Molecular characterization of mucinous breast cancer by low-coverage WGS
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina HiSeq 4000
ORGANISM(S): Homo sapiens
SUBMITTER: Bram Boeckx
PROVIDER: E-MTAB-7256 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Introduction: Mucinous tumors are the second most common form of epithelial ovarian tumor, yet the cell of origin for this histological sub-type remains undetermined. While these tumors are thought to arise through a stepwise progression from benign cystadenoma to borderline tumor to invasive carcinoma, few studies have attempted to comprehensively characterize the genetic changes specific to this subtype or its precursors. Methods: To explore the spectrum of genomic alterations common to mucinous tumors we performed high resolution genome-wide copy number analysis, mutation screening by Sanger sequencing and immunohistochemistry on a series of primary ovarian mucinous cystadenomas (n=20) and borderline tumors (n=22). Results: Integration of copy number data, targeted mutation screening of RAS/RAF pathway members and immunohistochemistry reveals that p16 loss and RAS/RAF pathway alterations are highly recurrent events that occur early during mucinous tumor development. The frequency of concurrence of these events was observed in 40% of benign cystadenomas and 68% of borderline tumors. Conclusions: This study is the largest and highest resolution analysis of mucinous benign and borderline tumors performed to date and provides strong support for these lesions being precursors of primary ovarian mucinous adenocarcinoma. The high level of uniformity in the molecular events underlying the pathogenesis of mucinous ovarian tumors provides an opportunity for treatments targeting specific mutations and pathways. Copy number data was generated for 42 mucinous ovarian tumours (20 benign, 22 borderline). Epithelial and stromal DNA from the tumours and matched-normal lymphocyte DNA were all analysed. Processed/normalized data for the germline DNA samples are not provided because they themselves are normalised to a diploid copy number, making all the probe values 2, which is not informative.
2012-08-26 | E-GEOD-39076 | biostudies-arrayexpress
Project description:The biology underlying nodal metastasis is poorly understood. Transcriptome profiling has helped to characterize both primary tumors seeding nodal metastasis and the metastasis themselves. The interpretation of these data, however, is not without ambiguities. Here we profiled the transcriptomes of 17 papillary thyroid cancer (PTC) nodal metastases, associated primary tumors and primary tumors from N0 patients. We also included patient-matched normal thyroid and lymph node samples as controls to address some limits of previous studies. We found that the transcriptomes of patient-matched primary tumors and metastases were more similar than of unrelated metastases/primary pairs, a result also reported in other organ systems, and that part of this similarity reflected patient background. We found that the comparison of patient-matched primary tumors and metastases was heavily confounded by the presence of lymphoid tissues in the metastasis samples. An original data adjustment procedure was developed to circumvent this problem. It revealed a differential expression of stroma-related gene expression signatures also regulated in other organ systems. The comparison of N0 vs. N+ primary tumors uncovered a signal irreproducible across independent PTC datasets. This signal was also detectable when comparing the normal thyroid tissues adjacent to N0 and N+ tumors, suggesting a cohort specific bias also likely to be present in previous studies with similar statistical power. Classification of N0 vs. N+ yielded an accuracy of 63%, but additional statistical controls not presented in previous studies, revealed that this is likely to occur by chance alone. To address this issue, we used large datasets from The Cancer Genome Atlas and showed that N0 vs. N+ classification rates could not be reached randomly for most cancers. Yet, it was significant, but of limited accuracy (<70%) for thyroid, breast and head and neck cancers. We profiled the transcriptomes of 11 primary PTCs with no detectable nodal invasion, 17 primary PTCs with nodal invasion and 17 patient-matched nodal metastases. We also profiled a number of control samples. These included 24 patient-matched normal thyroid tissues (11 from N0, 13 from N+ patients), and 4 normal lymph nodes; technical and biological replicates including additional nodal metastasis for 3 patients, adjacent blocks for 5 primary tumors, 4 normal thyroid tissues and 1 nodal metastasis.
2015-09-01 | E-GEOD-60542 | biostudies-arrayexpress
Project description:Gene expression profile of 8 mucinous borderline ovarian tumors and 9 mucinous ovarian carcinomas. Frozen tumor samples were laser-capture microdissected for their epithelial component. RNA was extracted. Gene expression profiling was completed using Affymetrix U133 Plus 2.0 oligonucleotide microarrays.
