Biology subjects

Temes, J.

Publications and source records attributed to Temes, J..

3 recordsLinked to original sources

bioRxiv2024

Synchronous L1 retrotransposition events promote chromosomal crossover early in human tumorigenesis

L1 retrotransposition is a significant source of genomic variation in human epithelial tumours, which can contribute to tumorigenesis. However, fundamental questions about the causes and consequences of L1 activity in cancer genomes remain unresolved, primarily due to the limitations of short-read sequencing technologies. Here, we employ multiplatform sequencing, with an emphasis on long reads, to analyse a fine selection of 10 tumours exhibiting high rates of somatic retrotransposition, encompassing over 6000 events. The analysis of L1 locus-specific single-nucleotide variants reveals a novel panorama of L1 loci activity. Furthermore, examination of the internal structure of somatic L1s uncovers the mechanisms behind their inactivation. A hidden landscape of chromosomal aberrations emerges in the light of long reads, where reciprocal translocations mediated by L1 insertion represent frequent events. Resolution of L1 bridges configuration elucidates the mechanisms of their formation, where typically two independent, but synchronous, somatic L1 insertions drive the reciprocal exchange between non-homologous chromosomes. Timing analyses indicate that L1 retrotransposition is an early driver of chromosomal instability, active before the first whole-genome doubling event. Overall, these findings highlight L1 activity as a more significant contributor to tumour genome plasticity than previously recognized, extending its impact beyond simple insertional mutagenesis.

cancer biology↗

bioRxiv2022

The evolution of two transmissible leukaemias colonizing the coasts of Europe

Transmissible cancers are malignant cell clones that spread among individuals through transfer of living cancer cells. Several such cancers, collectively known as bivalve transmissible neoplasia (BTN), are known to infect and cause leukaemia in marine bivalve molluscs. This is the case of BTN clones affecting the common cockle, Cerastoderma edule, which inhabits the Atlantic coasts of Europe and north-west Africa. To investigate the origin and evolution of contagious cancers in common cockles, we collected 6,854 C. edule specimens and diagnosed 390 cases of BTN. We then generated a reference genome for the species and assessed genomic variation in the genomes of 61 BTN tumours. Analysis of tumour-specific variants confirmed the existence of two cockle BTN lineages with independent clonal origins, and gene expression patterns supported their status as haemocyte-derived marine leukaemias. Examination of mitochondrial DNA sequences revealed several mitochondrial capture events in BTN, as well as co-infection of cockles by different tumour lineages. Mutational analyses identified two lineage-specific mutational signatures, one of which resembles a signature associated with DNA alkylation. Karyotypic and copy number analyses uncovered genomes marked by pervasive instability and polyploidy. Whole-genome duplication, amplification of oncogenes CCND3 and MDM2, and deletion of the DNA alkylation repair gene MGMT, are likely drivers of BTN evolution. Characterization of satellite DNA identified elements with vast expansions in the cockle germ line, yet absent from BTN tumours, suggesting ancient clonal origins. Our study illuminates the evolution of contagious cancers under the sea, and reveals long-term tolerance of extreme instability in neoplastic genomes.

evolutionary biology↗

bioRxiv2021

Aberrant integration of Hepatitis B virus DNA promotes major restructuring of human hepatocellular carcinoma genome architecture

Most cancers are characterized by the somatic acquisition of genomic rearrangements during tumour evolution that eventually drive the oncogenesis. There are different mutational mechanisms causing structural variation, some of which are specific to particular cancer types. Here, using multiplatform sequencing technologies, we identify and characterize a remarkable mutational mechanism in human hepatocellular carcinoma caused by Hepatitis B virus, by which DNA molecules from the virus are inserted into the tumour genome causing dramatic changes in its configuration, including non-homologous chromosomal fusions and megabase-size telomeric deletions. This aberrant mutational process, present in at least 8% of all HCC tumours, is active early during liver cancer evolution and can provide the driver rearrangements that a cancer clone requires to survive and grow.

cancer biology↗