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01-05-2015 | Review

The genetic classification of pancreatic neoplasia

Authors: Hanno Matthaei, Alexander Semaan, Ralph H. Hruban

Published in: Journal of Gastroenterology | Issue 5/2015

Abstract

Cancer is caused by the accumulation of inherited and/or acquired alterations in specific genes. The recent decline in the cost of DNA sequencing has allowed tumor sequencing to be conducted on a large scale, which, in turn, has led to an unprecedented understanding of the genetic events that drive neoplasia. This understanding, when integrated with meticulous histologic analyses and with clinical findings, has direct clinical implications. The recent sequencing of all of the major types of cystic and noncystic neoplasms of the pancreas has revealed opportunities for molecular diagnoses and for personalized treatment. This review summarizes the results from these recent studies focusing on the clinical relevance of genomic data.

Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW. Cancer genome landscapes. Science. 2013;339:1546–58.PubMedCentralPubMed

Wood L, Parsons DW, Jones S, Lin J, Sjöblom T, Leary RJ, et al. The genomic landscapes of human breast and colorectal cancers. Science. 2007;318:1108–13.PubMed

International Cancer Genome Consortium, Hudson TJ, Anderson W, Artez A, Barker AD, Bell C, et al. International network of cancer genome projects. Nature. 2010;464:993–8.

Bosman FT, Carneiro F, Hruban RH, Theise ND, editors. WHO classification of tumours of the digestive system. 4th ed. Lyon: International Agency for Research on Cancer; 2010.

Liang WS, Craig DW, Carpten J, Borad MJ, Demeure MJ, Weiss GJ, et al. Genome-wide characterization of pancreatic adenocarcinoma patients using next generation sequencing. PLoS One. 2012;7:e43192.PubMedCentralPubMed

Jones S, Zhang X, Parsons DW, Lin JC-H, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801–6.PubMedCentralPubMed

Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009;324:217.PubMedCentralPubMed

Wu J, Jiao Y, Dal Molin M, Maitra A, de Wilde RF, wood LD, et al. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc Natl Acad Sci U S A. 2011;108:21188–93.PubMedCentralPubMed

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.PubMedCentralPubMed

10.

Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331:1199–203.PubMedCentralPubMed

11.

Jiao Y, Yonescu R, Offerhaus GJA, Klimstra DS, Maitra A, Eshleman JR, et al. Whole-exome sequencing of pancreatic neoplasms with acinar differentiation. J Pathol. 2014;232:428–35.PubMedCentralPubMed

12.

Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6:224ra24.PubMedCentralPubMed

13.

Kanda M, Sadakari Y, Borges M, Topazian M, Farrell J, Syngal S, et al. Mutant TP53 in duodenal samples of pancreatic juice from patients with pancreatic cancer or high-grade dysplasia. Clin Gastroenterol Hepatol. 2013;11:719–30.e5.PubMed

14.

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.PubMedCentralPubMed

15.

Klimstra DS, Heffess CS, Oertel JE, Rosai J. Acinar cell carcinoma of the pancreas. A clinicopathologic study of 28 cases. Am J Surg Pathol. 1992;16:815–37.PubMed

16.

Okano K, Suzuki Y. Strategies for early detection of resectable pancreatic cancer. World J Gastroenterol. 2014;20:11230–40.PubMedCentralPubMed

17.

La Rosa S, Adsay V, Albarello L, Asioli S, Casnedi S, Franzi F, et al. Clinicopathologic study of 62 acinar cell carcinomas of the pancreas: insights into the morphology and immunophenotype and search for prognostic markers. Am J Surg Pathol. 2012;36:1782–95.PubMed

18.

Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.PubMed

19.

Wolfgang CL, Herman JM, Laheru DA, Klein AP, Erdek MA, Fishman EK, et al. Recent progress in pancreatic cancer. CA Cancer J Clin. 2013;63:318–48.PubMedCentralPubMed

20.

Reid MD, Bagci P, Adsay NV. Histopathologic assessment of pancreatic cancer: does one size fit all? J Surg Oncol. 2013;107:67–77.PubMed

21.

Matthaei H, Schulick RD, Hruban RH, Maitra A. Cystic precursors to invasive pancreatic cancer. Nat Rev Gastroenterol Hepatol. 2011;8:141–50.PubMedCentralPubMed

22.

