Comprehensive molecular characterization of gallbladder carcinoma and potential targets for intervention Journal Article
| Authors: | Giraldo, N. A.; Drill, E.; Satravada, B. A.; El Dika, I.; Brannon, A. R.; Dermawan, J.; Mohanty, A.; Ozcan, K.; Chakravarty, D.; Benayed, R.; Vakiani, E.; Abou-Alfa, G. K.; Kundra, R.; Schultz, N.; Li, B. T.; Berger, M. F.; Harding, J. J.; Ladanyi, M.; O'Reilly, E. M.; Jarnagin, W.; Vanderbilt, C.; Basturk, O.; Arcila, M. E. |
| Article Title: | Comprehensive molecular characterization of gallbladder carcinoma and potential targets for intervention |
| Abstract: | 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. ©2022 American Association for Cancer Research. |
| Keywords: | genetics; mutation; adenocarcinoma; tumor marker; carcinoma; gallbladder neoplasms; carcinoma, neuroendocrine; gallbladder tumor; humans; prognosis; human; biomarkers, tumor |
| Journal Title: | Clinical Cancer Research |
| Volume: | 28 |
| Issue: | 24 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2022-12-15 |
| Start Page: | 5359 |
| End Page: | 5367 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-22-1954 |
| PUBMED: | 36228155 |
| PROVIDER: | scopus |
| PMCID: | PMC9772093 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 January 2023 -- Source: Scopus |
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