiomyoma may be based on chemical compounds, humanized recombinant antibodies, vaccines based on markers of the uterine leiomyoma cells that are absent in the adult organism, or DNA and RNA preparations. Three different nosological forms of the disease associated with driver mutations in the MED12, HMGA2, and FH genes should be considered when developing or prescribing drugs. For example, synthetic inhibitors and vaccines based on matrix metalloproteinases MMP11 and MMP16 are expected to be effective only for the prevention of the occurrence of MED12-dependent nodules.

Genome-Wide Association and Pathway Analysis of Carcass and Meat Quality Traits in Karachai Young Goats.

Goats with diverse economic phenotypic traits play an important role in animal husbandry. However, the genetic mechanisms underlying complex phenotypic traits are unclear in goats. Genomic studies of variations provided a lens to identify functional genes. The work aimed to search for candidate genes related to body measurements and body weight of Karachai goats and develop an experimental PCR-RV test system for genotyping significant SNPs. Comparison of GWAS results for ages 4 and 8 months revealed 58 common SNPs for significant genotypes. 11 common SNPs were identified for body weight, 4 SNPs-for group of traits withers height, rump height, body length, 2 SNPs-for withers height and rump height, 1 SNP-for body length and chest depth. Structural annotation of genomic regions covering a window of ±0.20 Mb showed the presence of 288 genes; 52 of them had the described functions in accordance with gene ontology. The main molecular functions of proteins encoded by these genes are the regulation of transcription, cell proliferation, angiogenesis, body growth, fatty acid and lipid metabolism, nervous system development, and spermatogenesis. SNPs common to body weight and localized within a window of ±200 kb from the structural genes CRADD, HMGA2, MSRB3, FUT8, MAX, and RAB15 were selected to create a test system. The study of meat productivity after slaughter and chemical analysis of muscle tissue in Karachai goats at the age of 8 months of different genotypes according to the identified SNPs revealed that rs268269710 is the most promising for further research and use in breeding. The GG genotype is associated with a larger live weight of animals, a larger carcass yield, the content of the boneless part in it, and the ratio of protein and adipose tissue in meat preferred for dietary nutrition. These results will contribute to the genetic improvement of Karachai goats.

Current insights into the oncogenic roles of lncRNA LINC00355.

Long noncoding RNAs (lncRNAs) are a class of nonprotein-coding transcripts that are longer than 200 nucleotides. LINC00355 is a lncRNA located on chromosome 13q21.31 and is consistently upregulated in various cancers. It regulates the expression of downstream genes at both transcriptional and posttranscriptional levels, including eight microRNAs (miR-15a-5p, miR-34b-5p, miR-424-5p, miR-1225, miR-217-5p, miR-6777-3p, miR-195, and miR-466) and three protein-coding genes (ITGA2, RAD18, and UBE3C). LINC00355 plays a role in regulating various biological processes such as cell cycle progression, proliferation, apoptosis, epithelial-mesenchymal transition, invasion, and metastasis of cancer cells. It is involved in the regulation of the Wnt/β-catenin signaling pathway and p53 signaling pathway. Upregulation of LINC00355 has been identified as a high-risk factor in cancer patients and its increased expression is associated with poorer overall survival, recurrence-free survival, and disease-free survival. LINC00355 upregulation has been linked to several unfavorable clinical characteristics, including advanced tumor node metastasis and World Health Organization stages, reduced Karnofsky Performance Scale scores, increased tumor size, greater depth of invasion, and more extensive lymph node metastasis. LINC00355 induces chemotherapy resistance in cancer cells by regulating five downstream genes, namely HMGA2, ABCB1, ITGA2, WNT10B, and CCNE1 genes. In summary, LINC00355 is a potential oncogene with great potential as a diagnostic marker and therapeutic target for cancer.

TGM2, HMGA2, FXYD3, and LGALS4 genes as biomarkers in acquired oxaliplatin resistance of human colorectal cancer: A systems biology approach.