Maitra A, Fukushima N, Takaori K, Hruban RH. Precursors to invasive pancreatic cancer. Adv Anat Pathol. 2005;12:81–91.PubMed

23.

Lennon AM, Wolfgang CL, Canto MI, Klein AP, Herman JM, Goggins M, et al. The early detection of pancreatic cancer: what will it take to diagnose and treat curable pancreatic neoplasia? Cancer Res. 2014;74:3381–9.PubMed

24.

Kowalski J, Morsberger LA, Blackford A, Hawkins A, Yeo CJ, Hruban RH, et al. Chromosomal abnormalities of adenocarcinoma of the pancreas: identifying early and late changes. Cancer Genet Cytogenet. 2007;178:26–35.PubMed

25.

Biankin AV, Waddell N, Kassahn KS, Gingras M-C, Muthuswamy LB, Johns AL, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491:399–405.PubMedCentralPubMed

26.

Wood LD, Adsay NV, Hruban RH. Molecular surgical pathology. In: Cheng L, Eble JN, editors. New York: Springer; 2013. p. 17–42. doi:10.1007/978-1-4614-4900-3_2.

27.

Mehlen P, Delloye-Bourgeois C, Chédotal A. Novel roles for Slits and netrins: axon guidance cues as anticancer targets? Nat Rev Cancer. 2011;11:188–97.PubMed

28.

Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988;53:549–54.PubMed

29.

Tseng JF, Warshaw AL, Sahani DV, Lauwers GY, Rattner DW, Fernández-del Castillo C. Serous cystadenoma of the pancreas: tumor growth rates and recommendations for treatment. Ann Surg. 2005;242:413–9; discussion 419–21.PubMedCentralPubMed

30.

Hruban RH, van Mansfeld AD, Offerhaus GJ, van Weering DH, Allison DC, Goodman SN, et al. K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol. 1993;143:545–54.PubMedCentralPubMed

31.

Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004;10:789–99.PubMed

32.

Vakiani E, Solit DB. KRAS and BRAF: drug targets and predictive biomarkers. J Pathol. 2011;223:219–29.PubMed

33.

Wood L, Hruban RH. Pathology and molecular genetics of pancreatic neoplasms. Cancer J. 2012;18:492–501.PubMedCentralPubMed

34.

Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003;4:437–50.PubMed

35.

Calhoun ES, Jones JB, Ashfaq R, Adsay V, Baker SJ, Valentine V, et al. BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets. Am J Pathol. 2003;163:1255–60.PubMedCentralPubMed

36.

Goggins M, Offerhaus GJ, Hilgers W, Griffin CA, Shekher M, Tang D, et al. Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology. Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+. Am J Pathol. 1998;152:1501–7.PubMedCentralPubMed

37.

Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet. 1994;8:27–32.PubMed

38.

Attri J, Srinivasan R, Majumdar S, Radotra BD, Wig J. Alterations of tumor suppressor gene p16INK4a in pancreatic ductal carcinoma. BMC Gastroenterol. 2005;5:22.PubMedCentralPubMed

39.

Li J, Poi MJ, Tsai M-D. Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to cancer. Biochemistry. 2011;50:5566–82.PubMedCentralPubMed

40.

Rozenblum E, Schutte M, Goggins M, Hahn SA, Panzer S, Zahurak M, et al. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res. 1997;57:1731–4.PubMed

41.

Scarpa A, Capelli P, Mukai K, Zamboni G, Oda T, Iacono C, et al. Pancreatic adenocarcinomas frequently show p53 gene mutations. Am J Pathol. 1993;142:1534–43.PubMedCentralPubMed

42.

Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 1996;271:350–3.PubMed

43.

Iacobuzio-Donahue CA, Song J, Parmiagiani G, Yeo CJ, Hruban RH, Kern SE. Missense mutations of MADH4: characterization of the mutational hot spot and functional consequences in human tumors. Clin Cancer Res. 2004;10:1597–604.PubMed

44.

Kanda M, Matthaei H, Wu J, Hong S-M, Yu J, Borges M, et al. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology. 2012;142:730–9.PubMedCentralPubMed

45.

