Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma

Liangqing Dong; Dayun Lu; Ran Chen; Youpei Lin; Hongwen Zhu; Zhou Zhang; Shangli Cai; Peng Cui; Guohe Song; Dongning Rao; Xinpei Yi; Yingcheng Wu; Nixue Song; Fen Liu; Yunhao Zou; Shu Zhang; Xiaoming Zhang; Xiaoying Wang; Shuangjian Qiu; Jian Zhou; Shisheng Wang; Xu Zhang; Yongyong Shi; Daniel Figeys; Li Ding; Pei Wang; Bing Zhang; Henry Rodriguez; Qiang Gao; Daming Gao; Hu Zhou; Jia Fan

doi:10.1016/j.ccell.2021.12.006

Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma

Liangqing Dong, Dayun Lu, Ran Chen, Youpei Lin, Hongwen Zhu, Zhou Zhang, Shangli Cai, Peng Cui, Guohe Song, Dongning Rao, Xinpei Yi, Yingcheng Wu, Nixue Song, Fen Liu, Yunhao Zou, Shu Zhang, Xiaoming Zhang, Xiaoying Wang, Shuangjian Qiu, Jian ZhouShisheng Wang, Xu Zhang, Yongyong Shi, Daniel Figeys, Li Ding, Pei Wang, Bing Zhang, Henry Rodriguez, Qiang Gao, Daming Gao, Hu Zhou, Jia Fan

Research output: Contribution to journal › Article › peer-review

209 Scopus citations

Abstract

We performed proteogenomic characterization of intrahepatic cholangiocarcinoma (iCCA) using paired tumor and adjacent liver tissues from 262 patients. Integrated proteogenomic analyses prioritized genetic aberrations and revealed hallmarks of iCCA pathogenesis. Aflatoxin signature was associated with tumor initiation, proliferation, and immune suppression. Mutation-associated signaling profiles revealed that TP53 and KRAS co-mutations may contribute to iCCA metastasis via the integrin-FAK-SRC pathway. FGFR2 fusions activated the Rho GTPase pathway and could be a potential source of neoantigens. Proteomic profiling identified four patient subgroups (S1–S4) with subgroup-specific biomarkers. These proteomic subgroups had distinct features in prognosis, genetic alterations, microenvironment dysregulation, tumor microbiota composition, and potential therapeutics. SLC16A3 and HKDC1 were further identified as potential prognostic biomarkers associated with metabolic reprogramming of iCCA cells. This study provides a valuable resource for researchers and clinicians to further identify molecular pathogenesis and therapeutic opportunities in iCCA.

Original language	English
Pages (from-to)	70-87.e15
Journal	Cancer Cell
Volume	40
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2021.12.006
State	Published - Jan 10 2022

Keywords

FGFR2 fusion
intrahepatic cholangiocarcinoma
molecular subgroups
oncogenic drivers
prognostic biomarkers
proteogenomics

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10.1016/j.ccell.2021.12.006

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Dong, L., Lu, D., Chen, R., Lin, Y., Zhu, H., Zhang, Z., Cai, S., Cui, P., Song, G., Rao, D., Yi, X., Wu, Y., Song, N., Liu, F., Zou, Y., Zhang, S., Zhang, X., Wang, X., Qiu, S., ... Fan, J. (2022). Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma. Cancer Cell, 40(1), 70-87.e15. https://doi.org/10.1016/j.ccell.2021.12.006

@article{9e39405be1de4a3fb5732dc5e0e4f7a6,

title = "Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma",

abstract = "We performed proteogenomic characterization of intrahepatic cholangiocarcinoma (iCCA) using paired tumor and adjacent liver tissues from 262 patients. Integrated proteogenomic analyses prioritized genetic aberrations and revealed hallmarks of iCCA pathogenesis. Aflatoxin signature was associated with tumor initiation, proliferation, and immune suppression. Mutation-associated signaling profiles revealed that TP53 and KRAS co-mutations may contribute to iCCA metastasis via the integrin-FAK-SRC pathway. FGFR2 fusions activated the Rho GTPase pathway and could be a potential source of neoantigens. Proteomic profiling identified four patient subgroups (S1–S4) with subgroup-specific biomarkers. These proteomic subgroups had distinct features in prognosis, genetic alterations, microenvironment dysregulation, tumor microbiota composition, and potential therapeutics. SLC16A3 and HKDC1 were further identified as potential prognostic biomarkers associated with metabolic reprogramming of iCCA cells. This study provides a valuable resource for researchers and clinicians to further identify molecular pathogenesis and therapeutic opportunities in iCCA.",

keywords = "FGFR2 fusion, intrahepatic cholangiocarcinoma, molecular subgroups, oncogenic drivers, prognostic biomarkers, proteogenomics",

