scholarly journals Metastatic and recurrent adrenocortical cancer is not defined by its genomic landscape

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Tito Fojo ◽  
Lyn Huff ◽  
Thomas Litman ◽  
Kate Im ◽  
Maureen Edgerly ◽  
...  
Keyword(s):  
Copy Number ◽  
Expression Profiles ◽  
Low Frequency ◽  
Beta Catenin ◽  
Cancer Genes ◽  
Loss Of Function ◽  
Adrenocortical Cancer ◽  
Genomic Aberration ◽  
Transcript Length ◽  
Metastatic Sites

Abstract Background Adrenocortical carcinoma (ACC) is a rare, often-aggressive neoplasm of the adrenal cortex, with a 14–17 month median overall survival. We asked whether tumors from patients with advanced or metastatic ACC would offer clues as to putative genes that might have critical roles in disease progression or in more aggressive disease biology. Methods We conducted comprehensive genomic and expression analyses of ACCs from 43 patients, 30 female, and 42 from metastatic sites, including deep sequencing, copy number analysis, mRNA expression and microRNA arrays. Results Copy number gains and losses were similar to that previously reported for ACC. We identified a median mutation rate of 3.38 per megabase (Mb). The mutational signature was characterized by a predominance of C > T, C > A and T > C transitions. Only cancer genes TP53 (26%) and beta-catenin (CTNNB1, 14%) were mutated in more than 10% of samples. The TCGA-identified putative cancer genes MEN1 and PRKAR1A were found in low frequency—4.7 and 2.3%, respectively. The majority of the mutations were in genes not implicated in the etiology or maintenance of cancer. Specifically, amongst the 38 genes that were mutated in more than 9% of samples, only four were represented in Tier 1 of the 576 COSMIC Cancer Gene Census (CCGC). Thus, 82% of genes found to have mutations likely have no role in the etiology or biology of ACC; while the role of the other 18%, if any, remains to be proven. Finally, the transcript length for the 38 most frequently mutated genes in ACC is statistically longer than the average of all coding genes, raising the question of whether transcript length in part determined mutation probability. Conclusions We conclude that the mutational and expression profiles of advanced and metastatic tumors are very similar to those from newly diagnosed patients—with very little in the way of genomic aberration to explain differences in biology. With relatively low mutation rates, few major oncogenic drivers, and loss of function mutations in several epigenetic regulators, an epigenetic basis for ACC may be postulated and serve as the basis for future studies.

scholarly journals Identification and Characterization of Genes That Interact With lin-12 in Caenorhabditis elegans

Genetics ◽  
1997 ◽  
Vol 147 (4) ◽  
pp. 1675-1695 ◽  
Author(s):  
Frans E Tax ◽  
James H Thomas ◽  
Edwin L Ferguson ◽  
H Robert Horvitzt
Keyword(s):  
Cell Fate ◽  
Low Frequency ◽  
Signal Transduction Pathway ◽  
Temperature Shift ◽  
Egg Laying ◽  
Null Alleles ◽  
Temperature Sensitive ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Suppressor Mutations

Abstract We identified and characterized 14 extragenic mutations that suppressed the dominant egg-laying defect of certain lin-12 gain-of-function mutations. These suppressors defined seven genes: sup-l7, lag-2, sel-4, sel-5, sel-6, sel-7 and sel-8. Mutations in six of the genes are recessive suppressors, whereas the two mutations that define the seventh gene, lag-2, are semi-dominant suppressors. These suppressor mutations were able to suppress other lin-12 gain-of-function mutations. The suppressor mutations arose at a very low frequency per gene, 10-50 times below the typical loss-of-function mutation frequency. The suppressor mutations in sup1 7 and lag-2 were shown to be rare non-null alleles, and we present evidence that null mutations in these two genes cause lethality. Temperature-shift studies for two suppressor genes, sup1 7and lag-2, suggest that both genes act at approximately the same time as lin-12in specifying a cell fate. Suppressor alleles of six of these genes enhanced a temperature-sensitive loss-of-function allele of glp-1, a gene related to lin-12 in structure and function. Our analysis of these suppressors suggests that the majority of these genes are part of a shared lin-12/glp-1 signal transduction pathway, or act to regulate the expression or stability of lin-12 and glp-1.