Lüttges J, Galehdari H, Bröcker V, Schwarte-Waldhoff I, Henne-Bruns D, Klöppel G, et al. Allelic loss is often the first hit in the biallelic inactivation of the p53 and DPC4 genes during pancreatic carcinogenesis. Am J Pathol. 2001;158:1677–83.PubMedCentralPubMed

46.

Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, Yeo CJ, et al. Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res. 2000;60:2002–6.PubMed

47.

Shi C, Hruban RH, Klein AP. Familial pancreatic cancer. Arch Pathol Lab Med. 2009;133:365–74.PubMed

48.

Amundadottir LT, Thorvaldsson S, Gudbjartsson DF, Sulem P, Kristjansson K, Arnason S, et al. Cancer as a complex phenotype: pattern of cancer distribution within and beyond the nuclear family. PLoS Med. 2004;1:e65.PubMedCentralPubMed

49.

Klein AP, Brune KA, Petersen GM, Goggins M, Tersmette AC, Offerhaus GJA, et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res. 2004;64:2634–8.PubMed

50.

Petersen GM, Hruban RH. Familial pancreatic cancer: where are we in 2003? J Natl Cancer Inst. 2003;95:180–1.PubMed

51.

Hruban RH, Canto MI, Goggins M, Schulick R, Klein AP. Update on familial pancreatic cancer. Adv Surg. 2010;44:293–311.PubMedCentralPubMed

52.

Habbe N, Langer P, Sina-Frey M, Bartsch DK. Familial pancreatic cancer syndromes. Endocrinol Metab Clin N Am. 2006;35:417–30.

53.

Slater EP, Langer P, Niemczyk E, Strauch K, Butler J, Habbe N, et al. PALB2 mutations in European familial pancreatic cancer families. Clin Genet. 2010;78:490–4.PubMed

54.

Roberts NJ, Jiao Y, Yu J, Kopelovich L, Petersen GM, Bondy ML, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012;2:41–6.PubMedCentralPubMed

55.

Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467:1114–7.PubMedCentralPubMed

56.

Templeton AW, Brentnall TA. Screening and surgical outcomes of familial pancreatic cancer. Surg Clin N Am. 2013;93:629–45.PubMed

57.

Wang W, Chen S, Brune KA, Hruban RH, Parmigiani G, Klein AP. PancPRO: risk assessment for individuals with a family history of pancreatic cancer. J Clin Oncol. 2007;25:1417–22.PubMedCentralPubMed

58.

Norris AL, Roberts NJ, Jones S, Wheelan SJ, Papadopoulos N, Vogelstein B, et al. Familial and sporadic pancreatic cancer share the same molecular pathogenesis. Fam Cancer. 2014. doi:10.1007/s10689-014-9755-y.

59.

Blackford A, Serrano OK, Wolfgang CL, Parmigiani G, Jones S, Zhang X, et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res. 2009;15:4674–9.PubMedCentralPubMed

60.

Iacobuzio-Donahue CA, Fu B, Yachida S, Luo M, Abe H, Henderson CM, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;27:1806–13.PubMedCentralPubMed

61.

Cui Y, Brosnan JA, Blackford AL, Sur S, Hruban RH, Kinzler KW, et al. Genetically defined subsets of human pancreatic cancer show unique in vitro chemosensitivity. Clin Cancer Res. 2012;18:6519–30.PubMedCentralPubMed

62.

Villarroel MC, Rajeshkumar NV, Garrido-Laguna I, De Jesus-Acosta A, Jones S, Maitra A, et al. Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer. Mol Cancer Ther. 2011;10:3–8.PubMedCentralPubMed

63.

Williamson CT, Kubota E, Hamill JD, Klimowicz A, Ye R, Muzik H, et al. Enhanced cytotoxicity of PARP inhibition in mantle cell lymphoma harbouring mutations in both ATM and p53. EMBO Mol Med. 2012;4:515–27.PubMedCentralPubMed

64.

Riabinska A, Daheim M, Herter-Sprie GS, Winkler J, Fritz C, Hallek M, et al. Therapeutic targeting of a robust non-oncogene addiction to PRKDC in ATM-defective tumors. Sci Transl Med. 2013;5:189ra78.PubMed

65.

Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434:913–7.PubMed

66.

Fogelman DR, Wolff RA, Kopetz S, Javle M, Bradley C, Mok I, et al. Evidence for the efficacy of iniparib, a PARP-1 inhibitor, in BRCA2-associated pancreatic cancer. Anticancer Res. 2011;31:1417–20.PubMed

67.

Collura A, Lagrange A, Svrcek M, Marisa L, Buhard O, Guilloux A, et al. Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil–based chemotherapy. Gastroenterology. 2014;146:401–11.PubMed

68.

Kamiyama H, Rauenzahn S, Shim JS, Karikari CA, Feldmann G, Hua L, et al. Personalized chemotherapy profiling using cancer cell lines from selectable mice. Clin Cancer Res. 2013;19:1139–46.PubMedCentralPubMed

69.

Matthaei H, Norris AL, Tsiatis AC, Olino K, Hong S-M, Dal Molin M, et al. Clinicopathological characteristics and molecular analyses of multifocal intraductal papillary mucinous neoplasms of the pancreas. Ann Surg. 2012;255:326–33.PubMedCentralPubMed

70.

Hruban RH, Takaori K, Klimstra DS, Adsay NV, Albores-Saavedra J, Biankin AV, et al. An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol. 2004;28:977–87.PubMed

71.

Schmitz-Winnenthal FH, Z’graggen K, Volk C, Schmied BM, Büchler MW. Intraductal papillary mucinous tumors of the pancreas. Curr Gastroenterol Rep. 2003;5:133–40.PubMed

72.

Basturk O, Coban I, Adsay NV. Pancreatic cysts: pathologic classification, differential diagnosis, and clinical implications. Arch Pathol Lab Med. 2009;133:423–38.PubMed

73.

Tanaka M, Kobayashi K, Mizumoto K, Yamaguchi K. Clinical aspects of intraductal papillary mucinous neoplasm of the pancreas. J Gastroenterol. 2005;40:669–75.PubMed

74.

Sugiyama M, Izumisato Y, Abe N, Masaki T, Mori T, Atomi Y. Predictive factors for malignancy in intraductal papillary-mucinous tumours of the pancreas. Br J Surg. 2003;90:1244–9.PubMed

75.

Sohn TA, Yeo CJ, Cameron JL, Hruban RH, Fukushima N, Campbell KA, et al. Intraductal papillary mucinous neoplasms of the pancreas: an updated experience. Ann Surg. 2004;239:788–97; discussion 797–9.PubMedCentralPubMed

76.

Paini M, Crippa S, Partelli S, Scopelliti F, Tamburrino D, Baldoni A, et al. Molecular pathology of intraductal papillary mucinous neoplasms of the pancreas. World J Gastroenterol. 2014;20:10008–23.PubMedCentralPubMed

77.

Adsay NV, Merati K, Basturk O, Iacobuzio-Donahue C, Levi E, Cheng JD, et al. Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms: delineation of an “intestinal” pathway of carcinogenesis in the pancreas. Am J Surg Pathol. 2004;28:839–48.PubMed

78.

Tanaka M, Fernández-del Castillo C, Adsay V, Chari S, Falconi M, Jang J-Y, et al. International consensus guidelines for the management of IPMN and MCN of the pancreas. Pancreatology. 2012;2012(12):183–97.

79.

Fritz S, Klauss M, Bergmann F, Hackert T, Hartwig W, Strobel O, et al. Small (Sendai negative) branch-duct IPMNs: not harmless. Ann Surg. 2012;256:313–20.PubMed

80.

Fritz S, Fernández-del Castillo C, Mino-Kenudson M, Crippa S, Deshpande V, Lauwers GY, et al. Global genomic analysis of intraductal papillary mucinous neoplasms of the pancreas reveals significant molecular differences compared to ductal adenocarcinoma. Ann Surg. 2009;249:440–7.PubMedCentralPubMed

81.

Schönleben F, Qiu W, Bruckman KC, Ciau NT, Li X, Lauerman MH, et al. BRAF and KRAS gene mutations in intraductal papillary mucinous neoplasm/carcinoma (IPMN/IPMC) of the pancreas. Cancer Lett. 2007;249:242–8.PubMedCentralPubMed

82.

