Somatic mutations reveal asymmetric cellular dynamics in the early human embryo.

Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis

The Complex Landscape of Rearrangements in Smoldering and Symptomatic Multiple Myeloma Revealed By Whole-Genome Sequencing

INTRODUCTION: Multiple myeloma is a heterogeneous disease featured by recurrent translocations involving the IgH region. Such cytogenetic events have a driver role in early transformation of a normal plasma cell into a MM cell. Although several studies have reported the presence of limited number of other structural chromosomal events using different approaches, including conventional cytogenetics, high-resolution genome mapping, interphase fluorescence in situ hybridization (FISH) and whole exome sequencing, the full catalogue of genomic rearrangements in MM samples has never been carried out systematically. Here, we have utilized whole-genome sequencing technologies to perform a systematic, genome-wide analysis to uncover the frequency and nature of rearrangements in MM. MATERIAL AND METHODS: We performed Whole genome sequencing (WGS) using the Illumina X10 platform in 68 serial samples from 30 patients including 11 patients with smoldering myeloma, 13 newly-diagnosed patients and 44 relapsed patient samples to provide further insight into evolution of rearrangements in MM. Structural variations (translocations, deletions, inversions, internal tandem duplications, fusions) and copy number changes were analyzed using the analysis pipeline at the Wellcome Trust Sanger Institute as recently described (Nik-Zainal Nature 2016). RESULTS: We observed a total of 1295 rearrangements for a median of 27 per sample (range 2-138) including a median of 6 (range 1-36) inversions, 5 (range 1-33) internal tandem duplications, 10 (range 1-40) deletions, 7 (range 1-32) translocations and 5 fusions (0-20). While the vast majority of events was non-recurrent, the high prevalence of rearrangements at smoldering stage and in myeloma at diagnosis and further increase at the time of relapse suggest a much more complex genomic landscape than previously thought. Translocations involving the IGH locus were identified including t(11;14) in 6 (20%), t(4;14) in 4 (13%) and t(8;14) in 3 (10%) of 30 unique patients. We also report frequent involvement by light chain loci in the rearrangements. The MYC locus was recurrently affected by non-IGH rearrangements in 11/30 (36%) patients. The other main MYC partners were IGL (4/30) and IGK (2/30), while about one-third of cases were involved by rearrangements not involving immunoglobulins or other obvious partners. MYC is therefore frequently involved by rearrangements through immunoglobulin-independent mechanisms. Interestingly, many regions affected by recurrent copy number abnormalities (CNAs) were associated with rearrangements. In particular 7/14 (50%) 1q gains and 6/8 (75%) 1p deletions were involved by translocations and inversions respectively (i.e Figure 1a). Overall 15/22 chromosome 1 CNAs were associated with a specific rearrangements. A similar association between copy number changes and rearrangement breakpoints was observed among other recurrent genomic aberrations such as 6q deletions (6/12, 50%), 8p deletions (4/7, 57%) and 16q deletions (7/13, 53%). In addition to deletions, inversions, internal tandem duplications (ITDs) and translocations, we observed at least one and often more regions of chromothripsis in 10/30 (33%) patients. Chromothripsis represents a complex event characterized by localized chromosome shattering and repair occurring in a one-off catastrophic event (Korbel J. et al. Cell 2013) (Figure 1b) and known to be associated with worse prognosis in MM. In our series, chromothriptic events were always conserved during every investigated evolution process: suggesting an early onset of this complex event in myelomagenesis. CONCLUSION: We report for the first time a comprehensive catalogue of rearrangements in MM based on whole-genome sequencing data. Our data provide evidence that the genomic landscape of rearrangements in MM is very complex and heterogeneous than speculated before and besides IgH involves number of other recurrent chromosomal alteration mechanisms. These diverse aberrations, in many cases acquired early, may deregulate oncogenes as illustrated by the MYC locus

A faecal microbiota signature with high specificity for pancreatic cancer

Recent evidence suggests a role for the microbiome in pancreatic ductal adenocarcinoma (PDAC) aetiology and progression. To explore the faecal and salivary microbiota as potential diagnostic biomarkers. We applied shotgun metagenomic and 16S rRNA amplicon sequencing to samples from a Spanish case-control study (n=136), including 57 cases, 50 controls, and 29 patients with chronic pancreatitis in the discovery phase, and from a German case-control study (n=76), in the validation phase. Faecal metagenomic classifiers performed much better than saliva-based classifiers and identified patients with PDAC with an accuracy of up to 0.84 area under the receiver operating characteristic curve (AUROC) based on a set of 27 microbial species, with consistent accuracy across early and late disease stages. Performance further improved to up to 0.94 AUROC when we combined our microbiome-based predictions with serum levels of carbohydrate antigen (CA) 19-9, the only current non-invasive, Food and Drug Administration approved, low specificity PDAC diagnostic biomarker. Furthermore, a microbiota-based classification model confined to PDAC-enriched species was highly disease-specific when validated against 25 publicly available metagenomic study populations for various health conditions (n=5792). Both microbiome-based models had a high prediction accuracy on a German validation population (n=76). Several faecal PDAC marker species were detectable in pancreatic tumour and non-tumour tissue using 16S rRNA sequencing and fluorescence in situ hybridisation. Taken together, our results indicate that non-invasive, robust and specific faecal microbiota-based screening for the early detection of PDAC is feasible

Somatic mutations reveal asymmetric cellular dynamics in the early human embryo

Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic ce

Somatic mutations reveal asymmetric cellular dynamics in the early human embryo.

Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis

Corrigendum: Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells.

info:eu-repo/semantics/publishe

Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes

Long interspersed nuclear element–1 (L1) retrotransposons are mobile repetitive elements that are abundant in the human genome. L1 elements propagate through RNA intermediates. In the germ line, neighboring, nonrepetitive sequences are occasionally mobilized by the L1 machinery, a process called 3′ transduction. Because 3′ transductions are potentially mutagenic, we explored the extent to which they occur somatically during tumorigenesis. Studying cancer genomes from 244 patients, we found that tumors from 53% of the patients had somatic retrotranspositions, of which 24% were 3′ transductions. Fingerprinting of donor L1s revealed that a handful of source L1 elements in a tumor can spawn from tens to hundreds of 3′ transductions, which can themselves seed further retrotranspositions. The activity of individual L1 elements fluctuated during tumor evolution and correlated with L1 promoter hypomethylation. The 3′ transductions disseminated genes, exons, and regulatory elements to new locations, most often to heterochromatic regions of the genome

Mobile DNA in cancer. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes.

Long interspersed nuclear element-1 (L1) retrotransposons are mobile repetitive elements that are abundant in the human genome. L1 elements propagate through RNA intermediates. In the germ line, neighboring, nonrepetitive sequences are occasionally mobilized by the L1 machinery, a process called 3' transduction. Because 3' transductions are potentially mutagenic, we explored the extent to which they occur somatically during tumorigenesis. Studying cancer genomes from 244 patients, we found that tumors from 53% of the patients had somatic retrotranspositions, of which 24% were 3' transductions. Fingerprinting of donor L1s revealed that a handful of source L1 elements in a tumor can spawn from tens to hundreds of 3' transductions, which can themselves seed further retrotranspositions. The activity of individual L1 elements fluctuated during tumor evolution and correlated with L1 promoter hypomethylation. The 3' transductions disseminated genes, exons, and regulatory elements to new locations, most often to heterochromatic regions of the genome.SCOPUS: re.jinfo:eu-repo/semantics/publishe