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Gallbladder Cancer Vaccine Candidate Identified Through Genomic Analysis

NEW YORK – A genomic analysis of gallbladder cancer has uncovered alterations that could be therapeutic, including candidates for a cancer vaccine.

Researchers from the US- and India-based MedGenome, Genentech, and multiple international institutions analyzed more than 200 gallbladder cancer samples from patients in Chile, India, and South Korea. Gallbladder cancer affects more than 178,000 people each year and is highly fatal, with a median survival of less than a year and no targeted therapies. It is more common among populations in Asia and South America.

As they reported Monday in Nature Communications, the researchers identified a number of recurrent mutations within these samples. They in particular uncovered potentially actionable alterations in more than a fifth of the cases they analyzed, including ERBB2 mutations, microsatellite instability, and alterations affecting genes like ELF2 that generated neoantigens that could be targeted by a cancer vaccine.

"The work deepens our understanding of the underlying genomics of [gallbladder cancer], including the identification of new pathways, immune microenvironment, and actionable mutations," co-first author Eric Stawiski, vice president of bioinformatics at MedGenome, said in a statement.

The researchers obtained whole-exome sequencing data for 160 gallbladder cancer samples, the transcriptomes of 115 samples, and low-pass whole genome data for 146 samples. These samples came from 94 patients from South Korea, 64 from India, and nine from Chile. Overall, based on the exome sequencing data, they identified protein-altering somatic mutations in 10,224 genes, about half of which were recurrent mutations.

They specifically homed in on 25 significantly mutated genes, which included well-known oncogenes like ERBB2 and KRAS; tumor suppressor genes like TP53 and ARID2; and other less well-established cancer-linked genes like ELF3. 

Some of these alterations suggested potential treatment routes. For instance, ERBB2 amplifications were present within 13 percent of gallbladder cancer samples, and 68 percent of those samples overexpressed ERBB2. This indicated to the researchers that some gallbladder patients might be candidates for targeted HER2 therapy.

At the same time ELF3, an ETS-domain transcription factor was altered in 21 percent of samples. ELF3 mutations were more common among Korean and Chilean patients, affecting a respective 31 percent and 22 percent of patients, than among Indian patients, where they were found in 7 percent of patients. 

The researchers suspected that some of the alterations identified in their cohort — mutations in TP53, ELF3, ERBB2, and others — could generate neoantigens that activate T cells. Using the MedGenome OncoPept assay, they in particular noted the ELF3-derived neoantigens could activate CD8+ T-cells and induce high IFN-gamma levels, suggesting these neoantigens could potentially be used as a cancer vaccine to treat gallbladder cancer. 

In addition, three tumors from within the researchers' sample set had much higher mutation rates than others and testing revealed microsatellite instability. These samples, the researchers added, are candidates for checkpoint inhibitor therapy. 

In all, they identified actionable alterations in more than 20 percent of their cases. This finding suggested that folding genomic analysis in gallbladder cancer patient care will help improve outcomes through use of approved targeted therapies, the researchers noted.

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