Acquired resistance to oxaliplatin is considered as the primary reason for failure in colorectal cancer (CRC) therapy. Identifying the underlying resistance mechanisms may improve CRC treatment. The present study aims to identify the key genes involved in acquired oxaliplatin-resistant in CRC by confirming the oxaliplatin resistance index (OX-RI). To this aim, two public microarray datasets regarding oxaliplatin-resistant CRC cells with different OX-RI, GSE42387, and GSE76092 were downloaded from GEO database to identify differentially expressed genes (DEGs). The results indicated that the OX-RI affects the gene expression pattern significantly. Then, 54 common DEGs in both datasets including 18 up- and 36 down-regulated genes were identified. Protein-protein interaction (PPI) analysis revealed 13 up- (MAGEA6, TGM2, MAGEA4, SCHIP1, ECI2, CD33, AKAP12, MAGEA12, CALD1, WFDC2, VSNL1, HMGA2, and MAGEA2B) and 12 down-regulated (PDZK1IP1, FXYD3, ALDH2, CEACAM6, QPRT, GRB10, TM4SF4, LGALS4, ALDH3A1, USH1C, KCNE3, and CA12) hub genes. In the next step, two novel up-regulated hub genes including ECI2 and SCHIP1 were identified to be related to oxaliplatin resistance. Functional enrichment and pathway analysis indicated that metabolic pathways, proliferation, and epithelial-mesenchymal transition may play dominant roles in CRC progression and oxaliplatin resistance. In the next procedure, two in vitro oxaliplatin-resistant sub-lines including HCT116/OX-R4.3 and HCT116/OX-R10 cells with OX-IR 3.93 and 10.06 were established, respectively. The results indicated the up-regulation of TGM2 and HMGA2 in HCT116/OX-R10 cells with high OX-RI and down-regulation of FXYD3, LGALS4, and ECI2 in both cell types. Based on the results, TGM2, HMGA2, FXYD3, and LGALS4 genes are related to oxaliplatin-resistant CRC and may serve as novel therapeutic targets.

Uterine leiomyoma with RAD51B::NUDT3 fusion: a report of 2 cases

Three main uterine leiomyoma molecular subtypes include tumors with MED12 mutation, molecular aberrations leading to HMGA2 overexpression, and biallelic loss of FH. These aberrations are mutually exclusive and can be found in approximately 80–90% of uterine leiomyoma, in which they seem to be a driver event. Approximately 10% of uterine leiomyoma, however, does not belong to any of these categories. Uterine leiomyoma with HMGA2 overexpression is the most common subtype in cellular and second most common category of usual leiomyoma. In some of these tumors, rearrangement of HMGA2 gene is present. The most common fusion partner of HMGA2 gene is RAD51B. Limited data suggests that RAD51B fusions with other genes may be present in uterine leiomyoma. In our study, we described two cases of uterine leiomyoma with RAD51B::NUDT3 fusion, which occur in one case of usual and one case of highly cellular leiomyoma. In both cases, no other driver molecular aberrations were found. The results of our study showed that RAD51::NUDT3 fusion can occur in both usual and cellular leiomyoma. RAD51B may be a fusion partner of multiple genes other than HMGA2 and HMGA1. In these cases, RAD51B fusion seems to be mutually exclusive with other driver aberrations defining molecular leiomyoma subtypes. RAD51B::NUDT3 fusion should be added to the spectrum of fusions which may occur in uterine leiomyoma, which can be of value especially in cellular leiomyoma in the context of differential diagnosis against endometrial stromal tumors.

Giant uterine fibroids with chromosome 22 monosomy. A clinical case

We present a clinical case of giant uterine fibroids in this research, with the peculiarity of surgical treatment and the course of the postoperative period described. A series of genetic studies specific to uterine fibroids was performed, namely, mutations in the MED12 gene, overexpression of the HMGA2 gene, and chromosomal imbalance. We did not detect mutations of exon 2 of the MED12 gene and an increase in the expression of the HMGA2 gene in the patients myomatous node sample. The molecular karyotype arr(22)1 (chromosome 22 monosomy) was established by comparative genomic hybridization in the tissue of giant uterine fibroids.

Integration of Transcriptome and MicroRNA Profile Analysis of iMSCs Defines Their Rejuvenated State and Conveys Them into a Novel Resource for Cell Therapy in Osteoarthritis.

