Clinical assessment of the GNAS mutation status in patients with intraductal papillary mucinous neoplasm of the pancreas

  • Takao OhtsukaEmail author
  • Takahiro Tomosugi
  • Ryuichiro Kimura
  • So Nakamura
  • Yoshihiro Miyasaka
  • Kohei Nakata
  • Yasuhisa Mori
  • Makiko Morita
  • Nobuhiro Torata
  • Koji Shindo
  • Kenoki Ohuchida
  • Masafumi Nakamura
Review Article


Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is characterized by cystic dilation of the pancreatic duct, caused by mucin hypersecretion, with slow progression via the adenoma–carcinoma sequence mechanism. Mutation of GNAS at codon 201 is found exclusively in IPMNs, occurring at a rate of 41–75%. Recent advances in molecular biological techniques have demonstrated that GNAS mutation might play a role in the transformation of IPMNs after the appearance of neoplastic cells, rather than in the tumorigenesis of IPMNs. GNAS mutation is observed frequently in the intestinal subtype of IPMNs with MUC2 expression, and less frequently in IPMNs with concomitant pancreatic ductal adenocarcinoma (PDAC). Research has focused on assessing GNAS mutation status in clinical practice using various samples. In this review, we discuss the clinical application of GNAS mutation assessment to differentiate invasive IPMNs from concomitant PDAC, examine the clonality of recurrent IPMNs in the remnant pancreas using resected specimens, and differentiate pancreatic cystic lesions using cystic fluid collected by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), duodenal fluid, and serum liquid biopsy samples.


IPMN GNAS KRAS Pancreas Ductal adenocarcinoma 



This study was supported by a Grant-in-Aid from the Japan Society for the Promotion of Sciences for Scientific Research (B) (Grant no 16H05417).

Compliance with ethical standards

Conflict of interest

We have no conflicts of interest to declare.


