西奈山医院Daniel Schramek小组近日取得一项新成果。经过不懈努力，他们的最新研究提出了非整倍性选择促进乳腺癌驱动基因的获得。该项研究成果发表在2026年7月8日出版的《自然》上。

在这里，课题组建立了一种CRISPR敲除和激活相关的检测方法（CRISPR-KOALA），在免疫活性的癌症小鼠模型中实现了高通量双向遗传筛选。研究团队编制了一份基底样乳腺癌（BLBC）中10种最常见的人类染色体臂水平改变的纲要，BLBC是一种由大拷贝数改变（CNAs）驱动的疾病类型。使用CRISPR-KOALA，课题组人员筛选了这些手臂上3752个基因的母位同源物，并鉴定了90个癌症驱动基因，其中绝大多数的功能是未知的。这些基因驱动不同的信号通路，包括MAPK、HIPPO和WNT，反映了BLBC的高度异质性。

在Trp53突变的BLBC小鼠模型中，操纵已确定的癌症驱动基因克服了对CNAs的需求。从机制上讲，课题组发现PLGRKT是一个位于染色体9p上的强效致癌基因，并表明其促肿瘤活性与高度抗应激的线粒体和活性氧解毒能力的增强有关。总之，他们的研究结果表明，臂水平的CNAs可以选择特定的驱动基因来促进异质生物学过程。

据了解，染色体不稳定在癌症中非常普遍，并导致大规模的染色体不平衡，称为非整倍体。由于受影响的基因数量众多，非整倍性如何促进肿瘤发生仍然难以研究。

附：英文原文

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

Author: Al-Zahrani, Khalid N., Langille, Ellen R., Nurtanto, Jocelyn, Obersterescu, Andreea, Teng, Katie, Lowden, Christopher, Dessapt, Julien, Chiu, Cynthia H., Caldwell, Lauren V., Cook, David P., Prez-Castro, Miguel A., Berman, Jacob M., Tsai, Ricky, Bahcheli, Alexander T., Mbamalu, Geraldine, Wu, Shifei, Narimatsu, Masahiro, Lopes, Adele G., Fotiadou, Iosifina, Chan, Kin, Zhang, Linkang, Bang, K. W. Annie, Parsons, Michael J., Mourao, Larissa, Temel, E. Idil, McCulla, Liddy, Sravya, Palavalasa, Zhang, Li, Sajjakulnukit, Peter, Lyssiotis, Costas A., Borowsky, Alexander D., Scheele, Colinda L. G. J., Wahl, Daniel R., Jackson, Hartland W., Stewart, Katherine S., Fuchs, Elaine, Egan, Sean E., Pujana, Miguel Angel, Reimand, Jri, Wrana, Jeffrey L., Schramek, Daniel

Issue&Volume: 2026-07-08

Abstract: Chromosome instability is highly prevalent in cancer and drives large-scale chromosomal imbalances, known as aneuploidies1,2,3,4. How aneuploidy contributes to tumorigenesis remains difficult to study due to the vast numbers of genes affected. Here we established a CRISPR knockout- and activation-linked assay (CRISPR-KOALA), enabling high-throughput bidirectional genetic screens in immunocompetent mouse models of cancer. We developed a compendium of the ten most frequent human chromosome-arm-level alterations in basal-like breast cancer (BLBC), a disease type that is driven by large copy-number alterations (CNAs)5,6,7,8. Using CRISPR-KOALA, we screened the mouse orthologues of 3,752 genes on these arms and identified 90 cancer driver genes, the function of the vast majority of which is unknown. These genes drive distinct signalling pathways including MAPK, HIPPO and WNT, reflecting the high degree of BLBC heterogeneity. Manipulating the identified cancer driver genes overcomes the need for CNAs in Trp53-mutant BLBC mouse models. Mechanistically, we identify that PLGRKT is a potent oncogene that lies on chromosome 9p and show that its tumour-promoting activity is associated with highly stress-resistant mitochondria and an increased ability to detoxify reactive oxygen species. Together, our findings reveal that arm-level CNAs can function to select specific driver genes to promote heterogeneous biological processes.

DOI: 10.1038/s41586-026-10752-9

Source: https://www.nature.com/articles/s41586-026-10752-9