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.PubMedCentralPubMed

83.

Amato E, Molin MD, Mafficini A, Yu J, Malleo G, Rusev B, et al. Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas. J Pathol. 2014;233:217–27.PubMedCentralPubMed

84.

Dal Molin M, Matthaei H, Wu J, Blackford A, Debeljak M, Rezaee N, et al. Clinicopathological correlates of activating GNAS mutations in intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Ann Surg Oncol. 2013;20:3802–8.PubMed

85.

Kim ST, Lim DH, Jang K-T, Lim T, Lee J, Choi Y-L, et al. Impact of KRAS mutations on clinical outcomes in pancreatic cancer patients treated with first-line gemcitabine-based chemotherapy. Mol Cancer Ther. 2011;10:1993–9.PubMed

86.

Rachakonda PS, Bauer AS, Xie H, Campa D, Rizzato C, Canzian F, et al. Somatic mutations in exocrine pancreatic tumors: association with patient survival. PLoS One. 2013;8:e60870.PubMedCentralPubMed

87.

Yoshizawa K, Nagai H, Sakurai S, Hironaka M, Morinaga S, Saitoh K, et al. Clonality and K-ras mutation analyses of epithelia in intraductal papillary mucinous tumor and mucinous cystic tumor of the pancreas. Virchows Arch. 2002;441:437–43.PubMed

88.

Lubezky N, Ben-Haim M, Marmor S, Brazowsky E, Rechavi G, Klausner JM, et al. High-throughput mutation profiling in intraductal papillary mucinous neoplasm (IPMN). J Gastrointest Surg. 2011;15:503–11.PubMed

89.

Wada K. p16 and p53 gene alterations and accumulations in the malignant evolution of intraductal papillary-mucinous tumors of the pancreas. J Hepatobiliary Pancreat Surg. 2002;9:76–85.PubMed

90.

Kawahira H, Kobayashi S, Kaneko K, Asano T, Ochiai T. p53 protein expression in intraductal papillary mucinous tumors (IPMT) of the pancreas as an indicator of tumor malignancy. Hepatogastroenterology. 2000;47:973–7.PubMed

91.

Abe K, Suda K, Arakawa A, Yamasaki S, Sonoue H, Mitani K, et al. Different patterns of p16INK4A and p53 protein expressions in intraductal papillary-mucinous neoplasms and pancreatic intraepithelial neoplasia. Pancreas. 2007;34:85–91.PubMed

92.

Iacobuzio-Donahue CA, Klimstra DS, Adsay NV, Wilentz RE, Argani P, Sohn TA, et al. Dpc-4 protein is expressed in virtually all human intraductal papillary mucinous neoplasms of the pancreas: comparison with conventional ductal adenocarcinomas. Am J Pathol. 2000;157:755–61.PubMedCentralPubMed

93.

Biankin AV, Biankin SA, Kench JG, Morey AL, Lee C-S, Head DR, et al. Aberrant p16^INK4A and DPC4/Smad4 expression in intraductal papillary mucinous tumours of the pancreas is associated with invasive ductal adenocarcinoma. Gut. 2002;50:861–8.PubMedCentralPubMed

94.

Sahin F, Maitra A, Argani P, Sato N, Maehara N, Montgomery E, et al. Loss of Stk11/Lkb1 expression in pancreatic and biliary neoplasms. Mod Pathol. 2003;16:686–91.PubMed

95.

Schönleben F, Allendorf JD, Qiu W, Li X, Ho DJ, Ciau NT, et al. Mutational analyses of multiple oncogenic pathways in intraductal papillary mucinous neoplasms of the pancreas. Pancreas. 2008;36:168–72.PubMedCentralPubMed

96.

Chadwick B, Willmore-Payne C, Tripp S, Layfield LJ, Hirschowitz S, Holden J. Histologic, immunohistochemical, and molecular classification of 52 IPMNs of the pancreas. Appl Immunohistochem Mol Morphol. 2009;17:31–9.PubMed

97.

Hruban RH, Maitra A, Kern SE, Goggins M. Precursors to pancreatic cancer. Gastroenterol Clin N Am. 2007;36:831–49.

