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Updated: Oct 17, 2025
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Exome Sequencing of Pancreatic Acinar Carcinoma Identified Distinctive Mutation Patterns
Yuanhang Liu1, Massimo Raimondo2, Michael B Wallace2
1From the Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN.
Objectives:
Pancreatic acinar cell carcinoma (ACC) is a rare pancreatic cancer. The advancement of treatment is hampered because of the limited knowledge of its molecular mechanism.
Methods:
Whole-exome sequencing was performed on DNA extracted from 11 pure ACC surgical samples. Potential germline variants were removed on the basis of polymorphic databases, alternative allele frequency, coverage depth, and Catalogue of Somatic Mutations in Cancer (COSMIC) annotations after variant calling procedure. Mutation profiles and signatures were assessed through the Mutational Patterns package.
Results:
A median of 34 somatic mutations were detected (range, 19-60). Three novel recurrent small deletions were identified. Common pancreatic ductal adenocarcinoma mutations or neuroendocrine tumor mutants were not found. FAT atypical cadherin 4, mucin 5B, titin, and zinc finger homeobox 3 were consistently mutated across 4 independent ACC studies. A high contribution of COSMIC mutational signature 1 was seen in ACC, indicating deamination of 5-methylcytosine. The majority of the patients had COSMIC signatures 6, 15, or 20, relating to defective DNA mismatch repair. Six patients showed COSMIC mutational signature 10 because of the altered activity of DNA polymerase epsilon.
Conclusions:
Distinct mutational signatures pathways were found in ACC and targeting them may improve clinical outcome.
Insights
This study analyzed pancreatic acinar cell carcinoma (ACC) mutations, revealing distinct molecular pathways. Targeting these unique mutational signatures may offer new therapeutic strategies for ACC patients.
Area of Science:
- Oncology
- Genomics
- Cancer Research
Background:
- Pancreatic acinar cell carcinoma (ACC) is a rare malignancy.
- Limited understanding of ACC's molecular mechanisms hinders treatment development.
Purpose of the Study:
- To investigate the molecular landscape of pancreatic acinar cell carcinoma.
- To identify novel mutations and mutational signatures in ACC.
- To explore potential therapeutic targets based on distinct molecular pathways.
Main Methods:
- Whole-exome sequencing of 11 pure ACC surgical samples.
- Bioinformatic analysis to identify somatic mutations and remove germline variants.
- Assessment of mutation profiles and signatures using established databases and packages.
Main Results:
- A median of 34 somatic mutations per ACC sample was identified.
- Three novel recurrent small deletions were discovered.
- Consistent mutations in FAT atypical cadherin 4, MUC5B, TTN, and ZNF3 were observed across studies.
- Distinct mutational signatures were associated with DNA repair defects and DNA polymerase activity.
Conclusions:
- Pancreatic acinar cell carcinoma exhibits unique mutational signatures.
- These distinct molecular pathways present potential therapeutic targets.
- Targeting identified pathways may lead to improved clinical outcomes for ACC patients.
