Chmielecki 2014: comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes
Sequencing of acinar cell carcinomas found that they do not carry the KRAS mutation that drives ordinary pancreatic cancer; instead about a quarter have fusions activating BRAF or RAF1, which MEK-blocking drugs can shut down in the laboratory, and almost half have broken DNA repair genes that may make them sensitive to platinum and PARP inhibitors.
Overview
Targeted sequencing of 44 pancreatic acinar cell carcinomas. Recurrent gene fusions involving BRAF or RAF1 (including SND1-BRAF and HERPUD1-BRAF) were found in about 23 percent of tumours, with mutual exclusivity from other MAPK alterations, and cell lines expressing the fusions were sensitive to MEK inhibition.
About 45 percent of tumours carried inactivating alterations in DNA repair genes such as BRCA2, PALB2, ATM and MSH2, and KRAS mutations were rare. The genomic landscape was distinct from ductal adenocarcinoma, with high mutational heterogeneity and few recurrent point mutations.
- RAF fusions (BRAF or RAF1) in about 23 percent of acinar cell carcinomas, sensitive to MEK inhibitors in models.
- DNA repair gene inactivation in about 45 percent; KRAS mutations rare.
Acinar cell carcinoma should be sequenced: RAF fusions and DNA repair defects offer targeted and platinum or PARP inhibitor options that ductal adenocarcinoma rarely has.
- Therapeutic sensitivity was shown in cell models and case reports, not trials.
- Fusion detection depends on assay design; RNA-based testing finds more.
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