Top

Journal of Gastrointestinal Surgery

Published in:

01-08-2009 | Original Article

Molecular Analysis of PIK3CA, BRAF, and RAS Oncogenes in Periampullary and Ampullary Adenomas and Carcinomas

Authors: Frank Schönleben, Wanglong Qiu, John D. Allendorf, John A. Chabot, Helen E. Remotti, Gloria H. Su

Published in: Journal of Gastrointestinal Surgery | Issue 8/2009

Abstract

Background

Mutations of KRAS are known to occur in periampullary and ampullary adenomas and carcinomas. However, nothing is known about NRAS, HRAS, BRAF, and PIK3CA mutations in these tumors. While oncogenic BRAF contributes to the tumorigenesis of both pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasms/carcinomas (IPMN/IPMC), PIK3CA mutations were only detected in IPMN/IPMC. This study aimed to elucidate possible roles of BRAF and PIK3CA in the development of ampullary and periampullary adenomas and carcinomas.

Methods

Mutations of BRAF, NRAS, HRAS, KRAS, and PIK3CA were evaluated in seven adenomas, seven adenomas with carcinoma in situ, and 21 adenocarcinomas of the periampullary duodenal region and the ampulla of Vater. Exons 1 of KRAS; 2 and 3 of NRAS and HRAS; 5, 11, and 15 of BRAF; and 9 and 20 of PIK3CA were examined by direct genomic sequencing.

Results

In total, we identified ten (28.6%) KRAS mutations in exon 1 (nine in codon 12 and one in codon 13), two missense mutations of BRAF (6%), one within exon 11 (G469A), and one V600E hot spot mutation in exon 15 of BRAF. BRAF mutations were present in two of five periampullary tumors. All mutations appear to be somatic since the same alterations were not detected in the corresponding normal tissues.

Conclusion

Our data provide evidence that oncogenic properties of KRAS and BRAF but not NRAS, HRAS, and PIK3CA contribute to the tumorigenesis of periampullary and ampullary tumors; BRAF mutations occur more frequently in periampullary than ampullary neoplasms.

Sarmiento JM, Nagomey DM, Sarr MG, Farnell MB. Periampullary cancers: are there differences? Surg Clin North Am 2001;81:543–555. doi:10.1016/S0039-6109(05)70142-0.CrossRefPubMed

Baczako K, Buchler M, Beger HG, Kirkpatrick CJ, Haferkamp O. Morphogenesis and possible precursor lesions of invasive carcinoma of the papilla of Vater: epithelial dysplasia and adenoma. Hum Pathol 1985;16:305–310. doi:10.1016/S0046-8177(85)80018-6.CrossRefPubMed

Yeo CJ, Cameron JL, Sohn TA, Lillemoe KD, Pitt HA, Talamini MA, Hruban RH, Ord SE, Sauter PK, Coleman J, Zahurak ML, Grochow LB, Abrams RA. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg 1997;226:248–257. discussion 257–260. doi:10.1097/00000658-199709000-00004.CrossRefPubMed

Howe JR, Klimstra DS, Moccia RD, Conlon KC, Brennan MF. Factors predictive of survival in ampullary carcinoma. Ann Surg 1998;228:87–94. doi:10.1097/00000658-199807000-00013.CrossRefPubMed

Sohn TA, Yeo CJ, Cameron JL, Koniaris L, Kaushal S, Abrams RA, Sauter PK, Coleman J, Hruban RH, Lillemoe KD. Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 2000;4:567–579. doi:10.1016/S1091-255X(00)80105-5.CrossRefPubMed

Howe JR, Klimstra DS, Cordon-Cardo C, Paty PB, Park PY, Brennan MF. K-ras mutation in adenomas and carcinomas of the ampulla of Vater. Clin Cancer Res 1997;3:129–133.PubMed

Park SH, Kim YI, Park YH, Kim SW, Kim KW, Kim YT, Kim WH. Clinicopathologic correlation of p53 protein overexpression in adenoma and carcinoma of the ampulla of Vater. World J Surg 2000;24:54–59. doi:10.1007/s002689910011.CrossRefPubMed

Yoshida S, Todoroki T, Ichikawa Y, Hanai S, Suzuki H, Hori M, Fukao K, Miwa M, Uchida K. Mutations of p16Ink4/CDKN2 and p15Ink4B/MTS2 genes in biliary tract cancers. Cancer Res 1995;55:2756–2760.PubMed

Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996;271:350–353. doi:10.1126/science.271.5247.350.CrossRefPubMed

10.

Hruban RH, Wilentz RE, Kern SE. Genetic progression in the pancreatic ducts. Am J Pathol 2000;156:1821–1825.PubMed

11.