scholarly journals Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma

2020 ◽  
Vol 318 (3) ◽  
pp. G419-G427 ◽  
Author(s):  
Tatsuhide Nabeshima ◽  
Shin Hamada ◽  
Keiko Taguchi ◽  
Yu Tanaka ◽  
Ryotaro Matsumoto ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cancer Progression ◽  
Stress Responses ◽  
Target Genes ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Related Factor ◽  
Loss Of Function ◽  
P53 Expression ◽  
Nrf2 Activation

The activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) pathway contributes to cancer progression in addition to oxidative stress responses. Loss-of-function Keap1 mutations were reported to activate Nrf2, leading to cancer progression. We examined the effects of Keap1 deletion in a cholangiocarcinoma mouse model using a mutant K-ras/ p53 mouse. Introduction of the Keap1 deletion into liver-specific mutant K-ras/ p53 expression resulted in the formation of invasive cholangiocarcinoma. Comprehensive analyses of the gene expression profiles identified broad upregulation of Nrf2-target genes such as Nqo1 and Gstm1 in the Keap1-deleted mutant K-ras/ p53 expressing livers, accompanied by upregulation of cholangiocyte-related genes. Among these genes, the transcriptional factor Sox9 was highly expressed in the dysplastic bile duct. The Keap-Nrf2-Sox9 axis might serve as a novel therapeutic target for cholangiocarcinoma. NEW & NOTEWORTHY The Keap1-Nrf2 system has a wide variety of effects in addition to the oxidative stress response in cancer cells. Addition of the liver-specific Keap1 deletion to mice harboring mutant K-ras and p53 accelerated cholangiocarcinoma formation, together with the hallmarks of Nrf2 activation. This process involved the expansion of Sox9-positive cells, indicating increased differentiation toward the cholangiocyte phenotype.

scholarly journals Integrated Genomic Analysis of Sézary Syndrome

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Xin Mao ◽  
Tracy Chaplin ◽  
Bryan D. Young
Keyword(s):  
Copy Number ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Genomic Analysis ◽  
Gene Clusters ◽  
Sézary Syndrome ◽  
Sezary Syndrome ◽  
Snp Microarray ◽  
The Impact ◽  
Chromosome Regions

Sézary syndrome (SS) is a rare variant of primary cutaneous T-cell lymphoma. Little is known about the underlying pathogenesis of S. To address this issue, we used Affymetrix 10K SNP microarray to analyse 13 DNA samples isolated from 8 SS patients and qPCR with ABI TaqMan SNP genotyping assays for the validation of the SNP microarray results. In addition, we tested the impact of SNP loss of heterozygosity (LOH) identified in SS cases on the gene expression profiles of SS cases detected with Affymetrix GeneChip U133A. The results showed: (1) frequent SNP copy number change and LOH involving 1, 2p, 3, 4q, 5q, 6, 7p, 8, 9, 10, 11, 12q, 13, 14, 16q, 17, and 20, (2) reduced SNP copy number at FAT gene (4q35) in 75% of SS cases, and (3) the separation of all SS cases from normal control samples by SNP LOH gene clusters at chromosome regions of 9q31q34, 10p11q26, and 13q11q12. These findings provide some intriguing information for our current understanding of the molecular pathogenesis of this tumour and suggest the possibility of presence of functional SNP LOH in SS tumour cells.

Angiogenic and T-effector subgroups identified by gene expression profiling (GEP) and propensity for PBRM1 and BAP1 alterations in clear cell renal cell carcinoma (ccRCC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 343-343
Author(s):  
Pedro C. Barata ◽  
Shuchi Gulati ◽  
Andrew Elliott ◽  
Arpit Rao ◽  
Hans J. Hammers ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Trials ◽  
Hierarchical Clustering ◽  
Immune Cell ◽  
Expression Profiles ◽  
Gene Expression Signature ◽  
Predictive Biomarkers ◽  
Primary Tumors ◽  
Metastatic Sites ◽  
Patient Subgroups

