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Lynch Syndrome and Somatic Mismatch Repair Variants in Pancreas Cancer
Catherine A O'Connor1,2, Emily Harrold1,3, David Lin4
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
JAMA Oncology
|September 5, 2024
Summary
Microsatellite instability (MSI-H) in pancreatic cancer arises from Lynch syndrome or somatic mutations. Immune checkpoint blockade therapy shows significant benefit for patients with MSI-H pancreatic cancer.
Area of Science:
- Oncology
- Genetics
- Cancer Research
Background:
- Microsatellite instability (MSI-H) is common in Lynch syndrome (LS) tumors and predicts response to immune checkpoint blockade (ICB).
- Mismatch repair (MMR) gene variants cause MSI-H, but the role of somatic oncogenesis in pancreatic cancer (PC) MSI-H is unclear.
Purpose of the Study:
- To investigate clinicogenomic features of LS-related PC.
- To characterize somatic MSI-H cases in PC without germline variants.
- To assess ICB response and guide MS testing in PC.
Main Methods:
- Retrospective analysis of 55 PC patients with LS germline or somatic MMR variants.
- Orthogonal methods for MMR and MS status determination.
- AI classifier for low-cellularity specimens; analysis of zygosity and somatic comutation landscape.
Main Results:
- 32 patients had LS, 23 had somatic MMR variants. MSI-H was observed in 59% of LS and 43% of somatic cohorts.
- An AI classifier reclassified ~20% of cases, particularly those with low cellularity.
- 20 patients received ICB (17 MSI-H) with an 80% disease control rate.
Conclusions:
- MSI-H in pancreatic cancer originates from either Lynch syndrome or somatic oncogenesis.
- Accurate MS testing in PC requires orthogonal methods, with AI aiding low-cellularity samples.
- ICB offers significant benefits for patients with MSI-H pancreatic cancer.
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