McCarthy DM, Hruban RH, Argani P, Howe JR, Conlon KC, Brennan MF, Zahurak M, Wilentz RE, Cameron JL, Yeo CJ, Kern SE, Klimstra DS. Role of the DPC4 tumor suppressor gene in adenocarcinoma of the ampulla of Vater: analysis of 140 cases. Mod Pathol 2003;16:272–278. doi:10.1097/01.MP.0000057246.03448.26.CrossRefPubMed

12.

Peyssonnaux C, Eychene A. The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell 2001;93:53–62. doi:10.1016/S0248-4900(01)01125-X.CrossRefPubMed

13.

Dhillon AS, Meikle S, Peyssonnaux C, Grindlay J, Kaiser C, Steen H, Shaw PE, Mischak H, Eychene A, Kolch WA. Raf-1 mutant that dissociates MEK/extracellular signal-regulated kinase activation from malignant transformation and differentiation but not proliferation. Mol Cell Biol 2003;23:1983–1993. doi:10.1128/MCB.23.6.1983-1993.2003.CrossRefPubMed

14.

Aguirre-Ghiso JA, Estrada Y, Liu D, Ossowski L. ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). Cancer Res 2003;63:1684–1695.PubMed

15.

Garnett MJ, Marais R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell 2004;6:313–319. doi:10.1016/j.ccr.2004.09.022.CrossRefPubMed

16.

Calhoun ES, Jones JB, Ashfaq R, Adsay V, Baker SJ, Valentine V, Hempen PM, Hilgers W, Yeo CJ, Hruban RH, Kern SE. BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets. Am J Pathol 2003;163:1255–1260.PubMed

17.

Ishimura N, Yamasawa K, Karim Rumi MA, Kadowaki Y, Ishihara S, Amano Y, Nio Y, Higami T, Kinoshita Y. BRAF and K-ras gene mutations in human pancreatic cancers. Cancer Lett 2003;199:169–173. doi:10.1016/S0304-3835(03)00384-7.CrossRefPubMed

18.

Qiu W, Schonleben F, Li X, Su GH. Disruption of transforming growth factor beta-Smad signaling pathway in head and neck squamous cell carcinoma as evidenced by mutations of SMAD2 and SMAD4. Cancer Lett 2007;245:163–170. doi:10.1016/j.canlet.2006.01.003.CrossRefPubMed

19.

Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 2001;17:615–675. doi:10.1146/annurev.cellbio.17.1.615.CrossRefPubMed

20.

Domin J, Waterfield MD. Using structure to define the function of phosphoinositide 3-kinase family members. FEBS Lett 1997;410:91–95. doi:10.1016/S0014-5793(97)00617-0.CrossRefPubMed

21.

Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2:489–501. doi:10.1038/nrc839.CrossRefPubMed

22.

Vanhaesebroeck B, Alessi DR. The PI3K-PDK1 connection: more than just a road to PKB. Biochem J 2000;346(Pt 3):561–576. doi:10.1042/0264-6021:3460561.CrossRefPubMed

23.

Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304:554. doi:10.1126/science.1096502.CrossRefPubMed

24.

Lee JW, Soung YH, Kim SY, Lee HW, Park WS, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH. PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene 2005;24:1477–1480. doi:10.1038/sj.onc.1208304.CrossRefPubMed

25.

Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS, Cristiano BE, Pearson RB, Phillips WA. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 2004;64:7678–7681. doi:10.1158/0008-5472.CAN-04-2933.CrossRefPubMed

26.

Broderick DK, Di C, Parrett TJ, Samuels YR, Cummins JM, McLendon RE, Fults DW, Velculescu VE, Bigner DD, Yan H. Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas. Cancer Res 2004;64:5048–5050. doi:10.1158/0008-5472.CAN-04-1170.CrossRefPubMed

27.

Bachman KE, Argani P, Samuels Y, Silliman N, Ptak J, Szabo S, Konishi H, Karakas B, Blair BG, Lin C, Peters BA, Velculescu VE, Park BH. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 2004;3:772–775.PubMedCrossRef

28.

Qiu W, Schonleben F, Li X, Ho DJ, Close LG, Manolidis S, Bennett BP, Su GH. PIK3CA mutations in head and neck squamous cell carcinoma. Clin Cancer Res 2006;12:1441–1446. doi:10.1158/1078-0432.CCR-05–2173.CrossRefPubMed

29.

Schonleben F, Qiu W, Ciau NT, Ho DJ, Li X, Allendorf JD, Remotti HE, Su GH. PIK3CA mutations in intraductal papillary mucinous neoplasm/carcinoma of the pancreas. Clin Cancer Res 2006;12:3851–3855. doi:10.1158/1078-0432.CCR-06-0292.CrossRefPubMed

30.