Although MSCs grant pronounced potential for cell therapies, several factors, such as their heterogeneity restrict their use. To overcome these limitations, iMSCs (MSCs derived from induced pluripotent stem cells (iPSCs) have attracted attention. Here, we analyzed the transcriptome of MSCs, iPSCs and iMSCs derived from healthy individuals and osteoarthritis (OA) patients and explored miRNA-mRNA interactions during these transitions. We performed RNA-seq and gene expression comparisons and Protein-Protein-Interaction analysis followed by GO enrichment and KEGG pathway analyses. MicroRNAs' (miRNA) expression profile using miRarrays and differentially expressed miRNA's impact on regulating iMSCs gene expression was also explored. Our analyses revealed that iMSCs derivation from iPSCs favors the expression of genes conferring high proliferation, differentiation, and migration properties, all of which contribute to a rejuvenated state of iMSCs compared to primary MSCs. Additionally, our exploration of the involvement of miRNAs in this rejuvenated iMSCs transcriptome concluded in twenty-six miRNAs that, as our analysis showed, are implicated in pluripotency. Notably, the identified here interactions between hsa-let7b/i, hsa-miR-221/222-3p, hsa-miR-302c, hsa-miR-181a, hsa-miR-331 with target genes HMGA2, IGF2BP3, STARD4, and APOL6 could prove to be the necessary tools that will convey iMSCs into the ideal mean for cell therapy in osteoarthritis.

The relationship between rs968697 genetic polymorphism and gastric cancer susceptibility, TNM stage and survival prognosis

Background HMGA2 can promote the development of multiple malignancies. This study aimed to determine whether a putative functional genetic polymorphism (rs968697 T>C) in the HMGA2 gene promoter region was associated with malignancy susceptibility in the Chinese population. Methods The rs968697 genetic polymorphism was genotyped using the SNaPshot method in the case-control study. The odds ratios and 95% confidence intervals were calculated using a logistic regression model. STATA software was used to conduct the meta-analysis. Results The rs968697 genetic polymorphism was associated not only with susceptibility to malignant tumors [CC versus TT: OR = 0.45, 95%CI = 0.28–0.73, p = .001; CC versus (CT + TT): OR = 0.47, 95%CI = 0.29–0.75, p = .003] including gastric cancer (GC), but also with TNM stage and survival prognosis of GC patients. Genotype-tissue expression analysis, luciferase assay and bioinformatics analysis revealed that the rs968697 genetic polymorphism might affect the binding of transcription factors, especially POLR2A, which in turn regulate the expression of HMGA2. Conclusions The current research suggests that the rs968697 genetic polymorphism may be used as a biomarker for malignancy susceptibility and GC prognosis in the Chinese population.

A variant of uncertain significance in HMGA2 gene, in a child with Silver-Russell syndrome like phenotype: A case report

Silver-Russell Syndrome 5 (SRS5) is characterized by asymmetric Intrauterine Growth Restriction (IUGR), poor postnatal growth

Genomics of Dwarfism in Italian Local Chicken Breeds

The identification of the dwarf phenotype in chicken is based on body weight, height, and shank length, leaving the differentiation between dwarf and small breeds ambiguous. The aims of the present study were to characterize the sequence variations associated with the dwarf phenotype in three Italian chicken breeds and to investigate the genes associated with their phenotype. Five hundred and forty-one chickens from 23 local breeds (from 20 to 24 animals per breed) were sampled. All animals were genotyped with the 600 K chicken SNP array. Three breeds were described as "dwarf", namely, Mericanel della Brianza (MERI), Mugellese (MUG), and Pepoi (PPP). We compared MERI, MUG, and PPP with the four heaviest breeds in the dataset by performing genome-wide association studies. Results showed significant SNPs associated with dwarfism in the MERI and MUG breeds, which shared a candidate genomic region on chromosome 1. Due to this similarity, MERI and MUG were analyzed together as a meta-population, observing significant SNPs in the LEMD3 and HMGA2 genes, which were previously reported as being responsible for dwarfism in different species. In conclusion, MERI and MUG breeds seem to share a genetic basis of dwarfism, which differentiates them from the small PPP breed.