98.

Wilentz RE, Albores-Saavedra J, Hruban RH. Mucinous cystic neoplasms of the pancreas. Semin Diagn Pathol. 2000;17:31–42.PubMed

99.

Ghiorzo P. Genetic predisposition to pancreatic cancer. World J Gastroenterol. 2014;20:10778–89.PubMedCentralPubMed

100.

Kim SG, Wu T-T, Lee JH, Yun YK, Issa J-P, Hamilton SR, et al. Comparison of epigenetic and genetic alterations in mucinous cystic neoplasm and serous microcystic adenoma of pancreas. Mod Pathol. 2003;16:1086–94.PubMed

101.

Jimenez RE, Warshaw AL, Z’graggen K, Hartwig W, Taylor DZ, Compton CC, et al. Sequential accumulation of K-ras mutations and p53 overexpression in the progression of pancreatic mucinous cystic neoplasms to malignancy. Ann Surg. 1999;230:501–9; discussion 509–11.PubMedCentralPubMed

102.

Sorio C, Capelli P, Lissandrini D, Moore PS, Balzarini P, Falconi M, et al. Mucinous cystic carcinoma of the pancreas: a unique cell line and xenograft model of a preinvasive lesion. Virchows Arch. 2005;446:239–45.PubMed

103.

Lüttges J, Feyerabend B, Buchelt T, Pacena M, Klöppel G. The mucin profile of noninvasive and invasive mucinous cystic neoplasms of the pancreas. Am J Surg Pathol. 2002;26:466–71.PubMed

104.

Singhi AD, Nikiforova MN, Fasanella KE, McGrath KM, Pai RK, Ohori NP, et al. Preoperative GNAS and KRAS testing in the diagnosis of pancreatic mucinous cysts. Clin Cancer Res. 2014;20:4381–9.PubMed

105.

Moore PS, Zamboni G, Brighenti A, Lissandrini D, Antonello D, Capelli P, et al. Molecular characterization of pancreatic serous microcystic adenomas: evidence for a tumor suppressor gene on chromosome 10q. Am J Pathol. 2001;158:317–21.PubMedCentralPubMed

106.

Moore PS, Missiaglia E, Antonello D, Zamò A, Zamboni G, Corleto V, et al. Role of disease-causing genes in sporadic pancreatic endocrine tumors: MEN1 and VHL. Genes Chromosomes Cancer. 2001;32:177–81.PubMed

107.

Mohr VH, Vortmeyer AO, Zhuang Z, Libutti SK, Walther MM, Choyke PL, et al. Histopathology and molecular genetics of multiple cysts and microcystic (serous) adenomas of the pancreas in von Hippel-Lindau patients. Am J Pathol. 2000;157:1615–21.PubMedCentralPubMed

108.

Haddad NMN, Cavallerano JD, Silva PS. Von Hippel-Lindau disease: a genetic and clinical review. Semin Ophthalmol. 2013;28:377–86.PubMed

109.

Yang F, Fu D-L, Jin C, Long J, Yu X-J, Xu J, et al. Clinical experiences of solid pseudopapillary tumors of the pancreas in China. J Gastroenterol Hepatol. 2008;23:1847–51.PubMed

110.

Kang CM, Kim KS, Choi JS, Kim H, Lee WJ, Kim BR. Solid pseudopapillary tumor of the pancreas suggesting malignant potential. Pancreas. 2006;32:276–80.PubMed

111.

Tang LH, Aydin H, Brennan MF, Klimstra DS. Clinically aggressive solid pseudopapillary tumors of the pancreas: a report of two cases with components of undifferentiated carcinoma and a comparative clinicopathologic analysis of 34 conventional cases. Am J Surg Pathol. 2005;29:512–9.PubMed

112.

Meriden Z, Shi C, Edil BH, Ellison T, Wolfgang CL, Cornish TC, et al. Hyaline globules in neuroendocrine and solid-pseudopapillary neoplasms of the pancreas: a clue to the diagnosis. Am J Surg Pathol. 2011;35:981–8.PubMedCentralPubMed

113.

Reid MD, Saka B, Balci S, Goldblum AS, Adsay NV. Molecular genetics of pancreatic neoplasms and their morphologic correlates: an update on recent advances and potential diagnostic applications. Am J Clin Pathol. 2014;141:168–80.PubMed

114.

