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 21 publications

(31 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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“…Different alleles of a TSG can be deactivated via mutation, deletion [57], or copy-neutral loss of heterozygosity [58]. However, the same mechanisms can constrain each other, as shown in a recent finding that 1q trisomy inhibits p53 signaling and accelerates tumor progression [59].…”

Section: Discussionmentioning

confidence: 99%

CINner: modeling and simulation of chromosomal instability in cancer at single-cell resolution

Dinh,

Vázquez-García,

Chan

et al. 2024

Preprint

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Cancer development is characterized by chromosomal instability, manifesting in frequent occurrences of different genomic alteration mechanisms ranging in extent and impact. Mathematical modeling can help evaluate the role of each mutational process during tumor progression, however existing frameworks can only capture certain aspects of chromosomal instability (CIN). We present CINner, a mathematical framework for modeling genomic diversity and selection during tumor evolution. The main advantage of CINner is its flexibility to incorporate many genomic events that directly impact cellular fitness, from driver gene mutations to copy number alterations (CNAs), including focal amplifications and deletions, missegregations and whole-genome duplication (WGD). We apply CINner to find chromosome-arm selection parameters that drive tumorigenesis in the absence of WGD in chromosomally stable cancer types. We found that the selection parameters predict WGD prevalence among different chromosomally unstable tumors, hinting that the selective advantage of WGD cells hinges on their tolerance for aneuploidy and escape from nullisomy. Direct application of CINner to model the WGD proportion and fraction of genome altered (FGA) further uncovers the increase in CNA probabilities associated with WGD in each cancer type. CINner can also be utilized to study chromosomally stable cancer types, by applying a selection model based on driver gene mutations and focal amplifications or deletions. Finally, we used CINner to analyze the impact of CNA probabilities, chromosome selection parameters, tumor growth dynamics and population size on cancer fitness and heterogeneity. We expect that CINner will provide a powerful modeling tool for the oncology community to quantify the impact of newly uncovered genomic alteration mechanisms on shaping tumor progression and adaptation.

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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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Oncogene-like addiction to aneuploidy in human cancers

Cited by 21 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

CINner: modeling and simulation of chromosomal instability in cancer at single-cell resolution

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

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