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Updated: Nov 3, 2025
Pancreatic Tissue Dissection to Isolate Viable Single Cells
Published on: May 26, 2023
The pancreatic cancer genome revisited
Akimasa Hayashi1,2, Jungeui Hong1,3, Christine A Iacobuzio-Donahue4,5,6
1The David M. Rubenstein Center for Pancreatic Cancer Research, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Abstract:
Pancreatic cancer is a genetic disease, and the recurrent genetic alterations characteristic of pancreatic cancer indicate the cellular processes that are targeted for malignant transformation. In addition to somatic alterations in the most common driver genes (KRAS, CDKN2A, TP53 and SMAD4), large-scale studies have revealed major roles for genetic alterations of the SWI/SNF and COMPASS complexes, copy number alterations in GATA6 and MYC that partially define phenotypes of pancreatic cancer, and the role(s) of polyploidy and chromothripsis as factors contributing to pancreatic cancer biology and progression. Germline variants that increase the risk of pancreatic cancer continue to be discovered along with a greater appreciation of the features of pancreatic cancers with mismatch repair deficiencies and homologous recombination deficiencies that confer sensitivity to therapeutic targeting. Wild-type KRAS pancreatic cancers, some of which are driven by alternative oncogenic events affecting NRG1 or NTRK1 - for which targeted therapies exist - further underscore that pancreatic cancer is formally entering the era of precision medicine. Given the vast developments within this field, here we review the wide-ranging and most current information related to pancreatic cancer genomics with the goal of integrating this information into a unifying description of the life history of pancreatic cancer.
Insights
Pancreatic cancer is driven by genetic alterations in key genes and pathways. Understanding these genomic changes, including polyploidy and chromothripsis, is crucial for developing precision medicine approaches and targeted therapies.
Area of Science:
- Genomics
- Oncology
- Cancer Biology
Background:
- Pancreatic cancer is characterized by recurrent genetic alterations targeting cellular processes crucial for malignant transformation.
- Key somatic alterations involve driver genes (KRAS, CDKN2A, TP53, SMAD4), SWI/SNF and COMPASS complexes, and copy number changes in GATA6 and MYC.
- Genomic instability, including polyploidy and chromothripsis, significantly contributes to pancreatic cancer biology and progression.
Purpose of the Study:
- To review and integrate current information on pancreatic cancer genomics.
- To provide a unifying description of the life history of pancreatic cancer based on genomic insights.
- To highlight the evolving landscape of pancreatic cancer towards precision medicine.
Main Methods:
- Comprehensive review of large-scale genomic studies and recent findings in pancreatic cancer.
- Analysis of somatic and germline genetic alterations.
- Integration of data on genetic complexes, copy number alterations, and genomic instability.
Main Results:
- Identification of major roles for SWI/SNF and COMPASS complexes, GATA6, and MYC alterations in defining pancreatic cancer phenotypes.
- Discovery of germline variants increasing pancreatic cancer risk.
- Characterization of mismatch repair deficiencies and homologous recombination deficiencies conferring therapeutic sensitivity.
- Recognition of wild-type KRAS pancreatic cancers driven by NRG1 or NTRK1 alterations, amenable to targeted therapies.
Conclusions:
- Pancreatic cancer genomics is complex, involving multiple genetic alterations and pathways.
- Genomic insights are paving the way for precision medicine in pancreatic cancer treatment.
- Targeted therapies are becoming increasingly relevant for specific pancreatic cancer subtypes.
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