Chromosome instability and aneuploidy have long posed a conundrum in cancer biology, profoundly shaping tumor genomes yet remaining challenging to decode functionally. In a groundbreaking study published in Nature, Al-Zahrani et al. unveil a novel approach, CRISPR-KOALA, that systematically links large-scale chromosomal alterations to specific cancer-driving genes in basal-like breast cancer (BLBC).

BLBC, a highly aggressive subtype characterized by extensive copy-number alterations (CNAs), often harbors arm-level chromosomal imbalances whose contribution to tumorigenesis remains elusive. The researchers developed CRISPR-KOALA to conduct high-throughput bidirectional genetic screens directly in immunocompetent mouse models, overcoming previous barriers related to the complexity and scale of genes affected by aneuploidy.

By focusing on the ten most frequent human chromosome-arm alterations seen in BLBC, the team screened over 3,700 mouse orthologues of genes located on these arms. The screen identified 90 putative cancer driver genes—a majority of which had not been previously linked to cancer—revealing a diverse functional landscape shaping tumor biology. Among the implicated pathways were key signaling networks such as MAPK, HIPPO, and WNT, highlighting the heterogeneity intrinsic to BLBC progression.

Strikingly, manipulating these driver genes in Trp53-mutant mouse models was sufficient to bypass the need for whole-arm CNAs, suggesting that tumors exploit specific genes within broad chromosomal alterations to fuel oncogenesis. This finding challenges the traditional view that arm-level aneuploidies function merely as genomic chaos, instead presenting them as evolutionary selections for particular drivers.

One gene, PLGRKT, localized on chromosome 9p, emerged as a potent oncogene. The team showed that PLGRKT promotes tumor growth by enhancing mitochondrial robustness and boosting reactive oxygen species detoxification. This mechanistic insight connects chromosomal instability not only to genetic selection but also to metabolic adaptations that support cancer cell survival under stress.

Overall, this study delivers a transformative platform and a compendium of cancer drivers that illuminate how aneuploidy sculpts tumor heterogeneity. By delineating driver genes nested within widespread CNAs, it provides an invaluable resource for targeting breast cancer’s genetic complexity with greater precision.

The implications extend beyond breast cancer, offering a blueprint for dissecting arm-level aneuploidy in diverse malignancies. As cancer therapies increasingly focus on genetic vulnerabilities, CRISPR-KOALA represents a leap toward untangling the intricate link between chromosome-level alterations and oncogenic processes.

This work underscores the power of integrating genomic data with functional genetics in vivo, setting the stage for novel drug targets and therapeutic strategies aimed at the underexplored realm of aneuploidy-driven tumorigenesis.

---

Subject of Research: Chromosome instability and cancer driver genes in basal-like breast cancer

Article Title: Aneuploidy selects for the acquisition of driver genes in breast cancer

Article References:
Al-Zahrani, K.N., Langille, E.R., Nurtanto, J. et al. Aneuploidy selects for the acquisition of driver genes in breast cancer. Nature (2026). https://doi.org/10.1038/s41586-026-10752-9

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41586-026-10752-9

Un chien ou un chat partage-t-il davantage votre ADN ? La réponse de la science est contre-intuitive. Entre organisation chromosomique et maladies communes, les similitudes génétiques entre l'humain et ses animaux de compagnie réservent de vraies surprises. Et les enjeux dépassent largement la...

Un simple cas clinique ne suffit pas à changer la médecine, mais il peut parfois ouvrir de nouvelles pistes. C'est précisément ce qui s'est produit avec cette observation étonnante d'une patiente atteinte d'Alzheimer ayant montré une amélioration temporaire après l'administration de psilocybine.

Votre chat passe ses journées à explorer le quartier avant de rentrer réclamer sa gamelle et quelques caresses ? Selon une nouvelle étude, ces escapades pourraient aussi l'exposer à de nombreux microbes, parasites et virus susceptibles d'être rapportés jusqu'au foyer.

We tend to view ourselves and the complex cells that build us as a distinct branch of the tree of life from the compact, seemingly featureless cells of bacteria and archaea. But we've found that our genome is actually a hybrid, a mish-mash of genes from bacteria and archaea, along with some that have evolved in our own lineage.

Scientists gradually settled on a simple explanation for this: the first complex cells were the product of a fusion between archaeal cells and bacteria, with the bacteria ultimately evolving into the mitochondria, a chemical-power-generating structure that still retains a bit of its own genome. Over time, many of the other bacterial genes were transferred to the nucleus of what was becoming what we now call a eukaryote, intermingling with the archaeal genes there.

But a new study has taken a careful look at some of the genes shared by all eukaryotes and comes to the conclusion that the reality is a little more complicated and that there were several waves of gene transfers from bacteria. The big picture of a merger between bacteria and archaea is still right, but it was only part of a picture where gene transfers among species were commonplace.

Read full article

Comments

© MARK GARLICK/SCIENCE PHOTO LIBRARY

Une simple prise de sang pour prédire la dépression post-partum avant même qu'elle n'apparaisse. C'est la promesse d'un test développé aux États-Unis, capable de détecter ce trouble dans plus de 80 % des cas. Une avancée qui pourrait transformer la prise en charge des jeunes mères.