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Mutational spectrum and precision oncology for biliary tract carcinoma

Background: The genomic spectrum of biliary tract carcinoma (BTC) has been characterized and is associated with distinct anatomic and etiologic subtypes, yet limited studies have linked genomic alterations with personalized therapies in BTC patients. Methods: This study analyzed 803 patients with BT...

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Autores principales: Lin, Jianzhen, Cao, Yinghao, Yang, Xu, Li, Guangyu, Shi, Yang, Wang, Dongxu, Long, Junyu, Song, Yang, Mao, Jinzhu, Xie, Fucun, Bai, Yi, Zhang, Lei, Yang, Xiaobo, Wan, Xueshuai, Wang, Anqiang, Guan, Mei, Zhao, Lin, Hu, Ke, Pan, Jie, Huo, Li, Lu, Xin, Mao, Yilei, Sang, Xinting, Zhang, Henghui, Wang, Kai, Wang, Xiaoyue, Zhao, Haitao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978308/
https://www.ncbi.nlm.nih.gov/pubmed/33754015
http://dx.doi.org/10.7150/thno.56539
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author Lin, Jianzhen
Cao, Yinghao
Yang, Xu
Li, Guangyu
Shi, Yang
Wang, Dongxu
Long, Junyu
Song, Yang
Mao, Jinzhu
Xie, Fucun
Bai, Yi
Zhang, Lei
Yang, Xiaobo
Wan, Xueshuai
Wang, Anqiang
Guan, Mei
Zhao, Lin
Hu, Ke
Pan, Jie
Huo, Li
Lu, Xin
Mao, Yilei
Sang, Xinting
Zhang, Henghui
Wang, Kai
Wang, Xiaoyue
Zhao, Haitao
author_facet Lin, Jianzhen
Cao, Yinghao
Yang, Xu
Li, Guangyu
Shi, Yang
Wang, Dongxu
Long, Junyu
Song, Yang
Mao, Jinzhu
Xie, Fucun
Bai, Yi
Zhang, Lei
Yang, Xiaobo
Wan, Xueshuai
Wang, Anqiang
Guan, Mei
Zhao, Lin
Hu, Ke
Pan, Jie
Huo, Li
Lu, Xin
Mao, Yilei
Sang, Xinting
Zhang, Henghui
Wang, Kai
Wang, Xiaoyue
Zhao, Haitao
author_sort Lin, Jianzhen
collection PubMed
description Background: The genomic spectrum of biliary tract carcinoma (BTC) has been characterized and is associated with distinct anatomic and etiologic subtypes, yet limited studies have linked genomic alterations with personalized therapies in BTC patients. Methods: This study analyzed 803 patients with BTC:164 with gallbladder cancer, 475 with intrahepatic cholangiocarcinoma (ICC) and 164 with extrahepatic cholangiocarcinoma. We determined genomic alterations, mutational signatures related to etiology and histopathology and prognostic biomarkers. Personalized targeted therapies for patients harboring potentially actionable targets (PATs) were investigated. Results: The median tumor mutation burden (TMB) was 1.23 Mut/Mb, with 4.1% of patients having hypermutated BTCs. Unlike the results obtained from the Western population, the most frequently altered cancer-related genes in our cohort included TP53 (53%), KRAS (26%), ARID1A (18%), LRP1B (14%) and CDKN2A (14%). Germline mutations occurred mostly in DNA damage repair genes. Notably, 35.8% of the ICCs harbored aristolochic acid related signatures and an elevated TMB. TP53 and KRAS mutations and amplified 7q31.2 were demonstrated to negatively affect patient prognosis. Moreover, 19 genes were proposed to be PATs in BTCs, with 25.4% of patients harboring these PATs. Forty-six patients received PAT-matched targeted therapies, achieving a 26.1% objective response rate; the median progression-free survival (PFS) was 5.0 months, with 56.8% of patients obtaining PFS benefits. Conclusions: Extensive genomic diversity and heterogeneity were observed among BTC patients, with contributions according to potential etiology exposures, anatomical subtypes and clinicopathological characteristics. We also demonstrated that patients with refractory BTCs who have PATs can derive considerable benefit from receiving a matched therapy, initiating further prospective clinical trials guided by molecular profiling among this aggressive cancer.
