Functional impact of the hyperduplication genomophenotype in high copy number endometrial cancer

Florio, A.; Smadbeck, J.; Johnson, S.; Lin, W.-H.; Sadeghian, D.; Sotiriou, S.; Salvatori, R.; Feathers, R.; Berry, T.; Kinsella, L.; Harris, F.; McCune, A.; Murphy, S. J.; Ali, M.; Pezeshki, M.; Barrett, M. T.; Grcevich, L.; Capasso, I.; DeVitis, L. A.; Schivardi, G.; Occhiali, T.; Larish, A. M.; Weroha, J.; Borad, M. J.; Cheville, J.; Anastasiadis, P. Z.; Mariani, A.; Vasmatzis, G.

doi:10.1101/2024.09.20.613693

Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.09.20.613693

Functional impact of the hyperduplication genomophenotype in high copy number endometrial cancer

View original source ↗Export metadata ↓

Abstract

High copy number endometrial cancers (HCNEC) are dominated by excessive duplications scattered across the genome, termed here as the HyperDuplication GenomoPhenotype (HDGP). Although correlated with cancer progression, its biological significance and implications for therapy have not yet been established. We identified locations and sizes of duplications in 171 endometrial cancer cases and designated 71 HCNEC cases as HDGP. We also investigated the response to the pan-ERBB inhibitor afatinib in a subset of HDGP-EC cases with ERBB2/ERBB3 duplications using a patient-derived three-dimensional culture model. Our analysis demonstrates that beyond tandem duplications there is a more general pattern involving coordinated duplication of multiple distant regions of the genome, demonstrating preferential selectivity to over-expressed potential oncogenes within a broad network. This suggests that HDGP increases tumor fitness and resistance to therapy by perturbing important gene networks in concert rather than only driver genes, suggesting a mechanistic basis for the ineffectiveness of targeted drugs in these patients and highlighting the need for combination therapies in these highly aggressive cases.

Source connections

Published article ↗

Explore related subjects

genomics Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Florio, A., Smadbeck, J., Johnson, S., Lin, W.-H., Sadeghian, D., Sotiriou, S., Salvatori, R., Feathers, R., Berry, T., Kinsella, L., Harris, F., McCune, A., Murphy, S. J., Ali, M., Pezeshki, M., Barrett, M. T., Grcevich, L., Capasso, I., DeVitis, L. A., Schivardi, G., Occhiali, T., Larish, A. M., Weroha, J., Borad, M. J., Cheville, J., Anastasiadis, P. Z., Mariani, A., Vasmatzis, G.. 2024-09-24. Functional impact of the hyperduplication genomophenotype in high copy number endometrial cancer. https://doi.org/10.1101/2024.09.20.613693

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Integrative Nanopore and Illumina sequencing reveals age-associated tRNA modification and CCA-tail dynamics in yeast

Aging is characterized by a progressive loss of proteostasis. Transfer RNAs (tRNAs) are essential regulators of translation, yet their dynamics during aging remain poorly understood due to challenges in sequencing highly modified RNAs. Here we present a benchmarked Nanopore direct RNA sequencing (RNA004 chemistry) resource that profiles the Saccharomyces cerevisiae tRNAome during replicative aging at single-molecule resolution. Using in vitro transcribed tRNA controls, we establish modification detection thresholds and validate key findings with orthogonal Illumina sequencing. While overall tRNA abundance remains largely stable, our resource reveals age-associated terminal A cleavage at the 3' CCA tail of mature tRNAs, targeted T-loop and anticodon modification changes, and single-molecule evidence of modification co-occurrence. This dataset provides a resource for exploring tRNA regulation, translation fidelity, and longevity.

genomics↗

bioRxiv2026

A hydrogen-producing mitochondrion in an anaerobic eukaryotrophic rhizarian

Diverse eukaryotes thrive under low oxygen conditions, in part through highly modified mitochondrion-related organelles (MROs) that use alternate metabolic pathways to support ATP production and cofactor recycling. Anaerobic lifestyles have evolved repeatedly across the eukaryotic tree of life, each providing an independent opportunity to understand how eukaryotes adapt to life in low oxygen conditions. Here, we use single-cell transcriptomics to reconstruct the MRO metabolism of PCE SSF, a benthic eukaryotrophic flagellate and the first cultivated representative of Novel Clade 12 (NC12; Rhizaria), an independently anaerobic rhizarian lineage. PCE SSF possesses an anaerobic hydrogen-producing mitochondrion capable of hydrogenosome-type substrate-level phosphorylation. It also retains a nearly complete but likely branched tricarboxylic acid pathway that lacks citrate synthase and malate dehydrogenase. The function of citrate synthase may instead be fulfilled by the typically cytosolic ATP citrate lyase, previously reported in this context only in the anaerobic cercozoan, Brevimastigomonas motovehiculus. Unlike B. motovehiculus, however, PCE SSF retains only Complex II and the NuoE/NuoF subunits of the electron transport chain and lacks a mitochondrial genome. Together, these features indicate an atypical and reduced mitochondrial metabolism, highlighting the diversity of evolutionary solutions to anaerobic energy metabolism in eukaryotes.

genomics↗

bioRxiv2026

Targeted CRISPRi screening reveals unexpected resilience across the RNA polymerase III transcriptome

Increased RNA polymerase III (Pol III) activity and tRNA abundance are widely linked to cancer cell growth, yet the functional requirement for individual Pol III genes and core components remains unclear, in part due to the difficulty of achieving gene-specific perturbation of highly conserved loci. Here, we developed an inducible CRISPR interference platform and a custom single-guide RNA (sgRNA) library enabling gene-specific targeting of Pol III-transcribed genes and Pol III machinery. Genome-wide screening identified several Pol III dependencies in diploid fibroblasts and HEK293T cells, including multiple initiator methionine tRNA genes among the strongest fitness dependencies. Unexpectedly, glioblastoma models remained largely insensitive to repression of both individual Pol III genes and core Pol III components, despite efficient target repression. These findings establish a general strategy for gene-specific interrogation of conserved Pol III genes and indicate that glioblastoma models tolerate extensive perturbation of Pol III genes and machinery.

genomics↗