鉴定个性化癌症驱动基因并进一步揭示其致癌机制对于理解细胞转化机制和辅助临床诊断至关重要。几乎所有现有方法主要关注于在整体或个体水平上鉴定驱动基因，但未能进一步揭示其潜在的致癌机制。为填补这一空白，我们提出了一个可解释的框架PhenoDriver，用于鉴定个性化癌症驱动基因，阐明其在癌症发展中的作用，并揭示驱动基因与临床表型变化之间的关联。通过对988名乳腺癌患者的分析，我们展示了PhenoDriver在鉴定乳腺癌整体水平上的驱动基因方面相较于其他最先进的方法的出色表现。此外，我们的PhenoDriver还可以有效地鉴定个体患者中具有复发和罕见突变的驱动基因。我们进一步探索和揭示了PhenoDriver鉴定的一些已知和未知乳腺癌驱动基因（例如TP53、MAP3K1、HTT等）的致癌机制，并构建了它们调控临床异常表型的亚网络。值得注意的是，我们的大多数发现与现有生物学知识一致。基于个性化驱动基因配置文件，我们发现了两个已知的和一个未报告的乳腺癌亚型，并揭示了它们的分子机制。这些结果加深了我们对乳腺癌机制的理解，指导了治疗决策，并有助于开发靶向抗癌疗法。© 作者 2023。牛津大学出版社保留所有权利。有关权限，请发送电子邮件至：journals.permissions@oup.com。

Identifying personalized cancer driver genes and further revealing their oncogenic mechanisms is critical for understanding the mechanisms of cell transformation and aiding clinical diagnosis. Almost all existing methods primarily focus on identifying driver genes at the cohort or individual level but fail to further uncover their underlying oncogenic mechanisms. To fill this gap, we present an interpretable framework, PhenoDriver, to identify personalized cancer driver genes, elucidate their roles in cancer development and uncover the association between driver genes and clinical phenotypic alterations. By analyzing 988 breast cancer patients, we demonstrate the outstanding performance of PhenoDriver in identifying breast cancer driver genes at the cohort level compared to other state-of-the-art methods. Otherwise, our PhenoDriver can also effectively identify driver genes with both recurrent and rare mutations in individual patients. We further explore and reveal the oncogenic mechanisms of some known and unknown breast cancer driver genes (e.g. TP53, MAP3K1, HTT, etc.) identified by PhenoDriver, and construct their subnetworks for regulating clinical abnormal phenotypes. Notably, most of our findings are consistent with existing biological knowledge. Based on the personalized driver profiles, we discover two existing and one unreported breast cancer subtypes and uncover their molecular mechanisms. These results intensify our understanding for breast cancer mechanisms, guide therapeutic decisions and assist in the development of targeted anticancer therapies.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.