author = "Liangqing Dong and Dayun Lu and Ran Chen and Youpei Lin and Hongwen Zhu and Zhou Zhang and Shangli Cai and Peng Cui and Guohe Song and Dongning Rao and Xinpei Yi and Yingcheng Wu and Nixue Song and Fen Liu and Yunhao Zou and Shu Zhang and Xiaoming Zhang and Xiaoying Wang and Shuangjian Qiu and Jian Zhou and Shisheng Wang and Xu Zhang and Yongyong Shi and Daniel Figeys and Li Ding and Pei Wang and Bing Zhang and Henry Rodriguez and Qiang Gao and Daming Gao and Hu Zhou and Jia Fan",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2022",

month = jan,

day = "10",

doi = "10.1016/j.ccell.2021.12.006",

language = "English",

volume = "40",

pages = "70--87.e15",

journal = "Cancer Cell",

issn = "1535-6108",

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Dong, L, Lu, D, Chen, R, Lin, Y, Zhu, H, Zhang, Z, Cai, S, Cui, P, Song, G, Rao, D, Yi, X, Wu, Y, Song, N, Liu, F, Zou, Y, Zhang, S, Zhang, X, Wang, X, Qiu, S, Zhou, J, Wang, S, Zhang, X, Shi, Y, Figeys, D, Ding, L, Wang, P, Zhang, B, Rodriguez, H, Gao, Q, Gao, D, Zhou, H & Fan, J 2022, 'Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma', Cancer Cell, vol. 40, no. 1, pp. 70-87.e15. https://doi.org/10.1016/j.ccell.2021.12.006

TY - JOUR

T1 - Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma

AU - Dong, Liangqing

AU - Lu, Dayun

AU - Chen, Ran

AU - Lin, Youpei

AU - Zhu, Hongwen

AU - Zhang, Zhou

AU - Cai, Shangli

AU - Cui, Peng

AU - Song, Guohe

AU - Rao, Dongning

AU - Yi, Xinpei

AU - Wu, Yingcheng

AU - Song, Nixue

AU - Liu, Fen

AU - Zou, Yunhao

AU - Zhang, Shu

AU - Zhang, Xiaoming

AU - Wang, Xiaoying

AU - Qiu, Shuangjian

AU - Zhou, Jian

AU - Wang, Shisheng

AU - Zhang, Xu

AU - Shi, Yongyong

AU - Figeys, Daniel

AU - Ding, Li

AU - Wang, Pei

AU - Zhang, Bing

AU - Rodriguez, Henry

AU - Gao, Qiang

AU - Gao, Daming

AU - Zhou, Hu

AU - Fan, Jia

PY - 2022/1/10

Y1 - 2022/1/10

N2 - We performed proteogenomic characterization of intrahepatic cholangiocarcinoma (iCCA) using paired tumor and adjacent liver tissues from 262 patients. Integrated proteogenomic analyses prioritized genetic aberrations and revealed hallmarks of iCCA pathogenesis. Aflatoxin signature was associated with tumor initiation, proliferation, and immune suppression. Mutation-associated signaling profiles revealed that TP53 and KRAS co-mutations may contribute to iCCA metastasis via the integrin-FAK-SRC pathway. FGFR2 fusions activated the Rho GTPase pathway and could be a potential source of neoantigens. Proteomic profiling identified four patient subgroups (S1–S4) with subgroup-specific biomarkers. These proteomic subgroups had distinct features in prognosis, genetic alterations, microenvironment dysregulation, tumor microbiota composition, and potential therapeutics. SLC16A3 and HKDC1 were further identified as potential prognostic biomarkers associated with metabolic reprogramming of iCCA cells. This study provides a valuable resource for researchers and clinicians to further identify molecular pathogenesis and therapeutic opportunities in iCCA.

AB - We performed proteogenomic characterization of intrahepatic cholangiocarcinoma (iCCA) using paired tumor and adjacent liver tissues from 262 patients. Integrated proteogenomic analyses prioritized genetic aberrations and revealed hallmarks of iCCA pathogenesis. Aflatoxin signature was associated with tumor initiation, proliferation, and immune suppression. Mutation-associated signaling profiles revealed that TP53 and KRAS co-mutations may contribute to iCCA metastasis via the integrin-FAK-SRC pathway. FGFR2 fusions activated the Rho GTPase pathway and could be a potential source of neoantigens. Proteomic profiling identified four patient subgroups (S1–S4) with subgroup-specific biomarkers. These proteomic subgroups had distinct features in prognosis, genetic alterations, microenvironment dysregulation, tumor microbiota composition, and potential therapeutics. SLC16A3 and HKDC1 were further identified as potential prognostic biomarkers associated with metabolic reprogramming of iCCA cells. This study provides a valuable resource for researchers and clinicians to further identify molecular pathogenesis and therapeutic opportunities in iCCA.

KW - FGFR2 fusion

KW - intrahepatic cholangiocarcinoma

KW - molecular subgroups

KW - oncogenic drivers

KW - prognostic biomarkers

KW - proteogenomics

UR - http://www.scopus.com/inward/record.url?scp=85122284947&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2021.12.006

DO - 10.1016/j.ccell.2021.12.006

M3 - Article

C2 - 34971568

AN - SCOPUS:85122284947

SN - 1535-6108

VL - 40

SP - 70-87.e15

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma

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Keywords

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