Cancer Genomics And Translational Clinical Investigations In Primary Hepatobiliary Tumors

Primary hepatobiliary tumors(HBTs)include malignancies originated from hepatocytes,cholangiocytes,biliary tract and gallbladder.Patients with HBTs have poor prognoses,only 30%of them had resectable tumor lesions at their initial diagnoses.Various adjuvant antitumoral therapies bring limited clinical benefits for patients with advanced HBTs,highlighting the necessary of integrating clinicopathological features into clinical practice to precisely stratify patients,so that precision medicine could be achieved.In the last decade,the large-scale genomic sequencing has deciphered the mutational landscape and molecular characteristics of HBTs,expanding the dimension of stratification in HBT patients.However,the bottleneck is that how to effectively integrate the molecular information of the tumor genome into the clinical diagnosis and treatment.Moreover,the epidemiology and etiology of HBT patients in China are varied from western populations.Thus,we still need more preclinical researches and translational clinical practices to clarify the genomic features and to offer evidence of precision medicine in Chinese populations.In this study,we combine whole-exome sequencing and target-captured deep sequencing to identify the genomic alterations in HBT.In order to determine the clinical relevance and translational significance for these mutations,we correlate genomic alterations with clinicopathological features,therapeutic outcomes and survival prognoses.This study also preliminarily investigates the feasibility and efficacy of genome-driven oncology in patients with refractory HBTs.The present study contains three major parts:(1)The first part analyzes the mutational spectrum of DNA damage response(DDR)genes in a cohort of 357 patients with primary liver cancer(PLC).25.8%of these patients have at least one DDR gene mutation,15 of whom carry with germline mutations,and we prove that BRCA2 has susceptible genetic hereditary phenomena in three families of patients with intrahepatic cholangiocarcinoma(ICC).The most commonly altered DDR genes are ATM(5%)and BRCA(4.8%).The occurrence of DDR mutations is significantly correlated with a higher tumor mutation burden regardless of the PLC pathologic subtype.For DDR-mutated PLC,26.1%of patients possess at least one actionable alteration,and eight patients with the mutated BRCA are treated by olaparib.Efficacy outcomes reveal that patients with BRCA2 germline truncation mutations show an objective response.(2)The second part evaluate tumor aneuploidy burden(TAB)in a cohort of 158 ICC patients.We observe a significant positive association between the TAB and mutations in PBRM1 and BAP1,which belong to the chromatin-modifying molecules.Notably,26%of patients are classified as TAB-negative ICCs(TAB=0),and this subgroup possess significantly higher levels of tumor-infiltrating myeloid-derived macrophages.The multivariate Cox proportion hazard models identify the TAB-negative as an independently unfavorable predictor of either postsurgery DFS or OS in ICC patients,while TAB-high patients are more responsive and achieve longer progression-free survival for gemcitabine-based systemic chemotherapy.(3)The third part analyzes genomic alterations in 803 patients of biliary tract carcinomas(BTCs).Our results highlight that genomic diversity and heterogeneity are extensive among patients with BTC,as in addition to TP53(51%)and KRAS(23%),almost all cancer-driving mutations account for 5-15%of cases,with contributions according to anatomical subtype and clinicopathological characteristics.Mutational signatures are identified as a cholangiocarcinoma-like genotype to distinguish ICC from hepatocellular carcinoma samples as well as the cholangiocarcinoma phenotype in mixed hepato-cholangiocarcinoma patients.Based on patients' prognoses,we provide several independent predictive genomic biomarkers,especially TP53,KRAS and 7q31.2,for DFS or OS in BTC patients.A protein-coding gene,CAPZA2(located at 7q31.2),has been demonstrated to be a carcinogenic factor in cholangiocarcinoma.We also design molecular-directed therapies with a molecular tumor board for 46 patients with potentially actionable targets,achieving a 26.1%objective response rate,with a median progression-free survival of 5.0 months.In conclusion,the present study concentrates on identifying tumor mutations,quantifying tumor aneuploidy and characterizing the translational significances for patients with primary HBTs.On this basis of evidence-based medicine and the clinical practice of genome-driven oncology,this study preliminarily explores the integration of cancer genome into clinical applications.Our results provide a reference for precise medicine in HBT patients.