While the focus of this paper is on pancreatic tumors, the work is very important for understanding fibrolamellar hepatocellular carcinoma (FLC) of the liver.  FLC in the liver is almost always associated with the first part of the protein DNAJB1 being spliced onto the bulk of a protein called PRKACA (for those who want technical details, it is the active part of something called protein kinase A).

What is it that is special about the fusion of DNAJB1 to PRKACA?  Is there something unique about the DNAJB1 or would anything added onto the front end of PRKACA have a similar effect? This group reports that they have found a short segment of another protein, ATP1B1, fused to the front end of PRKACA that is found in tumors of the pancreas and liver.   The cells look very similar to those of fibrolamellar.  Thus, the results strongly suggest that it is not something specific about DNAJB1, but other things added onto the front end of PRKACA can contribute to forming tumors.  It remains to be show if there is anything else in these cells that are contributing to the tumors or expression of this new fusion gene is sufficient to produce the tumor.

https://www.ncbi.nlm.nih.gov/pubmed/31678302

Author’s Abstract:

BACKGROUND & AIMS:

Intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas and bile duct contain epithelial cells with numerous, large mitochondria and are cystic precursors to pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA), respectively. However, IOPNs do not have the genomic alterations found in other pancreatobiliary neoplasms. In fact, no recurrent genomic alterations have been described in IOPNs. PDACs without activating mutations in KRAS contain gene rearrangements, so we investigated whether IOPNs have recurrent fusions in genes.

METHODS:

We analyzed 20 resected pancreatic IOPNs and 3 resected biliary IOPNs using a broad RNA-based targeted sequencing panel to detect cancer-related fusion genes. Four invasive PDACs and 2 intrahepatic CCAs from the same patients as the IOPNs, were also available for analysis. Samples of pancreatic cyst fluid (n = 5, collected before surgery) and bile duct brushings (n = 2) were analyzed for translocations. For comparison, we analyzed pancreatobiliary lesions from 126 patients without IOPN (controls).

RESULTS:

All IOPNs evaluated were found to have recurring fusions of ATP1B1-PRKACB (n = 13), DNAJB1-PRKACA (n = 6), or ATP1B1-PRKACA (n = 4). These fusions also were found in corresponding invasive PDACs and intrahepatic CCAs, as well as in matched pancreatic cyst fluid and bile duct brushings. These gene rearrangements were absent from all 126 control pancreatobiliary lesions.

CONCLUSIONS:

We identified fusions in PRKACA and PRKACB genes in pancreatic and biliary IOPNs, as well as in PDACs and pancreatic cyst fluid and bile duct cells from the same patients. We did not identify these gene fusions in 126 control pancreatobiliary lesions. These fusions might be used to identify patients at risk for IOPNs and their associated invasive carcinomas.