Whole-exome sequencing of Parathyroid Carcinoma
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REPOSITORIES: ENA
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Project description:Intratumor mutational heterogeneity has been documented in primary non-small cell lung cancer. Here, we elucidate mechanisms of tumor evolution and heterogeneity in metastatic thoracic tumors (lung adenocarcinoma and thymic carcinoma) using whole-exome and transcriptome sequencing, SNP array for copy number alterations (CNA) and mass spectrometry-based quantitative proteomics of metastases obtained by rapid autopsy. APOBEC-mutagenesis, promoted by increased expression of APOBEC3 region transcripts and associated with a high-risk germline APOBEC3 variant, strongly correlated with mutational tumor heterogeneity. TP53 mutation status was associated with APOBEC hypermutator status. Interferon pathways were enriched in tumors with high APOBEC mutagenesis and IFN- induced expression of APOBEC3B in lung adenocarcinoma cells in culture suggesting a role for the immune microenvironment in the generation of mutational heterogeneity. CNA occurring late in tumor evolution correlated with downstream transcriptomic and proteomic heterogeneity, although global proteomic heterogeneity was significantly greater than transcriptomic and CNA heterogeneity. These results illustrate key mechanisms underlying multi-dimensional heterogeneity in metastatic thoracic tumors.
2019-05-07 | PXD012845 | Pride
Project description:Intratumoral genetic heterogeneity and mutational burden have been suggested to be the fuel and the source of resistance for many molecularly targeted therapies throughout a multitude of cancers. Emerging evidence indicates that tumor cells could hijack the powerful mutagenesis machinery mediated by the DNA deaminase APOBEC family proteins to intensify mutagenesis, promote intratumoral heterogeneity, and foster therapy resistance through a cell-autonomous mechanism. However, this mechanism has yet to be characterized. Utilizing prostate cancer (PCa) as a relevant model, we have identified the Synaptotagmin Binding Cytoplasmic RNA Interacting Protein (SYNCRIP) as a molecular brake for APOBEC-driven mutagenesis, intratumoral heterogeneity, and resistance to Androgen Receptor (AR) targeted therapies. Through a multi-disciplinary approach integrating bulk and single cell RNA-Seq (scRNA-Seq), whole-genome exome-sequencing (WES), and CRISPR library screening, we identified eight mutated resistance driver genes and revealed unparalleled details of how these heterogeneously aberrant subclones fuel the evolution of AR therapy resistance. For the first time, these findings exposed a cell-autonomous mechanism activating APOBEC-driven mutagenesis, consequently fueling mutational burden, genetic heterogeneity, and therapy resistance, and suggested that APOBEC proteins could be the potential therapeutic targets for preventing or overcoming resistance in PCa.
2023-07-20 | GSE202321 | GEO
Project description:Primary hyperparathyroidism is a common endocrine disorder frequently affecting postmenopausal women. In this study we have investigated expression of the prolactin receptor (PRLr) in a panel of 37 sporadic parathyroid tumours, as well as functionality in vitro in cultured parathyroid tumour cells. High levels of the prolactin receptor gene (PRLR) transcripts were demonstrated in parathyroid tissues as compared to other reference tissues and breast cancer cells. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours PRLr immunoreactivity was observed in cytoplasm in all cases and in addition in the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim PRLr was expressed in cytoplasm and granulae. In in vitro studies of short-term cultured human parathyroid tumour cells prolactin stimulation was associated with transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signaling pathways as documented by gene expression profiling. Moreover, PRLR gene expression in parathyroid tumors was significantly inversely correlated with plasma total Ca2+ levels. In conclusion, the prolactin receptor was found highly abundant in human parathyroid gland, parathyroid tumours, correlated with patient Ca2+ levels and functionally responsive to physiological levels of prolactin. These findings suggest a role for the prolactin receptor in human parathyroid adenomas.
2012-05-01 | GSE32387 | GEO
Project description:Primary hyperparathyroidism is a common endocrine disorder frequently affecting postmenopausal women. In this study we have investigated expression of the prolactin receptor (PRLr) in a panel of 37 sporadic parathyroid tumours, as well as functionality in vitro in cultured parathyroid tumour cells. High levels of the prolactin receptor gene (PRLR) transcripts were demonstrated in parathyroid tissues as compared to other reference tissues and breast cancer cells. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours PRLr immunoreactivity was observed in cytoplasm in all cases and in addition in the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim PRLr was expressed in cytoplasm and granulae. In in vitro studies of short-term cultured human parathyroid tumour cells prolactin stimulation was associated with transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signaling pathways as documented by gene expression profiling. Moreover, PRLR gene expression in parathyroid tumors was significantly inversely correlated with plasma total Ca2+ levels. In conclusion, the prolactin receptor was found highly abundant in human parathyroid gland, parathyroid tumours, correlated with patient Ca2+ levels and functionally responsive to physiological levels of prolactin. These findings suggest a role for the prolactin receptor in human parathyroid adenomas. Expression profiling was done in parathyroid adenomas subjected to prolactin treatment in culture. In addition, corresponding paraffin sections were obtained for verification of PRLr expression by immunohistochemistry. 200 mg/L prolactin (recombinant humanM-BM- prolactin, Cat. No. JM-4687-50, MBL Woburn, MA) was added to 1M-CM-^W 10^6 attached parathyroid tumour cells. Cells were harvested using RNAlater (QIAGEN) and homogenized with QIAshredder for RNA extraction after 3 h and 24 h in culture, respectively. Negative controls were collected in parallel with each case at the same time points. RNA was extracted using QIA Cube, and quality assessed with Bioanalyser and Nanodrop. Expression array profiling and data analysis was done at the KI core facility Bioinformatics and Expression Analysis (BEA, Novum, Huddinge) using the Affymetrix platform and the TITAN ST 1.1 array. A total of 16 samples were analysed including 4 parathyroid adenomas cultured for 3 h or 24 h in the presence of prolactin plus control samples cultured in parallel without prolactin.