Re-Analysis of Non-Small Cell Lung Cancer and Drug Resistance Microarray Datasets with Machine Learning

Non-small cell lung cancer is the most common type of lung cancer. Identification of genes associated with this disease may contribute to the treatment of the disease. Therefore, a lot of work is being done. In some of these studies, genetic data is obtained by microarray analysis and shared publicly in databases such as NCBI Gene Expression Omnibus. In today’s big data era, machine learning algorithms are frequently used to access valuable information from data stacks. Within the scope of this study, all (6 pieces) microarray datasets related to NSCLC and drug resistance in the NCBI GEO database were analyzed by R Studio. With support vector machine, k nearest neighbor, naïve Bayes, random forest, C5.0 decision tree, multilayer perceptron, and artificial neural network algorithms with principal component step, the datasets were analyzed separately and related genes were determined through the caret package, and the top 10 genes for each algorithm were given in the findings section in order of importance. In this resulting gene table, ELOVL7, HMGA2, SAT1, RRM1, IER3, SLC7A11, and U2AF1 genes are included in at least 2 different datasets. These identified genes are recommended to researchers working in a wet laboratory environment to be validated experimentally.

Study of mRNA of WT1, BAALC, EVI1, PRAME and HMGA2 genes in whole blood samples.

Simultaneous quantitative measurement of mRNA of the WT1, BAALC, EVI1, PRAME and HMGA2 genes in whole blood samples reflects the specific pathological proliferative activity in acute leukemia and their ratio is promising as a diagnostic marker. The transcriptome profile of acute leukemia cells is usually assessed using NGS or microarray techniques after a preliminary procedure for isolation of mononuclear cells. However, the results of using the multiplex PCR reaction for the simultaneous determination of all above mRNAs in whole blood samples have not been published so far. Determination of mRNA of WT1, BAALC, EVI1, PRAME and HMGA2 genes in venous blood level samples by multiplex RT-PCR. The study included 127 blood samples from patients who diagnosis of acute leukemia was subsequently confirmed. In the comparison group, 87 samples of patients without oncohematological diagnosis were selected, including 31 samples (K1) with a normal blood formula and 56 samples (K2) with a violation of the cellular composition - anemia, leukocytosis and thrombocytopenia. RNA isolation and reverse transcription were performed using the Ribozol-D and Reverta-L kits (TsNIIE, Russia). Determination of the mRNA expression level of the WT1, BAALC, EVI1, PRAME and HMGA2 genes by multiplex real-time PCR using a homemade multiplex PCR kit. The mRNA level was characterized by high interindividual variation and did not correlate with the rate of circulating leukocytes or blood blasts. Expression of WT1 mRNA was observed in whole blood only in one patient from the control group and in 112 (88%) patients with leukemia and was combined with a decrease in the level of HMGA2 mRNA expression and BAALC mRNA values. In contrast to the control groups, patients with leukemia had higher levels of BAALC mRNA in AML and ALL, increased PRAME mRNA in AML and APL, but lower levels of HMGA2 in APL.

Influence of the High Mobility Group A1 genetic polymorphism on indices of metabolic syndrome and insulin resistance in the Iraqi population: Case-control study

ABSTRACT: The high mobility group A1 gene (HMGA1) rs139876191 variant has been related to metabolic syndrome and type 2 diabetes, but data are lacking in Middle Eastern populations. The study aimed to assess whether the HMGA1 rs139876191 variant is associated with metabolic syndrome risk and whether this variant predicts the risk of insulin resistance. This case-control study was carried out at single center in Kirkuk city/ Iraq from February to August 2022. Polymorphisms in HMGA1 and genotyping were identified by Sanger sequencing of genomic DNA obtained from 91 Iraqi participants (61 patients with metabolic syndrome and 30 control). Lipid profile, serum (glucose and insulin), glycated hemoglobin, blood pressure, body mass index, and waist circumference were also measured. The high prevalence of the del/del genotype of rs139876191 was found. Minor allele frequency of rs139876191 was (0.16) in both metabolic syndrome and the control group. A non-significant difference in genotyping was identified between total metabolic syndrome and the control group. The del/ins variant was associated with significantly higher waist circumference, triglyceride(TG), low-density lipoprotein(LDL), very low-density lipoprotein(VLDL), and glycated hemoglobin(HbA1c) (P=0.03, 0.041, 0.007, 0.034, and 0.001 respectively), and with significantly lower high-density lipoprotein(HDL) (p=0.000). Linear regression analysis showed no significant effect of the variant (del/ins) on developing insulin resistance. Thus, rs139876191 polymorphism with del/ins genotype in the HMGA1 gene was not associated with metabolic syndrome risk but it was associated with indices of metabolic syndrome including waist circumference, TG, HDL, LDL, VLDL, and HbA1c. Besides, this variant did not predict the risk of insulin resistance.

