The Genetics of Pancreatic Cancer Progression

Chapter

Abstract

Pancreatic cancer is caused by mutations in specific cancer genes. While these cancer genes are often categorized into those that are inherited versus somatically acquired, they may also be categorized into those that occur during carcinogenesis versus those that accumulate during clonal progression. This newfound approach to understanding pancreatic cancer genetics now opens the door to understanding those events that play a role specifically in progression to metastatic disease.

Keywords

Ischemia Adenocarcinoma Triphosphate Guanosine Glean 

References

  1. Aguirre AJ, Bardeesy N, Sinha M, Lopez L, Tuveson DA, Horner J et al (2003) Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev 17(24):3112–3126PubMedCrossRefGoogle Scholar
  2. Balakrishnan A, Bleeker FE, Lamba S, Rodolfo M, Daniotti M, Scarpa A et al (2007) Novel somatic and germline mutations in cancer candidate genes in glioblastoma, melanoma, and pancreatic carcinoma. Cancer Res 67(8):3545–3550PubMedCrossRefGoogle Scholar
  3. Bosetti C, Bertuccio P, Negri E, La Vecchia C, Zeegers MP, Boffetta P (2012) Pancreatic cancer: overview of descriptive epidemiology. Mol Carcinog 51(1):3–13PubMedCrossRefGoogle Scholar
  4. Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB et al (1994) Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 8(1):27–32PubMedCrossRefGoogle Scholar
  5. Campbell PJ, Yachida S, Mudie LJ, Stephens PJ, Pleasance ED, Stebbings LA et al (2010) The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467(7319):1109–1113PubMedCrossRefGoogle Scholar
  6. de Jong MC, Farnell MB, Sclabas G, Cunningham SC, Cameron JL, Geschwind J-F et al (2010a) Liver-directed therapy for hepatic metastases in patients undergoing pancreaticoduodenectomy: a dual-center analysis. Ann Surg 252(1):142–148PubMedCrossRefGoogle Scholar
  7. de Jong MC, Tsai S, Cameron JL, Wolfgang CL, Hirose K, van Vledder MG et al (2010b) Safety and efficacy of curative intent surgery for peri-ampullary liver metastasis. J Surg Oncol 102(3): 256–263PubMedCrossRefGoogle Scholar
  8. Embuscado EE, Laheru D, Ricci F, Yun KJ, de Boom Witzel S, Seigel A et al (2005) Immortalizing the complexity of cancer metastasis: genetic features of lethal metastatic pancreatic cancer obtained from rapid autopsy. Cancer Biol Ther 4(5):548–554PubMedCrossRefGoogle Scholar
  9. Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M et al (2007) Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res 67(5):2187–2196PubMedCrossRefGoogle Scholar
  10. Fidler IJ, Hart IR (1982) Biological diversity in metastatic neoplasms: origins and implications. Science 217(4564):998–1003PubMedCrossRefGoogle Scholar
  11. Garcia-Porta J, Litvinchuk SN, Crochet PA, Romano A, Geniez PH, Lo-Valvo M et al (2012) Molecular phylogenetics and historical biogeography of the west-palearctic common toads (Bufo bufo species complex). Mol Phylogenet Evol 63(1):113–130PubMedCrossRefGoogle Scholar
  12. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E et al (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366(10):883–892PubMedCrossRefGoogle Scholar
  13. Goggins M, Shekher M, Turnacioglu K, Yeo CJ, Hruban RH, Kern SE (1998) Genetic alterations of the transforming growth factor beta receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res 58(23):5329–5332PubMedGoogle Scholar
  14. Goh AM, Coffill CR, Lane DP (2011) The role of mutant p53 in human cancer. J Pathol 223(2):116–126PubMedCrossRefGoogle Scholar
  15. Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E et al (1996) DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271(5247):350–353PubMedCrossRefGoogle Scholar
  16. Hidalgo M (2010) Pancreatic cancer. N Engl J Med 362(17):1605–1617PubMedCrossRefGoogle Scholar
  17. Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH et al (2005) Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7(5):469–483PubMedCrossRefGoogle Scholar
  18. Hishinuma S, Ogata Y, Tomikawa M, Ozawa I, Hirabayashi K, Igarashi S (2006) Patterns of recurrence after curative resection of pancreatic cancer, based on autopsy findings. J Gastrointest Surg 10(4):511–518PubMedCrossRefGoogle Scholar