2012-04-30 | E-GEOD-32387 | biostudies-arrayexpress
Project description:Transcriptional profiling of genes expressed in normal parathyroid glands (Normal) and adenomatous parathyroid glands from patients with primary hyperparathyroidism (PHPT). Stratagen Human Refernece RNA, pooled from 10 human cell lines, was used to identify genes, which are specifically expressed or suppressed in parathyroid tissue. Comparison between normal and tumor parathyroids shows genes that might be involved in hyperproliferation and PTH hypersecretion in tumors.
2016-12-01 | GSE83421 | GEO
Project description:We genetically characterized parathyroid adenomas with large glandular weights, for which independent observations suggest pronounced clinical manifestations. Large parathyroid adenomas (LPTAs) were defined as the 5% largest sporadic parathyroid adenomas identified among the 590 cases operated on in our institution during 2005-2009. The LPTA group showed a higher relative number of male cases and significantly higher levels of total plasma and ionized serum calcium (P <0.001). Further analysis of 21 LPTAs revealed low MIB-1 proliferation index (0.1-1.5%), MEN1 mutations in 5 cases and one HRPT2 mutation. Total or partial loss of parafibromin expression was observed in 10 tumors, two of which also showed loss of APC expression. Using array-CGH, we demonstrated recurrent copy number alterations most frequently involving loss in 1p (29%), gain in 5 (38%) and loss in 11q (33%). Totally 21 minimal overlapping regions were defined for losses in 1p, 7q, 9p, 11 and 15q, and gains in 3q, 5, 7p, 8p, 16q, 17p and 19q. In addition, 12 tumors showed gross alterations of entire or almost entire chromosomes, most frequently gain of 5 and loss of 11. While gain of 5 was the most frequent alteration observed in LPTAs, it was only detected in a small proportion (4/58 cases, 7%) of parathyroid adenomas. A significant positive correlation was observed between parathyroid hormone level and total copy number gain (r = 0.48, P = 0.031). These results support that LPTAs represent a group of patients with pronounced parathyroid hyperfunction and associated with specific genomic features. We applied high-resolution array-CGH to assess copy number alterations (CNAs) in 21 tumors representing the 5% largest sporadic parathyroid adenomas in our institution.
2012-05-08 | E-GEOD-36511 | biostudies-arrayexpress
Project description:Pulmonary hypertension (PH) is an incurable right heart failure disease. Parathyroid hormone (PTH) is secreted from the parathyroid gland and plays a crucial role in calcium homeostasis. PTH also acts on the cardiovascular system and affects cardiovascular prognosis. We assessed whether the regulation of PTH affected PH in a hypoxia (Hx)-induced PH mouse model. PTH treatment exacerbated right ventricular hypertrophy and right ventricular systolic pressure in Hx mice. Our data showed how is PTH effected for PH model murine lung.
2023-10-11 | GSE244861 | GEO
Project description:We genetically characterized parathyroid adenomas with large glandular weights, for which independent observations suggest pronounced clinical manifestations. Large parathyroid adenomas (LPTAs) were defined as the 5% largest sporadic parathyroid adenomas identified among the 590 cases operated on in our institution during 2005-2009. The LPTA group showed a higher relative number of male cases and significantly higher levels of total plasma and ionized serum calcium (P <0.001). Further analysis of 21 LPTAs revealed low MIB-1 proliferation index (0.1-1.5%), MEN1 mutations in 5 cases and one HRPT2 mutation. Total or partial loss of parafibromin expression was observed in 10 tumors, two of which also showed loss of APC expression. Using array-CGH, we demonstrated recurrent copy number alterations most frequently involving loss in 1p (29%), gain in 5 (38%) and loss in 11q (33%). Totally 21 minimal overlapping regions were defined for losses in 1p, 7q, 9p, 11 and 15q, and gains in 3q, 5, 7p, 8p, 16q, 17p and 19q. In addition, 12 tumors showed gross alterations of entire or almost entire chromosomes, most frequently gain of 5 and loss of 11. While gain of 5 was the most frequent alteration observed in LPTAs, it was only detected in a small proportion (4/58 cases, 7%) of parathyroid adenomas. A significant positive correlation was observed between parathyroid hormone level and total copy number gain (r = 0.48, P = 0.031). These results support that LPTAs represent a group of patients with pronounced parathyroid hyperfunction and associated with specific genomic features.
2012-05-09 | GSE36511 | GEO
Project description:Development of potent in vivo mutagenesis plasmids with broad mutational spectra
| PRJNA294841 | ENA
Project description:Studies on human parathyroid tissue are often limited to adenomatous tissue due to difficulty obtaining healthy tissue. We obtained nonhuman primate parathyroids to provide a suitable alternative for sequencing analysis that would bear the closest semblance to human organs as possible. We analyzed four M. mulatta normal parathyroid specimens to that show a continuous trajectory of cell states comprising the normal adult parathyroid. We calculated the predicted pseudotime progression based on transcriptomic signatures that were reflective of repopulating progenitors, progressing to chief cells, and ultimately oxyphils, and clustered genes based on their expression dynamics along this axis. As a comparator, we histologically characterized and sequenced four human adenomas with varying oxyphil and chief cell abundance to highlight similarities and differences to normal parathyroid cell expression dynamics. We noted abundant RARRES2 transcripts that were detected in both human adenoma and normal primate parathyroid cells, and provided co-immunostaining validation of Chemerin presence in PTH-expressing cells, which could play a previously unrecognized role in parathyroid endocrine function.
2024-03-12 | GSE233962 | GEO