2018-06-28 | E-MTAB-6844 | biostudies-arrayexpress
Project description:Gene expression profile of laser-capture microdissected epithelium component of 6 mucinous cystic neoplasms of the pancreas were included in the study. The expression arrays were generated with Affymetrix HU133A gene chips (18,462 genes/EST transcripts).
2018-06-28 | E-MTAB-6853 | biostudies-arrayexpress
Project description:Intestinal epithelia are protected by a layer of mucin secreted by goblet cells against mechanical and chemical injuries, potent causes of inflammation, and the most abundant secreted intestinal mucin is encoded by the Muc2 gene. Genetic deletion of Muc2 causes intestinal inflammation in early stage and tumors after 3 months. The underlying mechanisms are not clear, but epigenetic alterations, particularly, up- and down-regulated microRNAs are involved in the malignant transformation from colitis to cancer. We used miRNA array to profile the differential expression of the miRNAs in Muc2-/- mouse colonic epithelial lin comparison with those in wild-type mice. Total RNA were extracted from mouse colonic epithelial cells and Muc2-/- and +/+, and the RNA were hybridized on Affymetrix miRNA microarray to determine the alterations of miRNAs during colitis development and its malignant transformation from colitis to cancer. To the end, we found miRNA were differential expressed in the Muc2-/- mice, among them 20 miRNAs were significantly downregulated and 71 miRNAs were significantly upregulated in Muc2-/- mice, in comparison with Muc2+/+ mice (change fold >2 or <0.5; T<0.01, p value< 0.05, q value< 0.05).
2014-05-31 | E-GEOD-56577 | biostudies-arrayexpress
Project description:Background; MUC2 mucin produced by intestinal goblet cells is the major component of the intestinal mucus barrier. MUC2 homo-oligomerizes intracellularly into large secreted polymers which give mucus its viscous properties. The inflammatory bowel disease (IBD) ulcerative colitis is characterized by depleted goblet cells and a reduced mucus layer, whereas goblet cells and the mucus layer are increased in the other major inflammatory bowel disease, Crohnâs disease. Methods and Findings; By murine N-ethyl-N-nitrosourea-mutagenesis we identified two distinct non-complementing missense mutations in Muc2 exons encoding N- and C-terminal homo-oligomerization domains causing an ulcerative colitis-like phenotype. Both strains developed mild spontaneous distal intestinal inflammation, chronic diarrhea, rectal bleeding and prolapse, increased susceptibility to acute and chronic colitis induced by a luminal toxin, aberrant Muc2 biosynthesis, smaller goblet cell thecae (less stored mucin) and a diminished mucus barrier. Enhanced local production of IL-1beta, TNF-alpha and IFN-gamma was seen in the distal colon. The number of leukocytes within mesenteric lymph nodes was increased five-fold and leukocytes cultured in vitro produced both Th1 and Th2 cytokines (IFN-gamma, TNF-alpha and IL-13). Intestinal permeability was increased and the luminal bacterial flora were more heavily coated with immunoglobulin as occurs in IBD. This pathology was accompanied by accumulation of the Muc2 precursor and ultrastructural and biochemical evidence of endoplasmic reticulum (ER) stress in goblet cells, activation of the unfolded protein response, and altered intestinal expression of genes involved in ER stress, inflammation, apoptosis and wound repair. Expression of mutated Muc2 oligomerization domains in vitro demonstrated that aberrant Muc2 oligomerization underlies the ER stress. These models show that mutations in Muc2 oligomerization domains can lead to aberrant assembly of the Muc2 complex leading to ER stress, a depleted mucus barrier and intestinal inflammation. In ulcerative colitis we demonstrate similar accumulation of non-glycosylated MUC2 precursor in goblet cells together with ultrastructural and biochemical evidence of ER stress even in non-inflamed intestinal tissue. Conclusions; The observations that mucin misfolding and ER stress lead directly to intestinal inflammation and that ER stress and goblet cell pathology occur in ulcerative colitis suggest that ER stress-related mucin depletion could be a fundamental component of the pathogenesis of colitis. Experiment Overall Design: 3 individual mice from the Eeyore, Winnie or Wild-type strains were compared as groups. An Affymetrix ID was compared between groups if the ID was Present within two of the three mice within each grouping. IDs were compared by calculating the log2 of Group One average signal divided by Group 2 average signal.