  1. 1.
    Tanaka M, Chari S, Adsay V, Fernandez-del Castillo C, Falconi M, Shimizu M, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology. 2006;6:17–32.CrossRefGoogle Scholar
  2. 2.
    Tanaka M, Fernández-del Castillo C, Adsay V, Chari S, Falconi M, Jang JY, International Association of Pancreatology, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology. 2012;12:183–97.CrossRefGoogle Scholar
  3. 3.
    Tanaka M, Fernández-del Castillo C, Kamisawa T, Jang JY, Levy P, Ohtsuka T, et al. Revisions of International Consensus Fukuoka Guidelines for the management of IPMN of the pancreas. Pancreatology. 2017;17:738–53.CrossRefGoogle Scholar
  4. 4.
    Del Chiaro M, Verbeke C, Salvia R, Klöppel G, Werner J, McKay C, et al. European experts consensus statement on cystic tumours of the pancreas. Dig Liver Dis. 2013;45:703–11.CrossRefGoogle Scholar
  5. 5.
    European Study Group on Cystic Tumours of the Pancreas. European evidence-based guidelines on pancreatic cystic neoplasms. Gut. 2018;67:789–804.CrossRefGoogle Scholar
  6. 6.
    Wu J, Matthaei H, Maitra A, Dal Molin M, Wood LD, Eshleman JR, et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med. 2011;3:92ra66.CrossRefGoogle Scholar
  7. 7.
    Furukawa T, Kuboki Y, Tanji E, Yoshida S, Hatori T, Yamamoto M, et al. Whole-exome sequencing uncovers frequent GNAS mutations in intraductal papillary mucinous neoplasms of the pancreas. Sci Rep. 2011;1:161.CrossRefGoogle Scholar
  8. 8.
    Landis CA, Masters SB, Spada A, Pace AM, Bourne HR, Vallar L. GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature. 1989;340:692–6.CrossRefGoogle Scholar
  9. 9.
    Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med. 1991;325:1688–95.CrossRefGoogle Scholar
  10. 10.
    Kalfa N, Ecochard A, Patte C, Duvillard P, Audran F, Pienkowski C, et al. Activating mutations of the stimulatory g protein in juvenile ovarian granulosa cell tumors: a new prognostic factor? J Clin Endocrinol Metab. 2006;91:1842–7.CrossRefGoogle Scholar
  11. 11.
    Wilson CH, McIntyre RE, Arends MJ, Adams DJ. The activating mutation R201C in GNAS promotes intestinal tumourigenesis in Apc(Min/+) mice through activation of Wnt and ERK1/2 MAPK pathways. Oncogene. 2010;29:4567–75.CrossRefGoogle Scholar
  12. 12.
    Patra KC, Kato Y, Mizukami Y, Widholz S, Boukhali M, Revenco I, et al. Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism. Nat Cell Biol. 2018;20:811–22.CrossRefGoogle Scholar
  13. 13.
    Parvanescu A, Cros J, Ronot M, Hentic O, Grybek V, Couvelard A, et al. Lessons from McCune-Albright syndrome-associated intraductal papillary mucinous neoplasms: GNAS-activating mutations in pancreatic carcinogenesis. JAMA Surg. 2014;149:858–62.CrossRefGoogle Scholar
  14. 14.
    Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science. 2013;339:1546–58.CrossRefGoogle Scholar
  15. 15.
    Kumar D, Mehta A, Panigrahi MK, Nath S, Saikia KK. NPM1 mutation analysis in acute myeloid leukemia: comparison of three techniques—Sanger sequencing, pyrosequencing, and real-time polymerase chain reaction. Turk J Haematol. 2018;35:49–53.CrossRefGoogle Scholar
  16. 16.
    Yu J, Sadakari Y, Shindo K, Suenaga M, Brant A, Almario JAN, et al. Digital next-generation sequencing identifies low-abundance mutations in pancreatic juice samples collected from the duodenum of patients with pancreatic cancer and intraductal papillary mucinous neoplasms. Gut. 2017;66:1677–87.CrossRefGoogle Scholar
  17. 17.
    Taki K, Ohmuraya M, Tanji E, Komatsu H, Hashimoto D, Semba K, et al. GNAS(R201H) and Kras(G12D) cooperate to promote murine pancreatic tumorigenesis recapitulating human intraductal papillary mucinous neoplasm. Oncogene. 2016;35:2407–12.CrossRefGoogle Scholar
  18. 18.
    Qiu W, Tang SM, Lee S, Turk AT, Sireci AN, Qiu A, et al. Loss of activin receptor type 1B accelerates development of intraductal papillary mucinous neoplasms in mice with activated KRAS. Gastroenterology. 2016;150:218–28.CrossRefGoogle Scholar
  19. 19.
    Yamaguchi J, Mino-Kenudson M, Liss AS, Chowdhury S, Wang TC, Fernández-Del Castillo C, et al. Loss of Trefoil factor 2 from pancreatic duct glands promotes formation of intraductal papillary mucinous neoplasms in mice. Gastroenterology. 2016;151:1232–44.CrossRefGoogle Scholar
  20. 20.
