Genomic evolution and the impact of SLIT2 mutation in relapsed intrahepatic cholangiocarcinoma.
Bile Duct Neoplasms
/ genetics
Cholangiocarcinoma
/ genetics
Evolution, Molecular
Humans
Intercellular Signaling Peptides and Proteins
/ genetics
Mutation
Neoplasm Recurrence, Local
/ genetics
Nerve Tissue Proteins
/ genetics
Phosphatidylinositol 3-Kinases
Prognosis
Tumor Microenvironment
/ genetics
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
revised:
07
09
2021
received:
01
10
2020
accepted:
16
09
2021
pubmed:
21
9
2021
medline:
3
5
2022
entrez:
20
9
2021
Statut:
ppublish
Résumé
Intrahepatic cholangiocarcinoma (ICC) is aggressive and has high rates of relapse, conferring poor long-term survival after curative resection. Little is known about the genomic evolution that occurs during ICC relapse. We conducted whole-exome sequencing of 30 paired primary and relapsed tumors from 10 patients with ICC who received curative resection. We sought to identify frequently altered genes, infer tumor subclonal architectures, and track genomic evolution from primary to relapsed tumors. We examined functional effects and the mechanism of action of SLIT2, a gene specifically mutated in relapsed tumors, on tumor growth and metastasis and the tumor microenvironment. Our results indicated that relapsed ICCs were genetically derived from intrahepatic dissemination of primary tumors. However, they acquired additional mutations while maintaining most drivers, such as TP53 and IDH1. Multiregion sequencing suggested polyclonal seeding of ICC dissemination. Four of 10 relapsed ICCs acquired SLIT2 mutations that were not present in the corresponding primary tumors. Validation in an expanded sample revealed SLIT2 mutations in 2.3% (1/44) of primary ICCs and 29.5% (13/44) of relapsed ICCs. Biofunctional investigations revealed that inactivating mutation of SLIT2 resulted in activation of PI3K-Akt signaling in ICC cells, directly enhanced neutrophil chemotaxis, mediated tumor-associated neutrophil infiltration, and contributed to ICC growth and metastasis. We characterized genomic evolution during ICC relapse and identified SLIT2 as a driver of tumor dissemination and tumor-associated neutrophil infiltration.
Sections du résumé
BACKGROUND AND AIMS
Intrahepatic cholangiocarcinoma (ICC) is aggressive and has high rates of relapse, conferring poor long-term survival after curative resection. Little is known about the genomic evolution that occurs during ICC relapse.
APPROACH AND RESULTS
We conducted whole-exome sequencing of 30 paired primary and relapsed tumors from 10 patients with ICC who received curative resection. We sought to identify frequently altered genes, infer tumor subclonal architectures, and track genomic evolution from primary to relapsed tumors. We examined functional effects and the mechanism of action of SLIT2, a gene specifically mutated in relapsed tumors, on tumor growth and metastasis and the tumor microenvironment. Our results indicated that relapsed ICCs were genetically derived from intrahepatic dissemination of primary tumors. However, they acquired additional mutations while maintaining most drivers, such as TP53 and IDH1. Multiregion sequencing suggested polyclonal seeding of ICC dissemination. Four of 10 relapsed ICCs acquired SLIT2 mutations that were not present in the corresponding primary tumors. Validation in an expanded sample revealed SLIT2 mutations in 2.3% (1/44) of primary ICCs and 29.5% (13/44) of relapsed ICCs. Biofunctional investigations revealed that inactivating mutation of SLIT2 resulted in activation of PI3K-Akt signaling in ICC cells, directly enhanced neutrophil chemotaxis, mediated tumor-associated neutrophil infiltration, and contributed to ICC growth and metastasis.
CONCLUSIONS
We characterized genomic evolution during ICC relapse and identified SLIT2 as a driver of tumor dissemination and tumor-associated neutrophil infiltration.
Identifiants
pubmed: 34543483
doi: 10.1002/hep.32164
pii: 01515467-202204000-00008
doi:
Substances chimiques
Intercellular Signaling Peptides and Proteins
0
Nerve Tissue Proteins
0
Slit homolog 2 protein
R6FXH13RRC
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
831-846Informations de copyright
© 2021 American Association for the Study of Liver Diseases.
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