Genomic and molecular landscape of gallbladder cancer elucidating pathogenic mechanisms novel therapeutic targets and clinical implications

Abstract

Gallbladder cancer (GBC) is an aggressive malignancy with a poor prognosis, often diagnosed at advanced stages due to subtle early symptoms. Recent studies have provided a comprehensive view of GBC's genetic and mutational landscape, uncovering crucial pathways involved in its pathogenesis. Environmental exposures, particularly to heavy metals, have been linked to elevated GBC risk. Established signaling pathways, including hormonal, apoptotic, metabolic, inflammatory, and DNA damage repair pathways, are integral to GBC progression, and evidence points to the involvement of specific germline and somatic mutations in its development. Key mutations in genes such as KRAS, TP53, IDH1/2, ERBB, PIK3CA, MET, MYC, BRAF, MGMT, CDKN2A and p16 have been identified as contributors to tumorigenesis, with additional alterations including chromosomal aberrations and epigenetic modifications. These molecular insights reveal several potential therapeutic targets that could address the limited treatment options for GBC. Promising therapeutic avenues under investigation include immune checkpoint inhibitors, tyrosine kinase inhibitors, tumor necrosis factor-related apoptosis-inducing ligands (TRAIL), and phytochemicals. Numerous clinical trials are assessing the efficacy of these targeted therapies. This review provides a detailed examination of GBC's genetic and mutational underpinnings, highlighting critical pathways and emerging therapeutic strategies. We discuss the implications of germline and somatic mutations for early detection and individualized treatment, aiming to bridge current knowledge gaps. By advancing our understanding of GBC's molecular profile, we hope to enhance diagnostic accuracy and improve treatment outcomes, ultimately paving the way for precision medicine approaches in managing GBC.