Comprehensive molecular characterization of gallbladder carcinoma and potential targets for intervention
The largest sequencing study of gallbladder cancer at one centre, 244 samples on a 505-gene panel, found TP53 in 63%, HER2 changes in 15% and something actionable in a third of patients; SMAD4 and STK11 marked shorter survival.
Overview
244 gallbladder carcinoma samples (57% primary tumours and 43% metastases) from 233 patients were analysed with the MSK-IMPACT targeted panel of 505 cancer-associated genes; 85% were adenocarcinomas, 10% carcinomas with squamous differentiation and 5% neuroendocrine carcinomas. The most common oncogenic alterations were in the cell cycle (TP53 63%, CDKN2A 21%) and RTK-RAS pathways (ERBB2 15%, KRAS 11%). No recurrent structural variants were identified and the molecular landscape of primaries and metastases did not differ.
Variants in SMAD4 and STK11 were independently associated with reduced survival in metastatic disease. Alterations considered clinically actionable in gallbladder or other solid tumours (NTRK1 fusions, oncogenic variants in ERBB2, PIK3CA or BRCA1/2) were identified in 35% of patients, and 18% of patients with metastatic disease were treated off-label or enrolled in a trial on the basis of the findings.
- TP53 63%, CDKN2A 21%, ERBB2 15%, KRAS 11% among 244 samples.
- Clinically actionable alterations in 35% of patients; 18% of metastatic patients treated on them.
- SMAD4 and STK11 variants independently predicted shorter survival in metastatic disease; primaries and metastases did not differ.
The reference Western cohort for gallbladder cancer frequencies, deposited on cBioPortal as gbc_mskcc_2022, where the per-gene sample counts on OnCo were read. It supports panel testing at diagnosis: one patient in three has a targetable finding.
- Tertiary referral centre; metastatic and pretreated patients are over-represented.
- Actionability was graded with the OncoKB database, which OnCo does not reproduce.
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