Gallbladder Cancer: Current Insights in Genetic Alterations and Their Possible Therapeutic Implications

Abstract

Due to the fast progression in molecular technologies such as next-generation sequencing, knowledge of genetic alterations in gallbladder cancer (GBC) increases. This systematic review provides an overview of frequently occurring genetic alterations occurring in GBC and their possible therapeutic implications. A literature search was performed utilizing PubMed, EMBASE, Cochrane Library, and Web of Science. Only studies reporting genetic alterations in human GBC were included. In total, data were extracted from 62 articles, describing a total of 3893 GBC samples. Frequently detected genetic alterations (>5% in >5 samples across all studies) in GBC for which targeted therapies are available in other cancer types included mutations in ATM, ERBB2, and PIK3CA, and ERBB2 amplifications. High tumor mutational burden (TMB-H) and microsatellite instability (MSI-H) were infrequently observed in GBC (1.7% and 3.5%, respectively). For solid cancers with TMB-H or MSI-H pembrolizumab is FDA-approved and shows an objective response rates of 50% for TMB-H GBC and 41% for MSI-H biliary tract cancer. Only nine clinical trials evaluated targeted therapies in GBC directed at frequently altered genes (ERBB2, ARID1A, ATM, and KRAS). This underlines the challenges to perform such clinical trials in this rare, heterogeneous cancer type and emphasizes the need for multicenter clinical trials.

HKI-272 contributes to gemcitabine-mediated anti-proliferative and anti-metastatic effects through EGFR suppression in gallbladder cancer

“…To identify potential genes and proteins that interacted with EGFR, we constructed the gene-gene interaction network for EGFR to filter possible impacted genes using the GeneMania database ( Figure 7 D). The top 20 altered genes were closely associated with EGFR, including PIK3CA, 29 , 30 ADAM12, 31 and ANXA2, 32 which were involved in GBC and breast cancer. This network is predominantly composed of physical interaction (77.64%, pink lines) followed by co-expression (8.01%, purple lines) and prediction (5.37%, yellow lines).…”

Pancancer Analyses Reveal Genomics and Clinical Characteristics of the SETDB1 in Human Tumors

“…Malignant tumor is caused by genetic alterations, and mutated genes offer potential molecular therapeutic targets [ 20 , 21 ]. Given that SETDB1 genetic alterations were associated with molecular therapeutic targets for various human cancers, we investigated the genetic alteration levels of SETDB1 in various human cancers based on TCGA datasets.…”

Precursor Lesions of Gallbladder Carcinoma: Disease Concept, Pathology, and Genetics

“…As a result of the relative rarity, difficulties in obtaining preneoplastic cells and benign background epithelial cells for study, and other reasons, there is little scientific knowledge on gallbladder precursor lesions compared to lesions in other organs [ 70 , 71 ]. We hope recent new technologies will provide precision data regarding precursor neoplastic lesions of the gallbladder in the near future.…”