Refining classification of cholangiocarcinoma subtypes via proteogenomic integration reveals new therapeutic prospects

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Title
Refining classification of cholangiocarcinoma subtypes via proteogenomic integration reveals new therapeutic prospects
Author(s)
S Y Cho; Heeyoun Hwang; Y H Kim; B C Yoo; N Han; S Y Kong; M J Baek; K H Kim; M R Lee; J G Park; S S Han; W J Lee; C Park; J B Park; Jin Young Kim; S J Park; S M Woo
Bibliographic Citation
Gastroenterology, vol. 164, no. 7, pp. 1293-1309
Publication Year
2023
Abstract
Background & aims: Intrahepatic cholangiocarcinomas (iCCs) are characterized by their rarity, difficult diagnosis, and overall poor prognosis. The iCC molecular classification for developing precision medicine strategies was investigated. Methods: Comprehensive genomic, transcriptomic, proteomic, and phosphoproteomic analyses were performed on treatment-naive tumor samples from 102 patients with iCC who underwent surgical resection with curative intent. An organoid model was constructed for testing therapeutic potential. Results: Three clinically supported subtypes (stem-like, poorly immunogenic, and metabolism) were identified. NCT-501 (aldehyde dehydrogenase 1 family member A1 [ALDH1A1] inhibitor) exhibited synergism with nanoparticle albumin-bound-paclitaxel in the organoid model for the stem-like subtype. The oncometabolite dysregulations were associated with different clinical outcomes in the stem-like and metabolism subtypes. The poorly immunogenic subtype harbors the non-T-cell tumor infiltration. Integrated multiomics analysis not only reproduced the 3 subtypes but also showed heterogeneity in iCC. Conclusions: This large-scale proteogenomic analysis provides information beyond that obtained with genomic analysis, allowing the functional impact of genomic alterations to be discerned. These findings may assist in the stratification of patients with iCC and in developing rational therapeutic strategies.
Keyword
GenomicsTranscriptomicsProteomicsPhosphoproteomics
ISSN
0016-5085
Publisher
Elsevier
DOI
http://dx.doi.org/10.1053/j.gastro.2023.02.045
Type
Article
Appears in Collections:
1. Journal Articles > Journal Articles
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