Frequent GNAS Mutations in Low-grade Appendiceal Mucinous Neoplasms

Overview

Journal Br J Cancer

Specialty Oncology

Date 2013 Feb 14

PMID 23403822

Citations 75

Authors

G Nishikawa

S Sekine

R Ogawa

A Matsubara

T Mori

H Taniguchi

R Kushima

N Hiraoka

K Tsuta

H Tsuda

Y Kanai

Affiliations

Soon will be listed here.

Abstract

Background: The molecular basis for the development of appendiceal mucinous tumours, which can be a cause of pseudomyxoma peritonei, remains largely unknown.

Methods: Thirty-five appendiceal mucinous neoplasms were analysed for GNAS and KRAS mutations. A functional analysis of mutant GNAS was performed using a colorectal cancer cell line.

Results: A mutational analysis identified activating GNAS mutations in 16 of 32 low-grade appendiceal mucinous neoplasms (LAMNs) but in none of three mucinous adenocarcinomas (MACs). KRAS mutations were found in 30 LAMNs and in all MACs. We additionally analysed a total of 186 extra-appendiceal mucinous tumours and found that GNAS mutations were highly prevalent in intraductal papillary mucinous tumours of the pancreas (88%) but were rare or absent in mucinous tumours of the colorectum, ovary, lung and breast (0-9%). The prevalence of KRAS mutations was quite variable among the tumours. The introduction of the mutant GNAS into a colorectal cancer cell line markedly induced MUC2 and MUC5AC expression, but did not promote cell growth either in vitro or in vivo.

Conclusion: Activating GNAS mutations are a frequent and characteristic genetic abnormality of LAMN. Mutant GNAS might play a direct role in the prominent mucin production that is a hallmark of LAMN.

Citing Articles

Defining a 'cells to society' research framework for appendiceal tumours.

Holowatyj A, Overman M, Votanopoulos K, Lowy A, Wagner P, Washington M Nat Rev Cancer. 2025; .

PMID: 39979656 DOI: 10.1038/s41568-024-00788-2.

Cyclin-Dependent Kinase 4/6 Inhibition as a Novel Therapy for Peritoneal Mucinous Carcinomatosis With GNAS Mutations.

Weitz J, Nishizaki D, Liau J, Patel J, Ng I, Sun S J Clin Oncol. 2024; 43(6):705-715.

PMID: 39413348 PMC: 11829827. DOI: 10.1200/JCO.24.00511.

Appendiceal Mucocele Presenting as a Cecal Bulge on Surveillance Colonoscopy.

Le Donne M, Herman M Cureus. 2024; 16(9):e69283.

PMID: 39398782 PMC: 11470812. DOI: 10.7759/cureus.69283.

A combinatorial culture strategy to develop pseudomyxoma peritonei organoid models.

Varinelli L, Di Bella M, Guaglio M, Battistessa D, Pisati F, Cavalleri T J Surg Oncol. 2024; 130(6):1213-1224.

PMID: 39360464 PMC: 11826015. DOI: 10.1002/jso.27850.

Pseudomyxoma Peritonei Arising From a Mucinous Ovarian Borderline Tumor Treated With Paclitaxel, Cisplatin, and Bevacizumab: A Case Report.

Niwa K, Niwa K, Isobe M, Kyogoku R, Tanaka T Cureus. 2024; 16(8):e67554.

PMID: 39310419 PMC: 11416708. DOI: 10.7759/cureus.67554.

References

Song K, Choi Y, Kim J, Lee H, Lee T, Yoon J . Suppression of prostaglandin E2-induced MUC5AC overproduction by RGS4 in the airway. Am J Physiol Lung Cell Mol Physiol. 2009; 296(4):L684-92. DOI: 10.1152/ajplung.90396.2008. View

Miner T, Shia J, Jaques D, Klimstra D, Brennan M, Coit D . Long-term survival following treatment of pseudomyxoma peritonei: an analysis of surgical therapy. Ann Surg. 2005; 241(2):300-8. PMC: 1356916. DOI: 10.1097/01.sla.0000152015.76731.1f. View

Chua T, Moran B, Sugarbaker P, Levine E, Glehen O, Gilly F . Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Clin Oncol. 2012; 30(20):2449-56. DOI: 10.1200/JCO.2011.39.7166. View

Thomas R, Sobin L . Gastrointestinal cancer. Cancer. 1995; 75(1 Suppl):154-70. DOI: 10.1002/1097-0142(19950101)75:1+<154::aid-cncr2820751305>3.0.co;2-z. View

