Integrative genomic analyses of European intrahepatic cholangiocarcinoma: Novel ROS1 fusion gene and PBX1 as prognostic marker.
Clin Transl Med
; 14(6): e1723, 2024 Jun.
Article
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| MEDLINE
| ID: mdl-38877653
ABSTRACT
BACKGROUND:
Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct with a poor prognosis owing to limited therapeutic options. The incidence of intrahepatic CCA (iCCA) is increasing worldwide, and its molecular basis is emerging. Environmental factors may contribute to regional differences in the mutation spectrum of European patients with iCCA, which are underrepresented in systematic genomic and transcriptomic studies of the disease.METHODS:
We describe an integrated whole-exome sequencing and transcriptomic study of 37 iCCAs patients in Germany.RESULTS:
We observed as most frequently mutated genes ARID1A (14%), IDH1, BAP1, TP53, KRAS, and ATM in 8% of patients. We identified FGFR2BICC1 fusions in two tumours, and FGFR2KCTD1 and TMEM106BROS1 as novel fusions with potential therapeutic implications in iCCA and confirmed oncogenic properties of TMEM106BROS1 in vitro. Using a data integration framework, we identified PBX1 as a novel central regulatory gene in iCCA. We performed extended screening by targeted sequencing of an additional 40 CCAs. In the joint analysis, IDH1 (13%), BAP1 (10%), TP53 (9%), KRAS (7%), ARID1A (7%), NF1 (5%), and ATM (5%) were the most frequently mutated genes, and we found PBX1 to show copy gain in 20% of the tumours. According to other studies, amplifications of PBX1 tend to occur in European iCCAs in contrast to liver fluke-associated Asian iCCAs.CONCLUSIONS:
By analyzing an additional European cohort of iCCA patients, we found that PBX1 protein expression was a marker of poor prognosis. Overall, our findings provide insight into key molecular alterations in iCCA, reveal new targetable fusion genes, and suggest that PBX1 is a novel modulator of this disease.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas Proto-Oncogénicas
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Colangiocarcinoma
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Factor de Transcripción 1 de la Leucemia de Células Pre-B
Límite:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
País/Región como asunto:
Europa
Idioma:
En
Revista:
Clin Transl Med
Año:
2024
Tipo del documento:
Article
País de afiliación:
Alemania
Pais de publicación:
Estados Unidos