Genomic Alterations in Biliary Tract Cancer Using Targeted Sequencing

BackgroundRecently, immunotherapy with immune checkpoint inhibitors (ICIs) has shown promising efficacy in biliary tract cancer (BTC), which includes gallbladder cancer (GBC) and cholangiocarcinoma (CHOL). Understanding the association between immunotherapy outcomes and the genomic profile of advanced BTC may further improve the clinical benefits from immunotherapy.MethodsGenomic tumor DNA was isolated from 98 Chinese patients with advanced BTC and used for targeted next-generation sequencing of 416 cancer-related genes to identify the genomic alterations common to advanced BTC. Thirty-four patients had received ICI camrelizumab plus gemcitabine and oxaliplatin (from the NCT03486678 trial) as a first-line treatment. Tumor-infiltrating immune cells were evaluated using immunofluorescence staining.ResultsKRAS and TP53 mutations were much more frequent in the advanced-stage BTC cohort than in other cohorts with mostly early stage disease. Specifically, KRAS-TP53 co-mutations were favored in advanced CHOL, with a favorable response to immunotherapy, while single KRAS mutations predicted poor prognosis and immunotherapy outcomes for CHOL. Compared with GBC, CHOL had more mutations in genes involved in KRAS signaling; a high mutation load in these genes correlated with poor immunotherapy outcomes and may subsequently cause inferior immunotherapy outcomes for CHOL relative to GBC. Furthermore, a genomic signature including 11 genes was developed; their mutated subtype was associated with poor prognosis and immunotherapy outcomes in both CHOL and GBC. Transcriptome analyses suggested immune dysfunction in the signature mutated subtype, which was validated by tumor microenvironment (TME) evaluation based on detection of immune cell infiltration. Importantly, the signature wild-type subtype with favorable TME may be an advantageous population of immunotherapy.ConclusionsGenomic alterations in advanced BTC were associated with specific prognosis and immunotherapy outcomes. Combining genomic classification with TME evaluation further improved the stratification of immunotherapy outcomes.

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Therapeutic relevance of targeted sequencing in management of patients with advanced biliary tract cancer: DNA damage repair gene mutations as a predictive biomarker

European Journal of Cancer ◽

10.1016/j.ejca.2019.07.022 ◽

2019 ◽

Vol 120 ◽

pp. 31-39 ◽

Cited By ~ 9

Author(s):

Heejung Chae ◽

Deokhoon Kim ◽

Changhoon Yoo ◽

Kyu-pyo Kim ◽

Jae Ho Jeong ◽

...

Keyword(s):

Dna Damage ◽

Biliary Tract ◽

Biliary Tract Cancer ◽

Gene Mutations ◽

Predictive Biomarker ◽

Targeted Sequencing ◽

Repair Gene ◽

Tract Cancer ◽

Therapeutic Relevance ◽

Damage Repair

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Biliary tract cancer and genomic alterations in homologous recombinant deficiency: exploiting synthetic lethality with PARP inhibitors

Chinese Clinical Oncology ◽

10.21037/cco.2020.02.02 ◽

2020 ◽

Vol 9 (1) ◽

pp. 6-6 ◽

Cited By ~ 2

Author(s):

Daniel H. Ahn ◽

Tanios Bekaii-Saab

Keyword(s):

Biliary Tract ◽

Biliary Tract Cancer ◽

Synthetic Lethality ◽

Parp Inhibitors ◽

Genomic Alterations ◽

Tract Cancer

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Genomic Profiling of Blood-Derived Circulating Tumor DNA from Patients with Advanced Biliary Tract Cancer

Pathology & Oncology Research ◽

10.3389/pore.2021.1609879 ◽

2021 ◽

Vol 27 ◽

Author(s):

Chen Chen ◽

Tao Wang ◽

Mengmei Yang ◽

Jia Song ◽

Mengli Huang ◽

...

Keyword(s):

Biliary Tract ◽

Biliary Tract Cancer ◽

Circulating Tumor Dna ◽

Chinese Patients ◽

Ras Signaling ◽

Genomic Alterations ◽

Tissue Samples ◽

Genomic Changes ◽

Tract Cancer ◽

Tumor Dna

Background: Biliary tract cancer is a highly lethal malignancy with poor clinical outcome. Accumulating evidence indicates targeted therapeutics may provide new hope for improving treatment response in BTC, hence better understanding the genomic profile is particularly important. Since tumor tissue may not be available for some patients, a complementary method is urgently needed. Circulating tumor DNA (ctDNA) provides a noninvasive means for detecting genomic alterations, and has been regarded as a promising tool to guide clinical therapies.Methods: Next-generation sequencing of 150 cancer-related genes was used to detect gene alterations in blood-derived ctDNA from 154 Chinese patients with BTC. Genomic alterations were analyzed and compared with an internal tissue genomic database and TCGA database.Results: 94.8% patients had at least one change detected in their ctDNA. The median maximum somatic allele frequency was 6.47% (ranging 0.1–34.8%). TP53 and KRAS were the most often mutated genes. The frequencies of single nucleotide variation in commonly mutated genes in ctDNA were similar to those detected in tissue samples, TP53 (35.1 vs. 40.4%) and KRAS (20.1 vs. 22.6%). Pathway analysis revealed that mutated genes were mapped to several key pathways including PI3K-Akt, p53, ErbB and Ras signaling pathway. In addition, patients harboring LRP1B, TP53, and ErbB family mutations presented significantly higher tumor mutation burden.Conclusions: These findings demonstrated that ctDNA testing by NGS was feasible in revealing genomic changes and could be a viable alternative to tissue biopsy in patients with metastatic BTC.

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