Gallmeier E, Calhoun ES, Kern SE. No mutations in PIK3CA identified in pancreatic carcinoma. NOGO 2004;8:2.

31.

Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–954. doi:10.1038/nature00766.CrossRefPubMed

32.

Naoki K, Chen TH, Richards WG, Sugarbaker DJ, Meyerson M. Missense mutations of the BRAF gene in human lung adenocarcinoma. Cancer Res 2002;62:7001–7003.PubMed

33.

Yuen ST, Davies H, Chan TL, Ho JW, Bignell GR, Cox C, Stephens P, Edkins S, Tsui WW, Chan AS, Futreal PA, Stratton MR, Wooster R, Leung SY. Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res 2002;62:6451–6455.PubMed

34.

Chung CH, Wilentz RE, Polak MM, Ramsoekh TB, Noorduyn LA, Gouma DJ, Huibregtse K, Offerhaus GJ, Slebos RJ. Clinical significance of K-ras oncogene activation in ampullary neoplasms. J Clin Pathol 1996;49:460–464. doi:10.1136/jcp.49.6.460.CrossRefPubMed

35.

Gallinger S, Vivona AA, Odze RD, Mitri A, O’Beirne CP, Berk TC, Bapat BV. Somatic APC and K-ras codon 12 mutations in periampullary adenomas and carcinomas from familial adenomatous polyposis patients. Oncogene 1995;10:1875–1878.PubMed

36.

Hagemann C, Rapp UR. Isotype-specific functions of Raf kinases. Exp Cell Res 1999;253:34–46. doi:10.1006/excr.1999.4689.CrossRefPubMed

37.

Hakimi MA, Bochar DA, Chenoweth J, Lane WS, Mandel G, Shiekhattar R. A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc Natl Acad Sci U S A 2002;99:7420–7425. doi:10.1073/pnas.112008599.CrossRefPubMed

38.

Moskaluk CA, Hruban RH, Kern SE. p16 and K-ras mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res 1997;57:2140–2143.PubMed

39.

Rozenblum E, Schutte M, Goggins M, Hahn SA, Lu J, Panzer S, Zahurak M, Goodman SN, Hruban RH, Yeo CJ, Kern SE. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res 1997;57:1731–1734.PubMed

40.

Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, Einhorn E, Herlyn M, Minna J, Nicholson A, Roth JA, Albelda SM, Davies H, Cox C, Brignell G, Stephens P, Futreal PA, Wooster R, Stratton MR, Weber BL. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 2002;62:6997–7000.PubMed

41.

Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, Moses TY, Hostetter G, Wagner U, Kakareka J, Salem G, Pohida T, Heenan P, Duray P, Kallioniemi O, Hayward NK, Trent JM, Meltzer PS. High frequency of BRAF mutations in nevi. Nat Genet 2003;33:19–20. doi:10.1038/ng1054.CrossRefPubMed

42.

Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 2002;418:934. doi:10.1038/418934a.CrossRefPubMed

Title: Molecular Analysis of PIK3CA, BRAF, and RAS Oncogenes in Periampullary and Ampullary Adenomas and Carcinomas
Authors: Frank Schönleben
Wanglong Qiu
John D. Allendorf
John A. Chabot
Helen E. Remotti
Gloria H. Su
Publication date: 01-08-2009
Publisher: Springer-Verlag
Published in: Journal of Gastrointestinal Surgery / Issue 8/2009
Print ISSN: 1091-255X
Electronic ISSN: 1873-4626
DOI: https://doi.org/10.1007/s11605-009-0917-4

At a glance: The STEP trials

Springer Medicine

Molecular Analysis of PIK3CA, BRAF, and RAS Oncogenes in Periampullary and Ampullary Adenomas and Carcinomas

Abstract

Background

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 8/2009

Abdominal Computed Tomography for Diagnosing Postoperative Lower Gastrointestinal Tract Leaks

Surgeon Perceptions of Natural Orifice Translumenal Endoscopic Surgery (NOTES)

ERCC1 and XRCC1 Gene Polymorphisms Predict Response to Neoadjuvant Radiochemotherapy in Esophageal Cancer

Surgical Reintervention After Failed Antireflux Surgery: A Systematic Review of the Literature

Obesity and Gastroesophageal Reflux: Quantifying the Association Between Body Mass Index, Esophageal Acid Exposure, and Lower Esophageal Sphincter Status in a Large Series of Patients with Reflux Symptoms

Inhibition of Nucleostemin Upregulates CDX2 Expression in HT29 Cells in Response to Bile Acid Exposure: Implications in the Pathogenesis of Barrett’s Esophagus