1. Mutational spectrum and precision oncology for biliary tract carcinoma
- Author
-
Yi Bai, Jianzhen Lin, Xiaoyue Wang, Xinting Sang, Xin Lu, Xu Yang, Henghui Zhang, Lei Zhang, Xueshuai Wan, Yang Shi, Guangyu Li, Haitao Zhao, Dongxu Wang, Jie Pan, Jinzhu Mao, Li Huo, Junyu Long, Yilei Mao, Yinghao Cao, Fucun Xie, Mei Guan, Ke Hu, Anqiang Wang, Yang Song, Kai Wang, Lin Zhao, and Xiaobo Yang
- Subjects
0301 basic medicine ,Oncology ,Male ,ARID1A ,medicine.medical_treatment ,Medicine (miscellaneous) ,medicine.disease_cause ,Targeted therapy ,Cholangiocarcinoma ,0302 clinical medicine ,INDEL Mutation ,CDKN2A ,Medicine ,Molecular Targeted Therapy ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Intrahepatic Cholangiocarcinoma ,education.field_of_study ,Genomics ,Middle Aged ,targeted therapy ,DNA-Binding Proteins ,030220 oncology & carcinogenesis ,molecular screening ,Female ,Gallbladder Neoplasms ,KRAS ,Research Paper ,medicine.medical_specialty ,DNA Copy Number Variations ,precision medicine ,Population ,Polymorphism, Single Nucleotide ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Germline mutation ,Internal medicine ,biliary tract cancer ,Exome Sequencing ,Humans ,Gallbladder cancer ,education ,Cyclin-Dependent Kinase Inhibitor p16 ,Aged ,Neoplasm Staging ,business.industry ,Carcinoma ,genomic alterations ,medicine.disease ,030104 developmental biology ,Bile Ducts, Intrahepatic ,Bile Duct Neoplasms ,Receptors, LDL ,Mutation ,Tumor Suppressor Protein p53 ,business ,Transcription Factors - Abstract
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.
- Published
- 2021