Abraham SC, Wu T-T, Hruban RH, Lee JH, Yeo CJ, Conlon K, et al. Genetic and immunohistochemical analysis of pancreatic acinar cell carcinoma: frequent allelic loss on chromosome 11p and alterations in the APC/β-catenin pathway. Am J Pathol. 2002;160:953–62.PubMedCentralPubMed

115.

Kim M-J, Jang S-J, Yu E. Loss of E-cadherin and cytoplasmic-nuclear expression of β-catenin are the most useful immunoprofiles in the diagnosis of solid-pseudopapillary neoplasm of the pancreas. Hum Pathol. 2008;39:251–8.PubMed

116.

Kimura W, Nagai H, Kuroda A, Muto T, Esaki Y. Analysis of small cystic lesions of the pancreas. Int J Pancreatol. 1995;18:197–206.PubMed

117.

Laffan TA, Horton KM, Klein AP, Berlanstein B, Siegelman SS, Kawamoto S, et al. Prevalence of unsuspected pancreatic cysts on MDCT. AJR Am J Roentgenol. 2008;191:802–7.PubMedCentralPubMed

118.

Lee KS, Sekhar A, Rofsky NM, Pedrosa I. Prevalence of incidental pancreatic cysts in the adult population on MR imaging. Am J Gastroenterol. 2010;105:2079–84.PubMed

119.

Spinelli KS, Fromwiller TE, Daniel RA, Kiely JM, Nakeeb A, Komorowski RA, et al. Cystic pancreatic neoplasms: observe or operate. Ann Surg. 2004;239:651–7; discussion 657–9.PubMedCentralPubMed

120.

Matthaei H, Wylie D, Lloyd MB, Dal Molin M, Kemppainen J, Mayo SC, et al. miRNA biomarkers in cyst fluid augment the diagnosis and management of pancreatic cysts. Clin Cancer Res. 2012;18:4713–24.PubMedCentralPubMed

121.

Caponi S, Funel N, Frampton AE, Mosca F, Santarpia L, Van der Velde AG, et al. The good, the bad and the ugly: a tale of miR-101, miR-21 and miR-155 in pancreatic intraductal papillary mucinous neoplasms. Ann Oncol. 2013;24:734–41.PubMed

122.

Hollingsworth MA, Swanson BJ. Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer. 2004;4:45–60.PubMed

123.

Ringel J, Löhr M. The MUC gene family: their role in diagnosis and early detection of pancreatic cancer. Mol Cancer. 2003;2:9.PubMedCentralPubMed

124.

Stelow EB, Stanley MW, Bardales RH, Mallery S, Lai R, Linzie BM, et al. Intraductal papillary-mucinous neoplasm of the pancreas. The findings and limitations of cytologic samples obtained by endoscopic ultrasound-guided fine-needle aspiration. Am J Clin Pathol. 2003;120:398–404.PubMed

125.

Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063–72.PubMed

126.

Halfdanarson TR, Rabe KG, Rubin J, Petersen GM. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol. 2008;19:1727–33.PubMedCentralPubMed

127.

Halfdanarson TR, Rubin J, Farnell MB, Grant CS, Petersen GM. Pancreatic endocrine neoplasms: epidemiology and prognosis of pancreatic endocrine tumors. Endocr Relat Cancer. 2008;15:409–27.PubMedCentralPubMed

128.

Ekeblad S, Skogseid B, Dunder K, Öberg K, Eriksson B. Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution. Clin Cancer Res. 2008;14:7798–803.PubMed

129.

de Wilde RF, Edil BH, Hruban RH, Maitra A. Well-differentiated pancreatic neuroendocrine tumors: from genetics to therapy. Nat Rev Gastroenterol Hepatol. 2012;9:199–208.PubMedCentralPubMed

130.

Jensen RT, Berna MJ, Bingham DB, Norton JA. Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer. 2008;113:1807–43.PubMedCentralPubMed

131.

Elsaesser SJ, Allis CD. HIRA and Daxx constitute two independent histone H3.3-containing predeposition complexes. Cold Spring Harb Symp Quant Biol. 2010;75:27–34.PubMed

132.

