# Regional differences in gallbladder cancer pathogenesis: insights from a multi-institutional comparison of tumor mutations

Source: https://onco.cc/key-papers/paper-narayan-gallbladder-regional-mutations-cancer-2019/  
OnCo record `paper-narayan-gallbladder-regional-mutations-cancer-2019` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Comparing gallbladder tumours from Chile, Japan and the United States, Japanese patients were older with fewer stone-related cancers and different mutations, while SMAD4 loss was common everywhere and went with shorter survival.

## Summary

Primary tumours from 81 patients with gallbladder cancer treated in Chile (21), Japan (11) and the United States (49) between 1999 and 2016 underwent targeted sequencing of known cancer-associated genes. Japanese patients were older (median 72 years versus 59 in Chile and 66 in the United States), had more well-differentiated tumours (46% versus 0%) and fewer gallstone-associated cancers (36% versus 67% and 69%), and had a higher median mutation burden (6 versus 7 in Chile and 4 in the United States; P = 0.006).

Tumours from Japanese patients lacked ARID1A and PIK3CA mutations, whereas Chilean tumours lacked ERBB3 and ARID2 mutations. SMAD4 was mutated similarly across centres (38% in Chile, 36% in Japan, 27% in the United States) and was univariately associated with worse overall survival (median 10 versus 25 months; P = 0.039). At least one potentially actionable gene was altered in 80% of tumours.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Cancer
- Year: 2019
- DOI: 10.1002/cncr.31850
- Authors: Narayan RR, Creasy JM, Goldman DA, et al.
- Findings: SMAD4 mutated in 38% (Chile), 36% (Japan) and 27% (United States); median survival 10 versus 25 months with and without it.; Japanese tumours lacked ARID1A and PIK3CA mutations; Chilean tumours lacked ERBB3 and ARID2.; At least one potentially actionable alteration in 80% of tumours.
- What it means: Regional biology is real but partial: exposures and age differ, some genes differ, and SMAD4 loss emerges as the shared bad-prognosis marker. It is the paper behind the MSK 2018 gallbladder study on cBioPortal (gbc_msk_2018).
- Caveats: Only 11 Japanese and 21 Chilean tumours; absence of a mutation in such small groups is weak evidence.; Targeted panel, so tumour mutation burden is a panel count, not a per-megabase figure.

## Sources

- Narayan et al., Cancer 2019: regional differences in gallbladder cancer mutations (Chile, Japan, United States): https://doi.org/10.1002/cncr.31850
- PubMed: https://pubmed.ncbi.nlm.nih.gov/30427539/
- cBioPortal study gbc_msk_2018 (Gallbladder Cancer, MSK, Cancer 2018; 103 samples): https://www.cbioportal.org/study/summary?id=gbc_msk_2018

## Connected records

- cancers: [Gallbladder cancer](https://onco.cc/cancers/gallbladder/)
- targets: [ARID1A](https://onco.cc/targets/arid1a/), [ARID2](https://onco.cc/targets/arid2/), [HER3](https://onco.cc/targets/her3/), [PIK3CA / PI3K-alpha](https://onco.cc/targets/pik3ca/), [SMAD4](https://onco.cc/targets/smad4/)
- institutions: [Memorial Sloan Kettering Cancer Center](https://onco.cc/institutions/mskcc/)
- people: [Ghassan K. Abou-Alfa](https://onco.cc/people/ghassan-abou-alfa/)
- journals: [Cancer](https://onco.cc/journals/cancer-wiley/)

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