Carr N, Finch J, Ilesley I, Chandrakumaran K, Mohamed F, Mirnezami A . Pathology and prognosis in pseudomyxoma peritonei: a review of 274 cases. J Clin Pathol. 2012; 65(10):919-23. DOI: 10.1136/jclinpath-2012-200843. View

Lee S, Jeong E, Soung Y, Lee J, Yoo N, Lee S . Absence of GNAS and EGFL6 mutations in common human cancers. Pathology. 2007; 40(1):95-7. DOI: 10.1080/00313020701716375. View

Matsubara A, Sekine S, Kushima R, Ogawa R, Taniguchi H, Tsuda H . Frequent GNAS and KRAS mutations in pyloric gland adenoma of the stomach and duodenum. J Pathol. 2012; 229(4):579-87. DOI: 10.1002/path.4153. View

Wu J, Matthaei H, Maitra A, Dal Molin M, Wood L, Eshleman J . Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med. 2011; 3(92):92ra66. PMC: 3160649. DOI: 10.1126/scitranslmed.3002543. View

Yamada M, Sekine S, Ogawa R, Taniguchi H, Kushima R, Tsuda H . Frequent activating GNAS mutations in villous adenoma of the colorectum. J Pathol. 2012; 228(1):113-8. DOI: 10.1002/path.4012. View

10.

Zauber P, Berman E, Marotta S, Sabbath-Solitare M, Bishop T . Ki-ras gene mutations are invariably present in low-grade mucinous tumors of the vermiform appendix. Scand J Gastroenterol. 2011; 46(7-8):869-74. DOI: 10.3109/00365521.2011.565070. View

11.

Landis C, Masters S, Spada A, Pace A, Bourne H, Vallar L . GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature. 1989; 340(6236):692-6. DOI: 10.1038/340692a0. View

12.

Furukawa T, Kuboki Y, Tanji E, Yoshida S, Hatori T, Yamamoto M . Whole-exome sequencing uncovers frequent GNAS mutations in intraductal papillary mucinous neoplasms of the pancreas. Sci Rep. 2012; 1:161. PMC: 3240977. DOI: 10.1038/srep00161. View

13.

Kabbani W, Houlihan P, Luthra R, Hamilton S, Rashid A . Mucinous and nonmucinous appendiceal adenocarcinomas: different clinicopathological features but similar genetic alterations. Mod Pathol. 2002; 15(6):599-605. DOI: 10.1038/modpathol.3880572. View

14.

Nielsen G, Isaksson H, Finnbogason H, Gunnlaugsson G . Adenocarcinoma of the vermiform appendix. A population study. APMIS. 1991; 99(7):653-6. DOI: 10.1111/j.1699-0463.1991.tb01241.x. View

15.

Velcich A, Augenlicht L . Regulated expression of an intestinal mucin gene in HT29 colonic carcinoma cells. J Biol Chem. 1993; 268(19):13956-61. View

16.

Laburthe M, Augeron C, Roumagnac I, Maoret J, GRASSET E, Laboisse C . Functional VIP receptors in the human mucus-secreting colonic epithelial cell line CL.16E. Am J Physiol. 1989; 256(3 Pt 1):G443-50. DOI: 10.1152/ajpgi.1989.256.3.G443. View

17.

Smeenk R, van Velthuysen M, Verwaal V, Zoetmulder F . Appendiceal neoplasms and pseudomyxoma peritonei: a population based study. Eur J Surg Oncol. 2007; 34(2):196-201. DOI: 10.1016/j.ejso.2007.04.002. View

18.

Panarelli N, Yantiss R . Mucinous neoplasms of the appendix and peritoneum. Arch Pathol Lab Med. 2011; 135(10):1261-8. DOI: 10.5858/arpa.2011-0034-RA. View

19.

Szych C, Staebler A, Connolly D, Wu R, Cho K, Ronnett B . Molecular genetic evidence supporting the clonality and appendiceal origin of Pseudomyxoma peritonei in women. Am J Pathol. 1999; 154(6):1849-55. PMC: 1866622. DOI: 10.1016/S0002-9440(10)65442-9. View

20.

Lyons J, Landis C, Harsh G, Vallar L, Grunewald K, Feichtinger H . Two G protein oncogenes in human endocrine tumors. Science. 1990; 249(4969):655-9. DOI: 10.1126/science.2116665. View