Biology subjects

Alvarez, E. G.

Publications and source records attributed to Alvarez, E. G..

4 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↗

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↗

bioRxiv2017

Germline determinants of the somatic mutation landscape in 2,642 cancer genomes

Cancers develop through somatic mutagenesis, however germline genetic variation can markedly contribute to tumorigenesis via diverse mechanisms. We discovered and phased 88 million germline single nucleotide variants, short insertions/deletions, and large structural variants in whole genomes from 2,642 cancer patients, and employed this genomic resource to study genetic determinants of somatic mutagenesis across 39 cancer types. Our analyses implicate damaging germline variants in a variety of cancer predisposition and DNA damage response genes with specific somatic mutation patterns. Mutations in the MBD4 DNA glycosylase gene showed association with elevated C>T mutagenesis at CpG dinucleotides, a ubiquitous mutational process acting across tissues. Analysis of somatic structural variation exposed complex rearrangement patterns, involving cycles of templated insertions and tandem duplications, in BRCA1-deficient tumours. Genome-wide association analysis implicated common genetic variation at the APOBEC3 gene cluster with reduced basal levels of somatic mutagenesis attributable to APOBEC cytidine deaminases across cancer types. We further inferred over a hundred polymorphic L1/LINE elements with somatic retrotransposition activity in cancer. Our study highlights the major impact of rare and common germline variants on mutational landscapes in cancer.

genomics↗

bioRxiv2017

Pan-cancer analysis of whole genomes reveals driver rearrangements promoted by LINE-1 retrotransposition in human tumours

About half of all cancers have somatic integrations of retrotransposons. To characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 37 histological cancer subtypes. We identified 19,166 somatically acquired retrotransposition events, affecting 35% of samples, and spanning a range of event types. L1 insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, sometimes removing tumour suppressor genes, as well as inducing complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications in the development of human tumours.

genomics↗