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Updated: Aug 25, 2025
A Three-Dimensional Spheroid Model to Investigate the Tumor-Stromal Interaction in Hepatocellular Carcinoma
Published on: September 30, 2021
Comprehensive Molecular Characterization of Gallbladder Carcinoma and Potential Targets for Intervention
Nicolas A Giraldo1, Esther Drill2, Baby A Satravada3
1Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center, New York, New York.
Purpose:
Gallbladder carcinoma (GBC) is an uncommon and aggressive disease, which remains poorly defined at a molecular level. Here, we aimed to characterize the molecular landscape of GBC and identify markers with potential prognostic and therapeutic implications.
Experimental Design:
GBC samples were analyzed using the MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) platform (targeted NGS assay that analyzes 505 cancer-associated genes). Variants with therapeutic implications were identified using OncoKB database. The associations between recurrent genetic alterations and clinicopathologic characteristics (Fisher exact tests) or overall survival (univariate Cox regression) were evaluated. P values were adjusted for multiple testing.
Results:
Overall, 244 samples (57% primary tumors and 43% metastases) from 233 patients were studied (85% adenocarcinomas, 10% carcinomas with squamous differentiation, and 5% neuroendocrine carcinomas). The most common oncogenic molecular alterations appeared in the cell cycle (TP53 63% and CDKN2A 21%) and RTK_RAS pathways (ERBB2 15% and KRAS 11%). No recurrent structural variants were identified. There were no differences in the molecular landscape of primary and metastasis samples. Variants in SMAD4 and STK11 independently associated with reduced survival in patients with metastatic disease. Alterations considered clinically actionable in GBC or other solid tumor types (e.g., NTRK1 fusions or oncogenic variants in ERBB2, PIK3CA, or BRCA1/2) were identified in 35% of patients; 18% of patients with metastatic disease were treated off-label or enrolled in a clinical trial based on molecular findings.
Conclusions:
GBC is a genetically diverse malignancy. This large-scale genomic analysis revealed alterations with potential prognostic and therapeutic implications and provides guidance for the development of targeted therapies.
Insights
Gallbladder carcinoma (GBC) is genetically diverse. Genomic analysis identified molecular alterations in cell cycle and RTK_RAS pathways, offering potential prognostic and therapeutic targets for this aggressive cancer.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Gallbladder carcinoma (GBC) is an aggressive cancer with a poorly understood molecular basis.
- Identifying molecular drivers is crucial for developing targeted therapies and improving patient outcomes.
Purpose of the Study:
- To characterize the molecular landscape of GBC.
- To identify potential prognostic and therapeutic markers in GBC.
Main Methods:
- Utilized MSK-IMPACT, a targeted next-generation sequencing (NGS) assay analyzing 505 cancer-associated genes.
- Analyzed 244 GBC samples (primary tumors and metastases).
- Correlated genetic alterations with clinicopathologic features and overall survival, adjusting for multiple testing.
Main Results:
- The most frequent alterations were in TP53 (63%), CDKN2A (21%), ERBB2 (15%), and KRAS (11%).
- SMAD4 and STK11 variants were associated with reduced survival in metastatic GBC.
- Clinically actionable alterations were found in 35% of patients, with 18% of metastatic cases receiving targeted treatments or clinical trial enrollment.
Conclusions:
- GBC exhibits significant genetic diversity.
- Genomic profiling reveals potential prognostic and therapeutic targets, guiding the development of novel GBC therapies.
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