Recurrent GNAS Mutations Define an Unexpected Pathway for Pancreatic Cyst Development

A mutation in the gene GNAS serves as a marker for pancreatic cysts that can progress to become invasive adenocarcinomas, guiding therapy. Staying Out of the Operating Room Like bad traffic, surgery is something to be avoided if at all possible. This was the guiding principle of Wu et al. when conducting their research on pancreatic cysts, found in more than 2% of the population. Physician and patient face a dilemma: Some pancreatic cysts will progress to form dangerous invasive carcinoma and some persist harmlessly forever. So, to err on the side of safety, many harmless cysts are removed, exposing patients to unnecessary risk. By sequencing DNA from pancreatic cysts and invasive pancreatic cancers, the authors have now determined that the presence of mutations in two oncogenes can identify the cysts that are likely to progress to carcinoma and so are good candidates for surgical removal. (Without KRAS or GNAS mutations, the cyst may be better left in place.) The authors assessed DNA from the cyst fluid of 19 intraductal papillary mucinous neoplasms and the corresponding normal tissue by massively parallel sequencing for mutations in 169 cancer genes. Two results stood out—one expected and one unexpected. Fourteen of the 19 tumors showed mutations in the known pancreatic oncogene KRAS, and 6 of the 19 carried a mutation in GNAS, a well-known oncogene in other tumor types. Of a larger set of fluid samples from these cystic neoplasms (132), 96% carried a mutation in at least one of the two oncogenes. In contrast, 44 benign cysts exhibited no GNAS or KRAS mutations. Cystic fluid that contains DNA with both the GNAS and KRAS mutations indicates, with high sensitivity and specificity, that the lesion is likely to be an intraductal papillary mucinous neoplasm (at risk for developing into an invasive carcinoma) and not a benign serous cystadenomas. These genetic markers could distinguish between benign tumors and more problematic neoplasms, enabling some patients to avoid the undesirable experience of surgery. More than 2% of the adult U.S. population harbors a pancreatic cyst. These often pose a difficult management problem because conventional criteria cannot always distinguish cysts with malignant potential from those that are innocuous. One of the most common cystic neoplasms of the pancreas, and a bona fide precursor to invasive adenocarcinoma, is called intraductal papillary mucinous neoplasm (IPMN). To help reveal the pathogenesis of these lesions, we purified the DNA from IPMN cyst fluids from 19 patients and searched for mutations in 169 genes commonly altered in human cancers. In addition to the expected KRAS mutations, we identified recurrent mutations at codon 201 of GNAS. A larger number (113) of additional IPMNs were then analyzed to determine the prevalence of KRAS and GNAS mutations. In total, we found that GNAS mutations were present in 66% of IPMNs and that either KRAS or GNAS mutations could be identified in 96%. In eight cases, we could investigate invasive adenocarcinomas that developed in association with IPMNs containing GNAS mutations. In seven of these eight cases, the GNAS mutations present in the IPMNs were also found in the invasive lesion. GNAS mutations were not found in other types of cystic neoplasms of the pancreas or in invasive adenocarcinomas not associated with IPMNs. In addition to defining a new pathway for pancreatic neoplasia, these data suggest that GNAS mutations can inform the diagnosis and management of patients with cystic pancreatic lesions.