343 Background: With the emergence of multiple active treatment options in RCC, predictive biomarkers for optimal treatment selection are lacking. Gene expression data from IMmotion151 and Javelin Renal 101 clinical trials generated anti-angiogenic and immune signatures that warrant further validation. We aimed to describe the genomic and gene expression profiles in a multi-institutional database of patients with ccRCC, and its association with other biomarkers of interest. Methods: Whole transcriptome sequencing was performed for ccRCC patient samples submitted to a commercial CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ) from February 2019 to September 2020. Tumor GEP and hierarchical clustering based on the validated 66-gene signature (D’Costa et al, 2020) were used to identify patient subgroups. Samples from both primary tumors and metastatic sites were included. Results: A total of 316 patients with ccRCC, median age 62 (range 32-90), 71.8% men, were included. Tissue samples were obtained from primary tumor (46.5%), lung (12.3%), bone (9.5%), liver (4.7%) and other metastatic sites (27%). Gene expression analysis identified angiogenic, mixed and T-effector subgroups in 24.1%, 51.3% and 24.7%, respectively. Patients with angiogenic subgroup tumors compared to those with T-effector subgroup tumors were more likely to be older (63 versus 60 years, p=0.035), female (40.8% versus 16.7%, p=0.0009) and more frequently found in pancreatic/small bowel metastases (75% versus 12.5%, p=0.0103). Biomarkers of potential response to immunotherapy such as PD-L1 (p=0.0021), TMB (not significant), and dMMR/MSI-H status (not significant) were more frequent in the T-effector subgroup. PBRM1 mutations were more common in the angiogenic subgroup (62.0% vs 37.5%, p=0.0034) while BAP1 mutations were more common in the T-effector subgroup (18.6% versus 3.0%, p= 0.0035). Immune cell population abundance (e.g. NK cells, monocytes) and immune checkpoint gene expression (TIM-3, PD-L1, PD-L2, CTLA4) were also increased in the T-effector subgroup. Conclusions: Our hierarchical clustering results based on the 66-gene expression signature were concordant with results from prior studies. Patient subgroups identified by evaluation of angiogenic and T-effector signature scores exhibit significantly different mutations and immune profiles. These findings require prospective validation in future biomarker-selected clinical trials.

scholarly journals Genome-wide copy number analyses identified novel cancer genes in hepatocellular carcinoma

Hepatology ◽  
2011 ◽  
Vol 54 (4) ◽  
pp. 1227-1236 ◽  
Author(s):  
Deshui Jia ◽  
Lin Wei ◽  
Weijie Guo ◽  
Ruopeng Zha ◽  
Meiyan Bao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Copy Number ◽  
Cancer Genes ◽  
Genome Wide

scholarly journals lnc-SAMD14-4 can regulate expression of the COL1A1 and COL1A2 in human chondrocytes

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7491 ◽  
Author(s):  
Haibin Zhang ◽  
Cheng Chen ◽  
Yinghong Cui ◽  
Yuqing Li ◽  
Zhaojun Wang ◽  
...  
Keyword(s):  
Biological Function ◽  
Expression Profiles ◽  
Differentially Expressed ◽  
Human Chondrocytes ◽  
Loss Of Function ◽  
Knee Oa ◽  
System Disease ◽  
Chondrocyte Death ◽  
Differentially Expressed Mrna ◽  
Gain Loss

Osteoarthritis (OA) is the most common motor system disease in aging people, characterized by matrix degradation, chondrocyte death, and osteophyte formation. OA etiology is unclear, but long noncoding RNAs (lncRNAs) that participate in numerous pathological and physiological processes may be key regulators in the onset and development of OA. Because profiling of lncRNAs and their biological function in OA is not understood, we measured lncRNA and mRNA expression profiles using high-throughput microarray to study human knee OA. We identified 2,042 lncRNAs and 2,011 mRNAs that were significantly differentially expressed in OA compared to non-OA tissue (>2.0- or < − 2.0-fold change; p < 0.5), including 1,137 lncRNAs that were upregulated and 905 lncRNAs that were downregulated. Also, 1,386 mRNA were upregulated and 625 mRNAs were downregulated. QPCR was used to validate chip results. Gene Ontology analysis and the Kyoto Encyclopedia of Genes and Genomes was used to study the biological function enrichment of differentially expressed mRNA. Additionally, coding-non-coding gene co-expression (CNC) network construction was performed to explore the relevance of dysregulated lncRNAs and mRNAs. Finally, the gain/loss of function experiments of lnc-SAMD14-4 was implemented in IL-1β-treated human chondrocytes. In general, this study provides a preliminary database for further exploring lncRNA-related mechnisms in OA.