    Kopp JL, Dubois CL, Schaeffer DF, Samani A, Taghizadeh F, Cowan RW, et al. Loss of Pten and activation of Kras synergistically induce formation of intraductal papillary mucinous neoplasia from pancreatic ductal cells in mice. Gastroenterology. 2018;154:1509–23.CrossRefGoogle Scholar
  21. 21.
    Ideno N, Yamaguchi H, Ghosh B, Gupta S, Okumura T, Steffen DJ, et al. GNASR201C induces pancreatic cystic neoplasms in mice that express activated KRAS by inhibiting YAP1 signaling. Gastroenterology. 2018;155:1593–607.CrossRefGoogle Scholar
  22. 22.
    Tan MC, Basturk O, Brannon AR, Bhanot U, Scott SN, Bouvier N, et al. GNAS and KRAS mutations define separate progression pathways in intraductal papillary mucinous neoplasm-associated carcinoma. J Am Coll Surg. 2015;220:845–54.CrossRefGoogle Scholar
  23. 23.
    Tamura K, Ohtsuka T, Ideno N, Aso T, Shindo K, Aishima S, et al. Assessment of clonality of multisegmental main duct intraductal papillary mucinous neoplasms of the pancreas based on GNAS mutation analysis. Surgery. 2015;157:277–84.CrossRefGoogle Scholar
  24. 24.
    Furukawa T, Klöppel G, Volkan Adsay N, Albores-Saavedra J, Fukushima N, Horii A, et al. Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study. Virchows Arch. 2005;447:794–9.CrossRefGoogle Scholar
  25. 25.
    Aso T, Ohtsuka T, Ideno N, Kono H, Nagayoshi Y, Mori Y, et al. Diagnostic significance of a dilated orifice of duodenal papilla in intraductal papillary mucinous neoplasm of the pancreas. Gastrointest Endosc. 2012;76:313–20.CrossRefGoogle Scholar
  26. 26.
    Sadakari Y, Ohuchida K, Nakata K, Ohtsuka T, Aishima S, Takahata S, et al. Invasive carcinoma derived from the nonintestinal type intraductal papillary mucinous neoplasm of the pancreas has a poorer prognosis than that derived from intestinal type. Surgery. 2010;147:812–7.CrossRefGoogle Scholar
  27. 27.
    Furukawa T, Hatori T, Fujita I, Yamamoto M, Kobayashi M, Ohike N, et al. Prognostic relevance of morphological types of intraductal papillary mucinous neoplasms of the pancreas. Gut. 2011;60:509–16.CrossRefGoogle Scholar
  28. 28.
    Kuboki Y, Shimizu K, Hatori T, Yamamoto M, Shibata N, Shiratori K, et al. Molecular biomarkers for progression of intraductal papillary mucinous neoplasm of the pancreas. Pancreas. 2015;44:227–35.CrossRefGoogle Scholar
  29. 29.
    Basturk O, Hong SM, Wood LD, Adsay NV, Albores-Saavedra J, Biankin AV, et al. A revised classification system and recommendations from the Baltimore Consensus Meeting for neoplastic precursor lesions in the pancreas. Am J Surg Pathol. 2015;39:1730–41.CrossRefGoogle Scholar
  30. 30.
    Tanaka M, Yokohata K, Konomi H, Yamaguchi K, Chijiiwa K, Ohta M. Segmental balloon cytology for preoperative localization of in situ pancreatic cancer. Gastrointest Endosc. 1997;46:447–9.CrossRefGoogle Scholar
  31. 31.
    Yamaguchi K, Ohuchida J, Ohtsuka T, Nakano K, Tanaka M. Intraductal papillary-mucinous tumor of the pancreas concomitant with ductal carcinoma of the pancreas. Pancreatology. 2002;2:484–90.CrossRefGoogle Scholar
  32. 32.
    Ingkakul T, Sadakari Y, Ienaga J, Satoh N, Takahata S, Tanaka M. Predictors of the presence of concomitant invasive ductal carcinoma in intraductal papillary mucinous neoplasm of the pancreas. Ann Surg. 2010;251:70–5.CrossRefGoogle Scholar
  33. 33.
    Ohtsuka T, Kono H, Tanabe R, Nagayoshi Y, Mori Y, Sadakari Y, et al. Follow-up study after resection of intraductal papillary mucinous neoplasm of the pancreas; special references to the multifocal lesions and development of ductal carcinoma in the remnant pancreas. Am J Surg. 2012;204:44–8.CrossRefGoogle Scholar
  34. 34.
    Ideno N, Ohtsuka T, Kono H, Fujiwara K, Oda Y, Aishima S, et al. Intraductal papillary mucinous neoplasms of the pancreas with distinct pancreatic ductal adenocarcinomas are frequently of gastric subtype. Ann Surg. 2013;258:141–51.CrossRefGoogle Scholar
  35. 35.
    Tamura K, Ohtsuka T, Ideno N, Aso T, Shindo K, Aishima S, et al. Treatment strategy for main duct intraductal papillary mucinous neoplasms of the pancreas based on the assessment of the recurrences in the remnant pancreas after resection: a retrospective review. Ann Surg. 2014;259:360–8.CrossRefGoogle Scholar
  36. 36.
    Miyasaka Y, Ohtsuka T, Tamura K, Shindo K, Yamada D, Takahata S, et al. Predictive factors for the metachronous development of malignant lesions in the remnant pancreas after partial pancreatectomy for intraductal papillary mucinous neoplasm. Ann Surg. 2016;263:1180–7.CrossRefGoogle Scholar
