CRISPR screen on aneuploid chromosomes reveals 90 breast cancer driver genes, most previously unknown
For decades, cancer geneticists have known that aneuploidy, the gain or loss of entire chromosome arms, is nearly universal in cancer. But whether the specific genes on those arms are driving the disease, or simply coming along for the ride, has been a mostly unanswered question.
A team led by Khalid Al-Zahrani and Daniel Schramek at the Lunenfeld-Tanenbaum Research Institute in Toronto has now provided an answer. Using a custom-designed bidirectional CRISPR screen that can both activate and silence genes simultaneously, they interrogated all 3,752 genes on the ten most recurrently gained and lost chromosome arms in basal-like breast cancer (BLBC), the most aggressive and difficult-to-treat breast cancer subtype. The results, published July 8 in Nature, identify 90 driver genes, of which 77 to 81 have never been described as cancer drivers before.
A screening method that matches the biology
Chromosome-arm aneuploidy is fundamentally different from single-gene mutations. When an arm is gained, every gene on it is overexpressed; when it is lost, every gene is underexpressed. That means both gain-of-function (oncogene) and loss-of-function (tumour suppressor) events can happen simultaneously across the same arm, and conventional CRISPR screens, which can only knock genes out, miss half the picture.
CRISPR-KOALA (CRISPR Knockout- and Activation-Linked Assay) solves this by delivering two lentiviral constructs into the same cell: an sgRNA that knocks out genes via Cas9 cutting, and a dgRNA that activates genes via dCas9-VPR. Screens were performed in the mammary epithelium of immunocompetent Pten⁻/⁻;Trp53⁻/⁻ and Rb1⁻/⁻;Trp53⁻/⁻ mouse models, both established models of basal-like breast cancer.
The screen identified 34 tumour suppressors and 56 oncogenes. Only four of the 90 overlap with known cancer genes in the OncoKB database. The newly identified drivers activate distinct signalling pathways including MAPK, HIPPO, and WNT, reflecting the molecular heterogeneity of BLBC.
PLGRKT: from overlooked gene to potent oncogene
Among the most striking discoveries is PLGRKT (plasminogen receptor with a C-terminal lysine), located on chromosome 9p, a region frequently gained in BLBC. Activation of Plgrkt alone was sufficient to drive tumour formation in multiple mouse models, including both breast and skin tissue.
Mechanistically, the team found that PLGRKT’s role in cancer has nothing to do with its known function in plasminogen activation. Instead, the protein localizes to the inner mitochondrial membrane (confirmed by STED super-resolution microscopy co-localization with TIMM23). Overexpression of PLGRKT reprograms mitochondria to become highly stress-resistant: increased capacity to detoxify reactive oxygen species, enhanced survival under hypoxia, and a metabolic switch that allows energy generation without oxygen.
The finding is particularly clinically relevant because 9p is one of the most frequently gained regions in BLBC, and PLGRKT sits immediately adjacent to the immune checkpoint gene PD-L1.
Why aneuploidy matters
Basal-like breast cancer accounts for approximately 15–20% of all breast cancers but a disproportionate share of mortality. It is triple-negative (lacking ER, PR, and HER2 expression), does not respond to targeted therapies, and has a five-year survival rate below 30% in advanced stages. Most drug development has focused on the approximately 600 known cancer genes, the 90 identified here, nearly all of which are absent from that list, open a significant new territory for therapeutic targeting.
The finding also helps resolve a long-standing puzzle in cancer genetics: why chromosome-arm aneuploidies are so consistently selected for across tumours. The answer, the study suggests, is that each arm carries multiple driver genes that cooperate to promote cancer. The 10 most recurrent BLBC arms collectively harbour dozens of functionally validated drivers, not just passenger genes.
Caveats
All results are from mouse models and require validation in human tumours. Several of the drivers were undetectable in conventional in vitro screens, suggesting their effects depend on the tumour microenvironment or three-dimensional tissue context. Clinical translation, whether these new drivers represent druggable targets, will require further work.
Sources:
1. Al-Zahrani, K.N., Langille, E.R., Nurtanto, J. et al. “Aneuploidy selects for the acquisition of driver genes in breast cancer.” Nature (2026). DOI: 10.1038/s41586-026-10752-9
2. Nature Research Briefing. “CRISPR-KOALA reveals 81 new breast cancer driver genes.” d41586-026-02014-5
3. GenomeWeb. “CRISPR Screen Identifies 81 Apparent Cancer Drivers in Basal-Like Breast Cancer.” July 8, 2026.