Decoding driver and phenotypic genes in cancer: Unveiling the essence behind the phenomenon
Dequan Liu, Lei Liu, Xiaoman Zhang, Xinming Zhao, Xiaorui Li, Xiangyu Che, Guangzhen Wu
Abstract
Gray hair, widely regarded as a hallmark of aging. While gray hair is associated with aging, reversing this trait through gene targeting does not alter the fundamental biological processes of aging. Similarly, certain oncogenes (such as CXCR4, MMP-related genes, etc.) can serve as markers of tumor behavior, such as malignancy or prognosis, but targeting these genes alone may not lead to tumor regression. We pioneered the name of this class of genes as "phenotypic genes". Historically, cancer genetics research has focused on tumor driver genes, while genes influencing cancer phenotypes have been relatively overlooked. This review explores the critical distinction between driver genes and phenotypic genes in cancer, using the MAPK and PI3K/AKT/mTOR pathways as key examples. We also discuss current research techniques for identifying driver and phenotypic genes, such as whole-genome sequencing (WGS), RNA sequencing (RNA-seq), RNA interference (RNAi), CRISPR-Cas9, and other genomic screening methods, alongside the concept of synthetic lethality in driver genes. The development of these technologies will help develop personalized treatment strategies and precision medicine based on the characteristics of relevant genes. By addressing the gap in discussions on phenotypic genes, this review significantly contributes to clarifying the roles of driver and phenotypic genes, aiming at advancing the field of targeted cancer therapy. Certain oncogenes can serve as markers of tumor behavior, but targeting these genes alone may not lead to tumor regression, distinguishing them from traditional cancer driver genes, which we have termed "phenotypic genes." Techniques such as WGS, RNA-seq, RNAi, CRISPR-Cas9, and the concept of synthetic lethality will facilitate the accurate screening of phenotypic and driver genes, ultimately improving early cancer diagnosis, enabling personalized treatment strategies, and guiding combination drug therapies. Methods and significance of distinguishing driver and phenotypic genes in cancer. • The article defines “phenotypic genes” as regulators of cancer traits that do not directly drive tumor progression. • It showcases advanced genomic methods—WGS, RNA-seq, RNAi, and CRISPR-Cas9—for identifying driver and phenotypic genes. • Differentiating driver from phenotypic genes enables advancements in precision oncology and personalized cancer therapies.