Genome-wide analysis in the search for candidate genes associated with meat productivity traits in meat-and-dairy goats

The development of the tourism cluster in the North Caucasus causes the expansion of product range with high consumer characteristics, in particular, a sustainable offer of dairy and meat products labeled as environmentally friendly. In the range of such products with high dietary properties, a special role may be played by goat meat obtained from Karachay goats, which are the most common meat-and-dairy goats in the region. The aim of the work was to search for candidate genes associated with live weight and meat productivity of Karachay goats. GWAS analysis using Goat 50K BeadChip high-density DNA microarray determined a genome-wide level of significance for six SNPs located on chromosomes 5, 6, 10 and 16 associated with the live weight of young animals (4 and 8 months old). Three of the six SNPs within the ± 200 kb region were localized to HMGA2, CRADD, and MAX genes. These genes were selected to study the meat productivity traits of young goats with different genotypes. It was found that in the locus linked with HMGA2 gene, young goats with GG genotype were characterized by the best indicators of meat productivity. Compared to AA genotype animals, they had superiority in pre-slaughter weight, slaughter carcass weight, slaughter yield, boneless meat weight and loin eye area by 8.9%, 13.6%, 4.3% (P<0.05), 10.5% (P<0.05) respectively. Young goat meat of this genotype was characterized by the high protein content of 22.56% and low fat content of 9.12%. For the CRADD gene, animals with GG genotype had a higher pre-slaughter weight, slaughter weight, slaughter carcass yield, boneless meat weight and loin eye area. Animals with AG genotype were characterized by the lowest indicators. According to the above characteristics, the difference between the compared genotypes was 15.8%, 25.7% (P<0.01), 8.4% (P <0.05), 18.3%, and 15.7% (P 0.01) respectively. There were no significant differences in the chemical composition of muscle tissue between animals of different genotypes. HMGA2 and CRADD genes are promising for further research of Karachay goats breeding to increase meat productivity and meat quality.

Correction to: Overexpression of the HMGA2 gene in transgenic mice leads to the onset of pituitary adenomas

Correction to: Overexpression of the HMGA2 gene in transgenic mice leads to the onset of pituitary adenomas

Knockout of HMGA1 Promotes ATRA-Induced Differentiation in MLL-Rearranged Leukemia

