Oncogene-like addiction to aneuploidy in human cancers

Girish, Vishruth; Lakhani, Asad A.; Scaduto, Christine M.; Thompson, Sarah L.; Brown, Leanne M.; Hagenson, Ryan A.; Sausville, Erin L.; Mendelson, Brianna E.; Lukow, Devon A.; Yuan, Monet Lou; Kandikuppa, Pranav K.; Stevens, Eric C.; Lee, Sophia N.; Šalovská, Barbora; Li, Wenxue; Smith, John K.; Taylor, Alison M.; Martienssen, Robert A.; Liu, Yansheng; Sun, Ruping; Sheltzer, Jason M.

doi:10.1101/2023.01.09.523344

Cited by 15 publications

(22 citation statements)

References 129 publications

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“…Aneuploidy is also found in >88% of cancers: tumors with high levels of aneuploidy display poorer patient prognosis, respond less well to treatment, and have a higher rate of relapse 16,17 . Recent studies show that specific chromosome amplifications underlie these benefits [17][18][19][20][21] . Thus, aneuploidy can be a fast route to adaptation in a changing environment.…”

Section: Introductionmentioning

confidence: 99%

Comparative modeling reveals the molecular determinants of aneuploidy fitness cost in a wild yeast model

Rojas,

Hose,

Dutcher

et al. 2024

Preprint

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Although implicated as deleterious in many organisms, aneuploidy can underlie rapid phenotypic evolution. However, aneuploidy will only be maintained if the benefit outweighs the cost, which remains incompletely understood. To quantify this cost and the molecular determinants behind it, we generated a panel of chromosome duplications in Saccharomyces cerevisiae and applied comparative modeling and molecular validation to understand aneuploidy toxicity. We show that 74-94% of the variance in aneuploid strains growth rates is explained by the additive cost of genes on each chromosome, measured for single-gene duplications using a genomic library, along with the deleterious contribution of snoRNAs and beneficial effects of tRNAs. Machine learning to identify properties of detrimental gene duplicates provided no support for the balance hypothesis of aneuploidy toxicity and instead identified gene length as the best predictor of toxicity. Our results present a generalized framework for the cost of aneuploidy with implications for disease biology and evolution.

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Section: Introductionmentioning

confidence: 99%

Comparative modeling reveals the molecular determinants of aneuploidy fitness cost in a wild yeast model

Rojas,

Hose,

Dutcher

et al. 2024

Preprint

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“…With the advent of precision therapeutics and promising concepts aiming to allow drugging of virtually any protein ( 54 , 55 ), powerful models to connect tumor-specific alterations with potential synthetic lethal targets are promising. Large-scale chromosomal deletions are highly prevalent throughout many human cancers and can be routinely detected in cancer diagnostics, but only recently models to study them in detail have been described ( 56 , 57 ). Our model permitted in-detail characterization of tumor biology in chr8p-deleted tumors leading to a better understanding of the mechanisms driving increased tumor progression and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Chromosome 8p engineering reveals increased metastatic potential targetable by patient-specific synthetic lethality in liver cancer

Huth,

Dreher,

Lemke

et al. 2023

Sci. Adv.

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Large-scale chromosomal aberrations are prevalent in human cancer, but their function remains poorly understood. We established chromosome-engineered hepatocellular carcinoma cell lines using CRISPR-Cas9 genome editing. A 33–mega–base pair region on chromosome 8p (chr8p) was heterozygously deleted, mimicking a frequently observed chromosomal deletion. Using this isogenic model system, we delineated the functional consequences of chr8p loss and its impact on metastatic behavior and patient survival. We found that metastasis-associated genes on chr8p act in concert to induce an aggressive and invasive phenotype characteristic for chr8p-deleted tumors. Genome-wide CRISPR-Cas9 viability screening in isogenic chr8p-deleted cells served as a powerful tool to find previously unidentified synthetic lethal targets and vulnerabilities accompanying patient-specific chromosomal alterations. Using this target identification strategy, we showed that chr8p deletion sensitizes tumor cells to targeting of the reactive oxygen sanitizing enzyme Nudix hydrolase 17. Thus, chromosomal engineering allowed for the identification of novel synthetic lethalities specific to chr8p loss of heterozygosity.

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“…We found that WGD-positive tumors were more likely to have spread to regional or distant lymph nodes, which may warrant additional surveillance and interventions among Black patients. More broadly, chromosomal alterations are strongly associated with patient outcome, and analyzing tumor karyotypes as part of a standard pathological workup may improve our ability to preemptively detect aggressive disease 44,[67][68][69][70][71] . Additionally, recent research has demonstrated that WGD-positive cancer cells harbor unique genetic vulnerabilities.…”

Section: Discussionmentioning

confidence: 99%

An elevated rate of whole-genome duplication events in cancers from Black patients

Brown,

Hagenson,

Sheltzer

2023

Preprint

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In the United States, Black individuals have higher rates of cancer mortality than any other racial or ethnic group. The sources of these significant racial disparities are not fully understood, and may include social, environmental, and genetic factors that influence cancer onset, diagnosis, and treatment. Here, we examined genomic data from several large-scale cancer patient cohorts to search for racial associations in chromosome copy number alterations. We found that tumors from Black patients were significantly more likely to exhibit whole-genome duplications (WGDs), a genomic event that enhances metastasis and aggressive disease, compared to tumors from white patients. Among patients with WGD-positive cancers, there was no significant difference in survival between Black and white patients, suggesting that the increased incidence of WGD events could contribute to the disparities in patient outcome. Genomic analysis identified several somatic alterations associated with WGD events that were consistent between Black and white populations, indicating that the increase in WGD events may be driven by environmental or epigenetic factors in Black patients. In total, these findings identify a class of genomic alterations that may influence racial disparities in cancer patient outcome. As cancers that have undergone WGD events exhibit unique genetic vulnerabilities, therapies that selectively target WGD-positive cancers may be particularly effective at treating aggressive malignancies in Black patients.

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Oncogene-like addiction to aneuploidy in human cancers

Cited by 15 publications

References 129 publications

Comparative modeling reveals the molecular determinants of aneuploidy fitness cost in a wild yeast model

Comparative modeling reveals the molecular determinants of aneuploidy fitness cost in a wild yeast model

Chromosome 8p engineering reveals increased metastatic potential targetable by patient-specific synthetic lethality in liver cancer

An elevated rate of whole-genome duplication events in cancers from Black patients

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