2008-04-06 | E-GEOD-9913 | biostudies-arrayexpress
Project description:Integration of genomic copy number analysis (Affymetrix SNP6.0 arrays) and oncogenic RAS/RAF mutation status with clinical features and tumour progression. This study found that loss of the 9p and the CDKN2A locus with the most significantly enriched copy number aberration distinguishing serous border tumors from low grade serous carcinomas, suggesting this is a key step to tumor progression. Epithelial tissue from 57 serous borderline tumors (SBTs), 19 low grade serous carcinomas (LGSC)(data for 4 of the carcinomas have previously been submitted to GEO - Series GSE19539) and 355 high grade serous carinomas (HGSC)(TCGA, 2011; GSE19539; and 8 new) were analysed for copy number aberrations using Affymetrix SNP6.0 arrays and normalised SNP6.0 data. Stromal tissue from 38 SBT and 1 HGSC were analysed for copy number aberrations using Affymetrix SNP6.0 arrays. Matching lymphocyte DNA was availabe for 54 SBT, 3 LGSC and 1 HGSC. Sanger sequencing of KRAS, BRAF, NRAS, HRAS, ERBB2 and TP53 mutational hotspots was performed on the epithelial and stromal DNA. This information was then correlated with clinical features of the tumors.
2015-03-01 | E-GEOD-58579 | biostudies-arrayexpress
Project description:Current clinical next-generation sequencing is done by using gene panels and exome analysis, both of which involve selective capturing of target regions. However, capturing has limitations in sufficiently covering coding exons, especially GC-rich regions. We compared whole exome sequencing (WES) with the most recent PCR-free whole genome sequencing (WGS), showing that only the latter is able to provide hitherto unprecedented complete coverage of the coding region of the genome. Thus, from a clinical/technical point of view, WGS is the better WES so that capturing is no longer necessary for the most comprehensive genomic testing of Mendelian disorders.
| S-EPMC4757617 | biostudies-other
Project description:Background MUC2 mucin produced by intestinal goblet cells is the major component of the intestinal mucus barrier. MUC2 homo-oligomerizes intracellularly into large secreted polymers which give mucus its viscous properties. The inflammatory bowel disease (IBD) ulcerative colitis is characterized by depleted goblet cells and a reduced mucus layer, whereas goblet cells and the mucus layer are increased in the other major inflammatory bowel disease, Crohn’s disease. Methods and Findings By murine N-ethyl-N-nitrosourea-mutagenesis we identified two distinct non-complementing missense mutations in Muc2 exons encoding N- and C-terminal homo-oligomerization domains causing an ulcerative colitis-like phenotype. Both strains developed mild spontaneous distal intestinal inflammation, chronic diarrhea, rectal bleeding and prolapse, increased susceptibility to acute and chronic colitis induced by a luminal toxin, aberrant Muc2 biosynthesis, smaller goblet cell thecae (less stored mucin) and a diminished mucus barrier. Enhanced local production of IL-1beta, TNF-alpha and IFN-gamma was seen in the distal colon. The number of leukocytes within mesenteric lymph nodes was increased five-fold and leukocytes cultured in vitro produced both Th1 and Th2 cytokines (IFN-gamma, TNF-alpha and IL-13). Intestinal permeability was increased and the luminal bacterial flora were more heavily coated with immunoglobulin as occurs in IBD. This pathology was accompanied by accumulation of the Muc2 precursor and ultrastructural and biochemical evidence of endoplasmic reticulum (ER) stress in goblet cells, activation of the unfolded protein response, and altered intestinal expression of genes involved in ER stress, inflammation, apoptosis and wound repair. Expression of mutated Muc2 oligomerization domains in vitro demonstrated that aberrant Muc2 oligomerization underlies the ER stress. These models show that mutations in Muc2 oligomerization domains can lead to aberrant assembly of the Muc2 complex leading to ER stress, a depleted mucus barrier and intestinal inflammation. In ulcerative colitis we demonstrate similar accumulation of non-glycosylated MUC2 precursor in goblet cells together with ultrastructural and biochemical evidence of ER stress even in non-inflamed intestinal tissue. Conclusions The observations that mucin misfolding and ER stress lead directly to intestinal inflammation and that ER stress and goblet cell pathology occur in ulcerative colitis suggest that ER stress-related mucin depletion could be a fundamental component of the pathogenesis of colitis. Keywords: Single gene, multiple mutant comparison
2008-03-01 | GSE9913 | GEO
Project description:Mucus/MUC2 from TGM3-deficient mice is less cross-linked with isopeptide-bond cross-links compared to Mucus/MUC2 from WT mice. This results in protease-labile MUC2-molecules that become degraded in the colonic lumen
2022-02-09 | PXD029071 | Pride