scholarly journals Resistance to miltefosine results from amplification of the RTA3 floppase or inactivation of flippases in Candida parapsilosis

2021 ◽  
Author(s):  
Sean Bergin ◽  
Fang Zhao ◽  
Adam P Ryan ◽  
Carolin A Müller ◽  
Conrad A Nieduszynski ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Copy Number ◽  
Candida Parapsilosis ◽  
Copy Number Variations ◽  
Loss Of Function ◽  
Adaptive Laboratory Evolution ◽  
Pathogenic Yeast ◽  
Lipid Asymmetry ◽  
Evolution Experiment ◽  
Almost All

Flippases and floppases are two classes of proteins that have opposing functions in the maintenance of lipid asymmetry of the plasma membrane. Flippases translocate lipids from the exoplasmic leaflet to the cytosolic leaflet, and floppases act in the opposite direction. Phosphatidylcholine (PC) is a major component of the eukaryotic plasma membrane and is asymmetrically distributed, being more abundant in the exoplasmic leaflet. Here we show that gene amplification of a putative PC floppase or double disruption of two PC flippases in the pathogenic yeast Candida parapsilosis results in resistance to miltefosine, an alkylphosphocholine drug that affects PC metabolism that has recently been granted orphan drug designation approval by the US FDA for treatment of invasive candidiasis. We analysed the genomes of 170 C. parapsilosis isolates and found that 107 of them have copy number variations (CNVs) at the RTA3 gene. RTA3 encodes a putative PC floppase whose deletion is known to increase the inward translocation of PC in Candida albicans. RTA3 copy number ranges from 2 to >40 across the C. parapsilosis isolates. Interestingly, 16 distinct CNVs with unique endpoints were identified, and phylogenetic analysis shows that almost all of them have originated only once. We found that increased copy number of RTA3 correlates with miltefosine resistance. Additionally, we conducted an adaptive laboratory evolution experiment in which two C. parapsilosis isolates were cultured in increasing concentrations of miltefosine over 26 days. Two genes, CPAR2_303950 and CPAR2_102700, gained homozygous protein-disrupting mutations in the evolved strains and code for putative PC flippases homologous to S. cerevisiae DNF1. Our results indicate that alteration of lipid asymmetry across the plasma membrane is a key mechanism of miltefosine resistance. We also find that C. parapsilosis is likely to gain resistance to miltefosine rapidly, because many isolates carry loss-of-function alleles in one of the flippase genes.

scholarly journals OR28-01 Constitutive Activation of NRF2 Antioxidant Response Leads to Age-Dependent Goiter and Compensated Hypothyroidism in Male Mice

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Dionysios Chartoumpekis ◽  
Panos Ziros ◽  
Cédric Renaud ◽  
Massimo Bongiovanni ◽  
Ioannis Habeos ◽  
...  
Keyword(s):  
Thyroid Function ◽  
Expression Profiles ◽  
Adult Life ◽  
Model Organisms ◽  
Mrna Levels ◽  
Loss Of Function ◽  
Gene And Protein Expression ◽  
Age Dependent ◽  
Diffuse Goiter ◽  
Early Adult Life

