Research ArticleCancer

Recurrent GNAS Mutations Define an Unexpected Pathway for Pancreatic Cyst Development

Science Translational Medicine  20 Jul 2011:
Vol. 3, Issue 92, pp. 92ra66
DOI: 10.1126/scitranslmed.3002543

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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.

Footnotes

  • * These authors contributed equally to this work.

  • Citation: J.Wu, H. Matthaei, A. Maitra, M. Dal Molin, L. D.Wood, J. R. Eshleman, M. Goggins, M. I. Canto, R. D. Schulick, B. H. Edil, C. L. Wolfgang, A. P. Klein, L. A. Diaz Jr., P. J. Allen, C. M. Schmidt, K. W. Kinzler, N. Papadopoulos, R. H. Hruban, B. Vogelstein, Recurrent GNAS Mutations Define an Unexpected Pathway for Pancreatic Cyst Development. Sci. Transl. Med. 3, 92ra66 (2011).