  19. Hruban RH, Goggins M, Parsons J, Kern SE (2000) Progression model for pancreatic cancer. Clin Cancer Res 6(8):2969–2972PubMedGoogle Scholar
  20. Hruban RH, Adsay NV, Albores-Saavedra J, Compton C, Garrett ES, Goodman SN et al (2001) Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 25(5):579–586PubMedCrossRefGoogle Scholar
  21. Iacobuzio-Donahue CA, Fu B, Yachida S, Luo M, Abe H, Henderson CM et al (2009) DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 27(11):1806–1813PubMedCrossRefGoogle Scholar
  22. Ijichi H, Chytil A, Gorska AE, Aakre ME, Fujitani Y, Fujitani S et al (2006) Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression. Genes Dev 20(22):3147–3160PubMedCrossRefGoogle Scholar
  23. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90PubMedCrossRefGoogle Scholar
  24. Jones S, Zhang X, Parsons DW, Lin JC-H, Leary RJ, Angenendt P et al (2008a) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321(5897):1801–1806PubMedCrossRefGoogle Scholar
  25. Jones S, Chen W-D, Parmigiani G, Diehl F, Beerenwinkel N, Antal T et al (2008b) Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci USA 105(11):4283–4288PubMedCrossRefGoogle Scholar
  26. Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW et al (2009) Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 324(5924):217PubMedCrossRefGoogle Scholar
  27. Jones S, Li M, Parsons DW, Zhang X, Wesseling J, Kristel P et al (2012) Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types. Hum Mutat 33(1):100–103PubMedCrossRefGoogle Scholar
  28. Jonson T, Albrechtsson E, Axelson J, Heidenblad M, Gorunova L, Johansson B et al (2001) Altered expression of TGFB receptors and mitogenic effects of TGFB in pancreatic carcinomas. Int J Oncol 19(1):71–81PubMedGoogle Scholar
  29. Kanda M, Matthaei H, Wu J, Hong SM, Yu J, Borges M et al (2012) Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology 142(4):730–733.e9PubMedCrossRefGoogle Scholar
  30. Katz MHG, Wang H, Fleming JB, Sun CC, Hwang RF, Wolff RA et al (2009) Long-term survival after multidisciplinary management of resected pancreatic adenocarcinoma. Ann Surg Oncol 16(4):836–847PubMedCrossRefGoogle Scholar
  31. Kim WY, Sharpless NE (2006) The regulation of INK4/ARF in cancer and aging. Cell 127(2):265–275PubMedCrossRefGoogle Scholar
  32. Krumbholz A, Bininda-Emonds ORP, Wutzler P, Zell R (2009) Phylogenetics, evolution, and medical importance of polyomaviruses. Infect Genet Evol 9(5):784–799PubMedCrossRefGoogle Scholar
  33. Little EC, Wang C, Watson PM, Watson DK, Cole DJ, Camp ER (2012) Novel immunocompetent murine models representing advanced local and metastatic pancreatic cancer. J Surg Res 176(2):359–366PubMedCrossRefGoogle Scholar
  34. Maitra A, Hruban RH (2008) Pancreatic cancer. Annu Rev Pathol 3:157–188PubMedCrossRefGoogle Scholar
  35. Maitra A, Adsay NV, Argani P, Iacobuzio-Donahue C, De Marzo A, Cameron JL et al (2003) Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray. Mod Pathol 16(9):902–912PubMedCrossRefGoogle Scholar
  36. Malvezzi M, Arfé A, Bertuccio P, Levi F, La Vecchia C, Negri E (2011) European cancer mortality predictions for the year 2011. Ann Oncol 22(4):947–956PubMedCrossRefGoogle Scholar
  37. Massagué J (2008) TGFbeta in cancer. Cell 134(2):215–230PubMedCrossRefGoogle Scholar
  38. Matthaei H, Schulick RD, Hruban RH, Maitra A (2011) Cystic precursors to invasive pancreatic cancer. Nat Rev Gastroenterol Hepatol 8(3):141–150PubMedCrossRefGoogle Scholar
  39. McDermott U, Downing JR, Stratton MR (2011) Genomics and the continuum of cancer care. N Engl J Med 364(4):340–350PubMedCrossRefGoogle Scholar
  40. Meyerson M, Gabriel S, Getz G (2010) Advances in understanding cancer genomes through second-­generation sequencing. Nat Rev Genet 11(10):685–696PubMedCrossRefGoogle Scholar
  41. Morton JP, Timpson P, Karim SA, Ridgway RA, Athineos D, Doyle B et al (2010) Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc Natl Acad Sci USA 107(1):246–251PubMedCrossRefGoogle Scholar
  42. Mudali SV, Fu B, Lakkur SS, Luo M, Embuscado EE, Iacobuzio-Donahue CA (2006) Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status. Clin Exp Metastasis 23(7–8):357–365PubMedGoogle Scholar
  43. Murchison EP, Schulz-Trieglaff OB, Ning Z, