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Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution

ABSTRACT: Somatic L1 retrotransposition events have been shown to occur in epithelial cancers1-8. Here, we attempted to determine how early somatic L1 insertions occurred during the development of gastrointestinal (GI) cancers. Using L1-targeted resequencing (L1-seq), we studied different stages of four colorectal cancers arising from colonic polyps, seven pancreatic carcinomas, as well as seven gastric cancers. Surprisingly, we found somatic L1 insertions not only in all cancer types and metastases, but also in colonic adenomas, well-known cancer precursors. Some insertions were also present in low quantities in normal GI tissues, occasionally caught in the act of being clonally fixed in the adjacent tumors. Insertions in adenomas and cancers numbered in the hundreds and many were present in multiple tumor sections implying clonal distribution. Our results demonstrate that extensive somatic insertional mutagenesis occurs very early during the development of GI tumors, probably before dysplastic growth.

ORGANISM(S): Homo sapiens

PROVIDER: GSE63601 | GEO | 2015/08/10

SECONDARY ACCESSION(S): PRJNA268381

REPOSITORIES: GEO

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Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution

Project description:Somatic L1 retrotransposition events have been shown to occur in epithelial cancers1-8. Here, we attempted to determine how early somatic L1 insertions occurred during the development of gastrointestinal (GI) cancers. Using L1-targeted resequencing (L1-seq), we studied different stages of four colorectal cancers arising from colonic polyps, seven pancreatic carcinomas, as well as seven gastric cancers. Surprisingly, we found somatic L1 insertions not only in all cancer types and metastases, but also in colonic adenomas, well-known cancer precursors. Some insertions were also present in low quantities in normal GI tissues, occasionally caught in the act of being clonally fixed in the adjacent tumors. Insertions in adenomas and cancers numbered in the hundreds and many were present in multiple tumor sections implying clonal distribution. Our results demonstrate that extensive somatic insertional mutagenesis occurs very early during the development of GI tumors, probably before dysplastic growth. We assessed the impact of somatic L1 insertions on the expression of the corresponding protein-coding genes by comparing protein abundance in the polyp with the highest number of somatic L1 insertions with that of its paired normal colon using mass spectrometry analysis. Of the 10 validated somatic insertions that were in protein coding regions in the polyp, two proteins – KIAA1217 and WARS2 – were downregulated in the adenoma >90% and >70%, respectively.

2015-08-11 | PXD001626 | Pride

Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution

Project description:Somatic L1 retrotransposition events have been shown to occur in epithelial cancers1-8. Here, we attempted to determine how early somatic L1 insertions occurred during the development of gastrointestinal (GI) cancers. Using L1-targeted resequencing (L1-seq), we studied different stages of four colorectal cancers arising from colonic polyps, seven pancreatic carcinomas, as well as seven gastric cancers. Surprisingly, we found somatic L1 insertions not only in all cancer types and metastases, but also in colonic adenomas, well-known cancer precursors. Some insertions were also present in low quantities in normal GI tissues, occasionally caught in the act of being clonally fixed in the adjacent tumors. Insertions in adenomas and cancers numbered in the hundreds and many were present in multiple tumor sections implying clonal distribution. Our results demonstrate that extensive somatic insertional mutagenesis occurs very early during the development of GI tumors, probably before dysplastic growth. Here we show Human SNP 6.0 Array experiments on DNAs from four colorectal cancer patients (1BV, 2BV, 3BV, and 4BV) with polyps and metastases. Here we characterize the samples for CNVs and compare the samples' CNV status to their respective somatic L1 retrotransposition profile.

2015-08-10 | E-GEOD-63601 | biostudies-arrayexpress

Somatic L1 Retrotransposition of Colorectal Tumors

Project description:Somatic L1 Retrotransposition of Colorectal Tumors

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LINE-1 retrotransposition impacts the genome of human pre-implantation embryos and extraembryonic tissues [somatic tissues]

Project description:We did not detected de novo endogenous LINE-1 insertions in human somatic tissues

2023-03-31 | GSE149474 | GEO

L1 retrotransposition in neurons is mediated by MeCP2

Project description:L1 retrotransposons are active elements in the genome, capable of mobilization in neuronal progenitor cells. Previously, we showed that chromatin remodeling during neuronal differentiation allows for a transient stimulation of L1 transcription. The activity of L1 retrotransposons during brain development can impact gene expression and neuronal function. Here we show that L1 neuronal retrotransposition in rodents is increased in the absence of MeCP2, a protein involved in global methylation and human neurodevelopmental diseases. Using neuronal progenitor cells derived from human induced pluripotent stem cells and human tissues, we revealed that Rett syndrome patients, with MeCP2 mutations, have increased susceptibility for L1 retrotransposition. Our data demonstrate that disease-related genetic mutations can influence the frequency of neuronal L1 retrotransposition, thereby increasing brain-specific genetic mosaicism. Genetic reprogramming of somatic cells to a pluripotent state (induced pluripotent stem cells, or iPSCs) by over-expression of specific genes has been accomplished for fibroblasts derived from controls and Rett syndrome patients. Different clones from each were compared to respective original fibroblasts and a human embryonic stem cell line. Gene expression profiles measured using human genome Affymetrix Gene Chip arrays were grouped by hierarchical clustering, and correlation coefficients were computed for all pair-wise comparisons.

2010-11-11 | E-GEOD-21037 | biostudies-arrayexpress

Massive LINE1 retrotransposon Invasion in Tuberous Sclerosis Astrocytomas

Project description:Somatic retrotranspositions of various mobile genetic elements take place in tumors, and L1 retroelements physiologically transpose in neural progenitor cells during neurogenesis. We sequenced whole genomes of the neural progenitor cell-derived subependymal giant cell astrocytomas that typically affect patients suffering from the neurodevelopmental disease Tuberous Sclerosis. Here we show an unprecedented increased L1 retrotransposition in these tumors, with tens of thousands new genomic insertions, that preferentially invade genes involved in neural activity, synaptic transmission and cancer. The prevalent insertions are short, nested in preexisting L1 repeats in the same orientation, trimmed in both the 5’ and 3’ ends, representing unorthodox retrotransposition”. Most somatic L1 inserts in the genomically stable astrocytomas are nested in preexisting L1 elements. This preferred nested integration may act as a “lightning rod” mechanism dampening the effects of massive retrotransposition. In contrast, the enhanced transposition found in genomically unstable breast tumors includes regions of high-density clustered insertion, transposminos. These clustered insertions are expected to be more detrimental, as many of them are non-nested and frequently invade genic and exonic sequences. Exaggerated L1 retrotransposition may be a common stochastic damaging pathway in neurological disorders and cancer.

2016-12-31 | GSE56871 | GEO

The Epigenomic Landscape of Pituitary Adenomas Reveals Specific Alterations and Differentiates Among Acromegaly, Cushing's Disease and Endocrine-Inactive Subtypes

Project description:Recurrent single-nucleotide and small indel somatic mutations were infrequent among the three adenoma subtypes. However, somatic copy-number alterations (SCNA) were identified in all three pituitary adenoma subtypes. Methylation analysis revealed adenoma subtype-specific DNA methylation profiles, with GHsecreting adenomas being dominated by hypomethylated sites. Likewise, gene-expression patterns revealed adenoma subtype-specific profiles. Integrating DNA methylation and gene-expression data revealed that hypomethylation of promoter regions are related with increased expression of GH1 and SSTR5 genes in GH-secreting adenomas and POMC gene in ACTH secreting adenomas. Finally, multispectral IHC staining of immune-related proteins showed abundant expression of PD-L1 among all three adenoma subtypes.

2020-03-26 | GSE147548 | GEO

Transcriptome profile of human colorectal adenomas.

Project description:Background: Colorectal cancers are believed to arise predominantly from adenomas. Although these precancerous lesions have been subjected to extensive clinical, pathological, and molecular analyses, little is currently known about the global gene expression changes accompanying their formation. Results: To characterize the molecular processes underlying the transformation of normal colonic epithelium, we compared the transcriptomes of 32 prospectively collected adenomas with those of normal mucosa from the same individuals. Important differences emerged not only between the expression profiles of normal and adenomatous tissues, but also between those of small and large adenomas. A key feature of the transformation process was the remodeling of the Wnt pathway reflected in patent over- and underexpression of 78 known components of this signaling cascade. Conclusions: Our transcriptomic profiles of normal colonic mucosa and colorectal adenomas shed new light on the early stages of colorectal tumorigenesis. Keywords: tissue comparison

2007-08-03 | GSE8671 | GEO

Transcription profiling of human pedunculated, sporadic colorectal polyps and corresponding normal mucosa obtained during colonoscopies

2008-06-16 | E-GEOD-8671 | biostudies-arrayexpress

Label-free and targeted mass tandem (TMT-labelled) global proteomic analyses on mucus from the stomach, small and large intestine of a domestic and laboratory dogs

Project description:Gastrointestinal (GI) mucus is continuously secreted and lines the entire length of the GI tract. Essential for health, it keeps the noxious luminal content away from the epithelium and propels forward the digesta. The aim of our study was to characterize the composition and structures of mucus throughout the various GI segments in dog. Mucus from the stomach, small intestine (duodenum, jejunum, ileum), and large intestine (cecum, proximal and distal colon) was collected from 5 dogs. pH and water content of GI mucus and digesta were analyzed. Composition of all GI-tract segments from a domestic and a laboratory dog was determined by label-free global proteomics. A colonic-focussed composition analysis with TMT-labelled proteomics was used on jenunal and proximal and distal colonic mucus samples from 3 laboratory and 1 domestic dog. Finally, the composition of jejunal and colonic mucus samples of 3 laboratory and 1 domestic dog was evaluated with lipidomics and metabolomics. Structural properties were investigated using cryoSEM and rheology. The proteome was similar across the different GI segments. The highest abundant secreted gel-forming mucin in the gastric mucus was mucin 5AC, whether mucin 2 had highest abundance in the intestinal mucus. Lipid and metabolite abundance was generally higher in the jejunal mucus than the colonic mucus. In conclusion, the mucus is a highly viscous and hydrated material. The proteins, lipids and metabolites were similar throughout the GI tract, although abundances depended on location. These data provide an important baseline for future studies on human and canine intestinal diseases and the dog model in drug absorption.

2022-03-07 | PXD029356 | Pride

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