Abstract Background: Familial non-toxic multinodular goiter (MNG) is a rare disease. KEAP1 gene (Kelch-like ECH-associated protein 1) that encodes the main inhibitor of nuclear factor erythroid 2-related transcription factor 2 (Nrf2), a central mediator of antioxidant responses, has been found to be one of the mutated genes that lead to familial MNG. The proposed association of KEAP1 with familial MNG is based on only two loss-of-function mutations in respective Japanese families, only one of which included proper phenotyping and demonstration of co-segregation of phenotype and mutation. To date, there is no experimental evidence from model organisms to support that decreased Keap1 levels can cause goiter. Hypothesis: We hypothesized that enhanced Nrf2 signaling induced by loss of Keap1 function in mice can lead to goiter. Methods: To this end, male Keap1 hypomorphic C57BL/6J mice that express ~80% less Keap1 in their tissues (Keap1 knockdown mice:“Keap1KD”) were studied at 3 and 12 months of age and compared to wild-type mice (WT). Plasma, thyroids and pituitary glands were collected for assessment of thyroid function by radioimmunoassays and for histology as well as gene and protein expression by quantitative PCR and immunoblotting respectively. Results: Keap1KD showed diffuse goiter that began to develop in early adult life and became highly prominent at the age of 12 months when the thyroids of Keap1KD were 6-fold heavier than WT. Histomorphometry assessment of thyroids showed that Keap1KD had ~3-fold larger follicle area and colloid compartment but no thyroid nodules or hyperplasia was detected. Keap1KD also showed primary hypothyroidism already in early adult life that was eventually well-compensated over time by increased TSH levels (at age of 12 months: WT TSH=47.7±9.1 mU/L, Keap1KD TSH=460±74 mU/L). This was also reflected in the pituitary gland of Keap1KD where Tshb mRNA was ~3-fold higher than WT. Despite a known stimulatory effect of Nrf2 on Tg gene transcription and Tg protein abundance, these measures were decreased in the thyroid of Keap1KD mice. No clear patterns were observed in the expression profiles of other thyroid hormone synthesis-specific factors, such as Duox1, Duoxa1, Duox2, Duoxa2, Tpo, Nis, Dio1, Dio2, Dehal1 mRNA levels, with the exception of Tg-processing and Tg-degrading cathepsins, including an increase in mature forms of cathepsins D, L and S. Conclusions: Keap1KD mice showed age-dependent diffuse goiter and compensated hypothyroidism. The precise mechanism accounting for the thyroidal phenotype remains to be elucidated, but it may involve enhanced Tg solubilization and excessive lysosomal Tg degradation. This study unravels novel roles of the druggable Keap1/Nrf2 pathway in thyroid function and economy. Subclinical hypothyroidism in Keap1KD mice may have broader implications regarding their use in metabolic research.

scholarly journals Spemann organizer transcriptome induction by early beta-catenin, Wnt, Nodal, and Siamois signals in Xenopus laevis

2017 ◽  
Vol 114 (15) ◽  
pp. E3081-E3090 ◽  
Author(s):  
Yi Ding ◽  
Diego Ploper ◽  
Eric A. Sosa ◽  
Gabriele Colozza ◽  
Yuki Moriyama ◽  
...  
Keyword(s):  
Xenopus Laevis ◽  
Gene Signature ◽  
Dorsal Side ◽  
Beta Catenin ◽  
Loss Of Function ◽  
Spemann Organizer ◽  
Signature Genes ◽  
A Genome ◽  
Vertebrate Model ◽  
Chloride Treatment

The earliest event in Xenopus development is the dorsal accumulation of nuclear β-catenin under the influence of cytoplasmic determinants displaced by fertilization. In this study, a genome-wide approach was used to examine transcription of the 43,673 genes annotated in the Xenopus laevis genome under a variety of conditions that inhibit or promote formation of the Spemann organizer signaling center. Loss of function of β-catenin with antisense morpholinos reproducibly reduced the expression of 247 mRNAs at gastrula stage. Interestingly, only 123 β-catenin targets were enriched on the dorsal side and defined an early dorsal β-catenin gene signature. These genes included several previously unrecognized Spemann organizer components. Surprisingly, only 3 of these 123 genes overlapped with the late Wnt signature recently defined by two other groups using inhibition by Dkk1 mRNA or Wnt8 morpholinos, which indicates that the effects of β-catenin/Wnt signaling in early development are exquisitely regulated by stage-dependent mechanisms. We analyzed transcriptome responses to a number of treatments in a total of 46 RNA-seq libraries. These treatments included, in addition to β-catenin depletion, regenerating dorsal and ventral half-embryos, lithium chloride treatment, and the overexpression of Wnt8, Siamois, and Cerberus mRNAs. Only some of the early dorsal β-catenin signature genes were activated at blastula whereas others required the induction of endomesoderm, as indicated by their inhibition by Cerberus overexpression. These comprehensive data provide a rich resource for analyzing how the dorsal and ventral regions of the embryo communicate with each other in a self-organizing vertebrate model embryo.

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