Introduction: HMGA1 is a small non-histone chromatin protein characterized by 3 AT-hooks, which modulates transcription by altering the chromatin architecture. It tends to be highly expressed in poorly differentiated cells including hematopoietic stem cells. In various kinds of solid tumors, HMGA1 has been reported to play as an oncogene, and its upregulation was reported to be associated with poorer clinical outcomes. However, although recent study demonstrated that HMGA1 was associated with progression of JAK2V617F positive myeloproliferative neoplasms to myelofibrosis or leukemia, the roles of HMGA1 in myeloid malignancies were still unclear. Therefore, we analyzed its function in myeloid malignancies using HMGA1 knockout (KO) mice. We could not detect clear differences in peripheral blood counts or bone marrow cells, and generated various kinds of models of acute myeloid leukemia (AML). Knockout of HMGA1 could not delay the onset of these leukemia, but we could demonstrate that leukemic cells with MLL-ENL fusion gene which lacked in HMGA1 gene were more susceptible to all-trans retinoic acid (ATRA)-induced expression of CD11b, which suggested that HMGA1 could be associated with the differentiation process induced by ATRA. Method: We generated Vav-iCre HMGA1flox/flox mice, and we first analyzed the fraction of peripheral blood cells and bone marrow cells of these mice using flow cytometry. Next, to evaluate roles of HMGA1 in AML, we made various murine models of AML. We collected c-kit positive fractions of bone marrow cells from the KO mice or Vav-iCre(-) HMGA1flox/flox mice and retrovirally introduced MLL-ENL, MOZ-TIF2, BCL2-MYC fusions. Primary transplantation was performed to sublethally irradiated (5Gy) mice with 4.0×105 infected cells for each fusion gene. Secondary transplantation was also performed for MLL-ENL and BCL2-MYC with 1.0×104 cells for each. Blood samples were collected weekly, and disease-free survivals were compared by Kaplan-Meier method with Vav-iCre(-) HMGA1flox/flox mice. Also, leukemic cells infected with MLL-ENL were collected, and these cells were cultured for four days with different concentrations (1μM, 5μM or 10μM) of ATRA. Flow cytometry analysis was performed to evaluate the differentiation induced by ATRA with antibodies to murine CD11b, c-kit and Gr-1. Result: There was no significant difference in birth rate between Vav-iCre(+) and Vav-iCre(-) mice, which suggested that HMGA1 was not essential for fetal hematopoiesis. Peripheral blood cell counts were measured at week 8 and week 20, and fractions of peripheral blood and bone marrow cells were assessed at week 8 using flow cytometry, but no significant differences were observed. As for AML models, there were no significant differences in survival periods after primary or secondary transplantation. Leukemic cells retrovirally induced with MLL-ENL were collected from primary recipients, and these cells were treated with ATRA. Although growth rates were not show significantly different, expression levels of CD11b after exposure to ATRA were significantly higher in Vav-Cre (+) mice (5μM: 70% vs 44%, respectively; p=0.035. 10μM: 80% vs 46%, respectively; p=0.0006) as shown in the following figure. Discussion: We established HMGA1 KO mice and assessed the function of HMGA1 both in normal and leukemic hemopoiesis. Although HMGA1 might have little effect on normal hematogenesis, it seemed that HMGA1 had inhibitory effect on ATRA-induced differentiation process of MLL-ENL leukemic cells. Though more conditions including AML types and differentiation methods should be tested and the molecular mechanisms should be scrutinized, there is a possibility that inhibition of HMGA1 is effective in combination with differentiation treatments. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Identification of Genomic Regions and Candidate Genes Associated with Body Weight and Body Conformation Traits in Karachai Goats.

The objective of this study was to identify the SNPs and candidate genes related to body weight and seven body conformation traits at the age of 8 months in the Russian aboriginal Karachai goats (n = 269) by conducting genome-wide association studies (GWAS), using genotypes generated by Goat SNP BeadChip (Illumina Inc., USA). We identified 241 SNPs, which were significantly associated with the studied traits, including 47 genome-wide SNPs (p < 10−5) and 194 suggestive SNPs (p < 10−4), distributed among all goat autosomes except for autosome 23. Fifty-six SNPs were common for two and more traits (1 SNP for six traits, 2 SNPs for five traits, 12 SNPs for four traits, 20 SNPs for three traits, and 21 SNPs for two traits), while 185 SNPs were associated with single traits. Structural annotation within a window of 0.4 Mb (±0.2 Mb from causal SNPs) revealed 238 candidate genes. The largest number of candidate genes was identified at Chr13 (33 candidate genes for the five traits). The genes identified in our study were previously reported to be associated with growth-related traits in different livestock species. The most significant genes for body weight were CRADD, HMGA2, MSRB3, MAX, HACL1 and RAB15, which regulate growth processes, body sizes, fat deposition, and average daily gains. Among them, the HMGA2 gene is a well-known candidate for prenatal and early postnatal development, and the MSRB3 gene is proposed as a candidate gene affecting the growth performance. APOB, PTPRK, BCAR1, AOAH and ASAH1 genes associated with withers height, rump height and body length, are involved in various metabolic processes, including fatty acid metabolism and lipopolysaccharide catabolism. In addition, WDR70, ZBTB24, ADIPOQ, and SORCS3 genes were linked to chest width. KCNG4 was associated with rump height, body length and chest perimeter. The identified candidate genes can be proposed as molecular markers for growth trait selection for genetic improvement in Karachai goats.