Goldberg AD, Banaszynski LA, Noh K-M, Lewis PW, Elsaesser SJ, Stadler S, et al. Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell. 2010;140:678–91.PubMedCentralPubMed

133.

Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, et al. Altered telomeres in tumors with ATRX and DAXX mutations. Science. 2011;333:425.PubMedCentralPubMed

134.

Heaphy CM, Subhawong AP, Hong S-M, Goggins MG, Montgomery EA, Gabrielson E, et al. Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. Am J Pathol. 2011;179:1608–15.PubMedCentralPubMed

135.

Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell. 2005;8:179–83.PubMed

136.

Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554.PubMed

137.

Ohki R, Saito K, Chen Y, Kawase T, Hiraoka N, Saigawa R, et al. PHLDA3 is a novel tumor suppressor of pancreatic neuroendocrine tumors. Proc Natl Acad Sci U S A. 2014;111:E2404–13.PubMedCentralPubMed

138.

Kawase T, Ohki R, Shibata T, Tsutsumi S, Kamimura N, Inazawa J, et al. PH domain-only protein PHLDA3 is a p53-regulated repressor of Akt. Cell. 2009;136:535–50.PubMed

139.

Fendrich V, Bartsch DK. Surgical treatment of gastrointestinal neuroendocrine tumors. Langenbecks Arch Surg. 2011;396:299–311.PubMed

140.

Panzuto F, Boninsegna L, Fazio N, Campana D, Pia Brizzi M, Capurso G, et al. Metastatic and locally advanced pancreatic endocrine carcinomas: analysis of factors associated with disease progression. J Clin Oncol. 2011;29:2372–7.PubMed

141.

Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010;28:69–76.PubMedCentralPubMed

142.

Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008;26:4311–8.PubMedCentralPubMed

143.

Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514–23.PubMedCentralPubMed

144.

Raymond E, Dahan L, Raoul J-L, Bang Y-J, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501–13.PubMed

145.

Chmielecki J, Hutchinson KE, Frampton GM, Chalmers ZR, Johnson A, Shi C, et al. Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes. Cancer Discov. 2014;4;1398–405.

146.

Hutchinson KE, Lipson D, Stephens PJ, Otto G, Lehmann BD, Lyle PL, et al. BRAF fusions define a distinct molecular subset of melanomas with potential sensitivity to MEK inhibition. Clin Cancer Res. 2013;19:6696–702.PubMed

147.

Klimstra DS, Wenig BM, Adair CF, Heffess CS. Pancreatoblastoma. A clinicopathologic study and review of the literature. Am J Surg Pathol. 1995;19:1371–89.PubMed

148.

Salman B, Brat G, Yoon Y-S, Hruban RH, Singhi AD, Fishman EK, et al. The diagnosis and surgical treatment of pancreatoblastoma in adults: a case series and review of the literature. J Gastrointest Surg. 2013;17:2153–61.PubMed

149.

Abraham SC, Wu TT, Klimstra DS, Finn LS, Lee JH, Yeo CJ, et al. Distinctive molecular genetic alterations in sporadic and familial adenomatous polyposis-associated pancreatoblastomas : frequent alterations in the APC/β-catenin pathway and chromosome 11p. Am J Pathol. 2001;159:1619–27.PubMedCentralPubMed

150.

Moore PS, Orlandini S, Zamboni G, Capelli P, Rigaud G, Falconi M, et al. Pancreatic tumours: molecular pathways implicated in ductal cancer are involved in ampullary but not in exocrine nonductal or endocrine tumorigenesis. Br J Cancer. 2001;84:253–62.PubMedCentralPubMed

151.

Cavallini A, Falconi M, Bortesi L, Crippa S, Barugola G, Butturini G. Pancreatoblastoma in adults: a review of the literature. Pancreatology. 2009;9:73–80.PubMed

Title: The genetic classification of pancreatic neoplasia
Authors: Hanno Matthaei
Alexander Semaan
Ralph H. Hruban
Publication date: 01-05-2015
Publisher: Springer Japan
Published in: Journal of Gastroenterology / Issue 5/2015
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI: https://doi.org/10.1007/s00535-015-1037-4

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