Biology subjects

Oitaben, A.

Publications and source records attributed to Oitaben, A..

3 recordsLinked to original sources

bioRxiv2024

Genomic Insights Guiding Personalized First-Line Immunotherapy Response in Lung and Bladder Tumors

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, particularly in advanced non-small cell lung cancer (NSCLC) and muscle-invasive bladder cancer (MIBC). However, identifying reliable predictive biomarkers for ICI response remains a significant challenge. In this study, we analyzed real-world cohorts of advanced NSCLC and MIBC patients treated with ICIs as first-line therapy. Tumor samples underwent Whole Genome Sequencing (WGS) to identify specific somatic variants and assess tumor mutational burden (TMB). Additionally, mutational signature extraction and pathway enrichment analyses were performed to uncover the underlying mechanisms of ICI response. We also characterized HLA-I haplotypes and investigated LINE-1 retrotransposition. Distinct mutation patterns were identified in patients who responded to treatment, suggesting potential biomarkers for predicting ICI effectiveness. In NSCLC, tumor mutational burden (TMB) did not differ significantly between responders and non-responders, while in MIBC, higher TMB was linked to better responses. Specific mutational signatures and HLA haplotypes were associated with ICI response in both cancers. Pathway analysis showed that NSCLC responders had active inflammatory and immune pathways, while non-responders had pathways such related to FGFR3 and neural crest differentiation associated to resistance mechanisms. In MIBC, responders had alterations in DNA repair, leading to more neoantigens and a stronger ICI response. Importantly, for the first time, we found that LINE-1 activation was positively linked to ICI response, especially in MIBC. These findings reveal promising biomarkers and mechanistic insights, offering a new perspective on predicting ICI response and opening up exciting possibilities for more personalized immunotherapy strategies in NSCLC and MIBC.

genomics↗

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↗