CRISPR/Cas9-3NLS/sgHMGA2@PDA nanosystem is the potential efficient gene editing therapy for gastric cancer with HMGA2 high expression.

Gene therapy is one of the target therapies with promising clinical use for gastric cancer (GC). However, the delivery of the CRISPR/Cas9/sgRNA (RNP) gene editing tool severely limits the practical therapeutic effect of GC. Therefore, it is a great challenge to develop an RNP delivery system that is simple to prepare and can rapidly encapsulate RNP while achieving high delivery and gene editing efficiency. We developed, for the first time, the CRISPR/Cas9@PDA nano-delivery system that can achieve high-efficiency delivery (95%) of CRISPR/Cas9-3NLS/sgHMGA2 and high-efficient HMGA2 gene editing (82%) of GC cells. In particular, the experiment’s weak alkaline environment can not only protect the activity of CRISPR/Cas9-3NLS/sgHMGA2 but also trigger the self-polymerization of polydopamine (PDA). Meanwhile, the presence of KE in the CRISPR/Cas9 amino acid sequence can achieve the directional growth of PDA, thus forming a core–shell structure that protects CRISPR/Cas9-3NLS/sgHMGA2. This efficient CRISPR/Cas9-3NLS/sgHMGA2 delivery and HMGA2 gene editing ability has also been verified in mice, which can significantly inhibit tumor growth in mice. The success of building the delivery system and its ideal treating effect give hope to the efficacious treatment for the GC patients with HMGA2 high expression.

Molecular subclass of uterine fibroids predicts tumor shrinkage in response to ulipristal acetate.

Precision medicine carries great potential for management of all tumor types. The aim of this retrospective study was to investigate if the two most common genetically distinct uterine fibroid subclasses, driven by aberrations in MED12 and HMGA2 genes, respectively, influence response to treatment with the progesterone receptor modulator ulipristal acetate. Changes in diameter and mutation status were derived for 101 uterine fibroids surgically removed after ulipristal acetate treatment. A significant difference in treatment response between the two major subclasses was detected. MED12 mutant fibroids had 4.4 times higher odds of shrinking in response to ulipristal acetate treatment as compared to HMGA2 driven fibroids (95% confidence interval 1.37-13.9; P= 0.013), and in a multivariate analysis molecular subclassification was an independent predictive factor. Compatible with this finding, gene expression and DNA methylation analyses revealed subclass specific differences in progesterone receptor signaling. The work provides a proof-of-principle that uterine fibroid treatment response is influenced by molecular subclass and that the genetic subclasses should be taken into account when evaluating current and future uterine fibroid therapies.

Chromosome Translocations, Gene Fusions, and Their Molecular Consequences in Pleomorphic Salivary Gland Adenomas.

Salivary gland tumors are a heterogeneous group of tumors originating from the major and minor salivary glands. The pleomorphic adenoma (PA), which is the most common subtype, is a benign lesion showing a remarkable morphologic diversity and that, upon recurrence or malignant transformation, can cause significant clinical problems. Cytogenetic studies of >500 PAs have revealed a complex and recurrent pattern of chromosome rearrangements. In this review, we discuss the specificity and frequency of these rearrangements and their molecular/clinical consequences. The genomic hallmark of PA is translocations with breakpoints in 8q12 and 12q13-15 resulting in gene fusions involving the transcription factor genes PLAG1 and HMGA2. Until recently, the association between these two oncogenic drivers was obscure. Studies of the Silver–Russel syndrome, a growth retardation condition infrequently caused by mutations in IGF2/HMGA2/PLAG1, have provided new clues to the understanding of the molecular pathogenesis of PA. These studies have demonstrated that HMGA2 is an upstream regulator of PLAG1 and that HMGA2 regulates the expression of IGF2 via PLAG1. This provides a novel explanation for the 8q12/12q13-15 aberrations in PA and identifies IGF2 as a major oncogenic driver and therapeutic target in PA. These studies have important diagnostic and therapeutic implications for patients with PA.