Genomic alterations in biliary tract cancer predict prognosis and immunotherapy outcomes

Abstract

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.

Comprehensive germline and somatic genomic profiles of Chinese patients with biliary tract cancer

“…Inactivation of the APC gene leads to disruption of β-catenin degradation, allowing free β-catenin to accumulate in the cytoplasm and translocate into the nucleus; as it was widely detected in the BTC cells, this was indicated as an early event for the carcinogenesis of BTC ( 42 ). Meanwhile, we found that TP53 and CREBBP alterations were enriched in early-stage BTC patients, which contradicted the result from the previous study ( 43 , 44 ). This difference may be contributed by relatively small sample sizes in their studies and difference in the patient characteristics.…”

Developing an Immune-Related Signature for Predicting Survival Rate and the Response to Immune Checkpoint Inhibitors in Patients With Glioma

“…Due to the high level of malignancy and poor prognosis of glioma (Xun et al, 2021), the development of accurate methods is required to predict the associated prognosis and to create effective therapy for patients with glioma. At present, immunotherapy demonstrates high levels of effectiveness in the treatment of malignant tumors (Chen et al, 2021b;Sprooten et al, 2021). Results of previous studies have demonstrated that TIME exhibits a high association with the occurrence and development of several tumor types, and this may act as an important prognostic indicator (Berraondo et al, 2016;Elola et al, 2018).…”

Construction and validation of a cuproptosis-related lncRNA signature for the prediction of the prognosis of LUAD and LUSC

“…TMB serves as a biomarker for prognosis and immunotherapy according to prior study 24 . As a result, the link between TMB and the aforementioned signature was examined in the current investigation.…”