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spelling pubmed-79783082021-03-21 Mutational spectrum and precision oncology for biliary tract carcinoma Lin, Jianzhen Cao, Yinghao Yang, Xu Li, Guangyu Shi, Yang Wang, Dongxu Long, Junyu Song, Yang Mao, Jinzhu Xie, Fucun Bai, Yi Zhang, Lei Yang, Xiaobo Wan, Xueshuai Wang, Anqiang Guan, Mei Zhao, Lin Hu, Ke Pan, Jie Huo, Li Lu, Xin Mao, Yilei Sang, Xinting Zhang, Henghui Wang, Kai Wang, Xiaoyue Zhao, Haitao Theranostics Research Paper Background: The genomic spectrum of biliary tract carcinoma (BTC) has been characterized and is associated with distinct anatomic and etiologic subtypes, yet limited studies have linked genomic alterations with personalized therapies in BTC patients. Methods: This study analyzed 803 patients with BTC:164 with gallbladder cancer, 475 with intrahepatic cholangiocarcinoma (ICC) and 164 with extrahepatic cholangiocarcinoma. We determined genomic alterations, mutational signatures related to etiology and histopathology and prognostic biomarkers. Personalized targeted therapies for patients harboring potentially actionable targets (PATs) were investigated. Results: The median tumor mutation burden (TMB) was 1.23 Mut/Mb, with 4.1% of patients having hypermutated BTCs. Unlike the results obtained from the Western population, the most frequently altered cancer-related genes in our cohort included TP53 (53%), KRAS (26%), ARID1A (18%), LRP1B (14%) and CDKN2A (14%). Germline mutations occurred mostly in DNA damage repair genes. Notably, 35.8% of the ICCs harbored aristolochic acid related signatures and an elevated TMB. TP53 and KRAS mutations and amplified 7q31.2 were demonstrated to negatively affect patient prognosis. Moreover, 19 genes were proposed to be PATs in BTCs, with 25.4% of patients harboring these PATs. Forty-six patients received PAT-matched targeted therapies, achieving a 26.1% objective response rate; the median progression-free survival (PFS) was 5.0 months, with 56.8% of patients obtaining PFS benefits. Conclusions: Extensive genomic diversity and heterogeneity were observed among BTC patients, with contributions according to potential etiology exposures, anatomical subtypes and clinicopathological characteristics. We also demonstrated that patients with refractory BTCs who have PATs can derive considerable benefit from receiving a matched therapy, initiating further prospective clinical trials guided by molecular profiling among this aggressive cancer. Ivyspring International Publisher 2021-03-04 /pmc/articles/PMC7978308/ /pubmed/33754015 http://dx.doi.org/10.7150/thno.56539 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Lin, Jianzhen
Cao, Yinghao
Yang, Xu
Li, Guangyu
Shi, Yang
Wang, Dongxu
Long, Junyu
Song, Yang
Mao, Jinzhu
Xie, Fucun
Bai, Yi
Zhang, Lei
Yang, Xiaobo
Wan, Xueshuai
Wang, Anqiang
Guan, Mei
Zhao, Lin
Hu, Ke
Pan, Jie
Huo, Li
Lu, Xin
Mao, Yilei
Sang, Xinting
Zhang, Henghui
Wang, Kai
Wang, Xiaoyue
Zhao, Haitao
Mutational spectrum and precision oncology for biliary tract carcinoma
title Mutational spectrum and precision oncology for biliary tract carcinoma
title_full Mutational spectrum and precision oncology for biliary tract carcinoma
title_fullStr Mutational spectrum and precision oncology for biliary tract carcinoma
title_full_unstemmed Mutational spectrum and precision oncology for biliary tract carcinoma
title_short Mutational spectrum and precision oncology for biliary tract carcinoma
title_sort mutational spectrum and precision oncology for biliary tract carcinoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978308/
https://www.ncbi.nlm.nih.gov/pubmed/33754015
http://dx.doi.org/10.7150/thno.56539
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