Abstract
The rapid evolution of sequencing technologies has profoundly advanced precision oncology. Whole-exome sequencing (WES), whole-genome sequencing (WGS), and whole-transcriptome sequencing (RNA-Seq) enable comprehensive characterization of tumor biology by detecting actionable mutations, gene fusions, splice variants, copy number alterations, and pathway dysregulation. These approaches also provide critical insights into biomarkers such as homologous recombination deficiency (HRD), tumor mutational burden (TMB), and microsatellite instability (MSI), which are increasingly essential for guiding therapeutic decisions. Importantly, comprehensive genomic profiling not only refines patient stratification for targeted therapies but also sheds light on tumor-immune interactions and the tumor microenvironment, paving the way for more effective immunotherapeutic combinations. WGS is considered the gold standard for detecting germline mutations and complex structural variants, while WES remains central for detecting somatic driver mutations that guide targeted therapies. RNA-Seq complements these methods by capturing gene expression dynamics, identifying clinically relevant fusions, and revealing mechanisms of resistance. Together with advances in bioinformatics and artificial intelligence, these tools translate molecular data into actionable strategies for patient care. This review integrates insights from WGS, WES, and RNA-Seq with an overview of FDA- and EMA-approved targeted therapies, organized by tumor type, and highlights the molecular signaling pathways that drive cancer development and treatment. By bridging genomic profiling with regulatory-approved therapies, we outline current advances and future perspectives in delivering personalized cancer care.