  37. 37.
    Felsenstein M, Noë M, Masica DL, Hosoda W, Chianchiano P, Fischer CG, et al. IPMNs with co-occurring invasive cancers: neighbours but not always relatives. Gut. 2018;67:1652–62.CrossRefGoogle Scholar
  38. 38.
    Yamaguchi K, Kanemitsu S, Hatori T, Maguchi H, Shimizu Y, Tada M, et al. Pancreatic ductal adenocarcinoma derived from IPMN and pancreatic ductal adenocarcinoma concomitant with IPMN. Pancreas. 2011;40:571–80.CrossRefGoogle Scholar
  39. 39.
    Tamura K, Ohtsuka T, Date K, Fujimoto T, Matsunaga T, Kimura H, et al. Distinction of invasive carcinoma derived from intraductal papillary mucinous neoplasms from concomitant ductal adenocarcinoma of the pancreas using molecular biomarkers. Pancreas. 2016;45:826–35.CrossRefGoogle Scholar
  40. 40.
    Omori Y, Ono Y, Tanino M, Karasaki H, Yamaguchi H, Furukawa T, et al. Pathways of progression from intraductal papillary mucinous neoplasm to pancreatic ductal adenocarcinoma based on molecular features. Gastroenterology. (in press).
  41. 41.
    Date K, Ohtsuka T, Fujimoto T, Tamura T, Kimura H, Matsunaga T, et al. Molecular evidence for monoclonal skip progression in main duct intraductal papillary mucinous neoplasms of the pancreas. Ann Surg. 2017;265:969–77.CrossRefGoogle Scholar
  42. 42.
    Kadayifci A, Atar M, Wang JL, Forcione DG, Casey BW, Pitman MB, et al. Value of adding GNAS testing to pancreatic cyst fluid KRAS and carcinoembryonic antigen analysis for the diagnosis of intraductal papillary mucinous neoplasms. Dig Endosc. 2017;29:111–7.CrossRefGoogle Scholar
  43. 43.
    Singhi AD, McGrath K, Brand RE, Khalid A, Zeh HJ, Chennat JS, et al. Preoperative next-generation sequencing of pancreatic cyst fluid is highly accurate in cyst classification and detection of advanced neoplasia. Gut. 2018;67:2131–41.CrossRefGoogle Scholar
  44. 44.
    Springer S, Wang Y, Dal Molin M, Masica DL, Jiao Y, Kinde I, et al. A combination of molecular markers and clinical features improve the classification of pancreatic cysts. Gastroenterology. 2015;149:1501–10.CrossRefGoogle Scholar
  45. 45.
    Jones M, Zheng Z, Wang J, Dudley J, Albanese E, Kadayifci A, et al. Impact of next-generation sequencing on the clinical diagnosis of pancreatic cysts. Gastrointest Endosc. 2016;83:140–8.CrossRefGoogle Scholar
  46. 46.
    Minaga K, Takenaka M, Katanuma A, Kitano M, Yamashita Y, Kamata K, et al. Needle tract seeding: an overlooked rare complication of endoscopic ultrasound-guided fine-needle aspiration. Oncology. 2017;93:107–12.CrossRefGoogle Scholar
  47. 47.
    Matsunaga T, Ohtsuka T, Asano K, Kimura H, Ohuchida K, Kitada H, et al. S100P in duodenal fluid is a useful diagnostic marker for pancreatic ductal adenocarcinoma. Pancreas. 2017;46:1288–95.CrossRefGoogle Scholar
  48. 48.
    Kanda M, Knight S, Topazian M, Syngal S, Farrell J, Lee J, et al. Mutant GNAS detected in duodenal collections of secretin-stimulated pancreatic juice indicates the presence or emergence of pancreatic cysts. Gut. 2013;62:1024–33.CrossRefGoogle Scholar
  49. 49.
    Ideno N, Ohtsuka T, Matsunaga T, Kimura H, Watanabe Y, Tamura K, et al. Clinical significance of GNAS mutation in intraductal papillary mucinous neoplasm of the pancreas with concomitant pancreatic ductal adenocarcinoma. Pancreas. 2015;44:311–20.CrossRefGoogle Scholar
  50. 50.
    Cohen JD, Javed AA, Thoburn C, Wong F, Tie J, Gibbs P, et al. Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers. Proc Natl Acad Sci USA. 2017;114:10202–7.CrossRefGoogle Scholar
  51. 51.
    Berger AW, Schwerdel D, Costa IG, Hackert T, Strobel O, Lam S, et al. Detection of hot-spot mutations in circulating cell-free DNA from patients with intraductal papillary mucinous neoplasms of the pancreas. Gastroenterology. 2016;15:267–70.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Takao Ohtsuka
    • 1
    • 2
    Email author
  • Takahiro Tomosugi
    • 1
  • Ryuichiro Kimura
    • 1
  • So Nakamura
    • 1
  • Yoshihiro Miyasaka
    • 1
  • Kohei Nakata
    • 1
  • Yasuhisa Mori
    • 1
  • Makiko Morita
    • 1
  • Nobuhiro Torata
    • 1
  • Koji Shindo
    • 1
  • Kenoki Ohuchida
    • 1
  • Masafumi Nakamura
    • 1
  1. 1.Department of Surgery and Oncology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  2. 2.Department of Endoscopic Diagnostics and TherapeuticsKyushu University HospitalFukuokaJapan

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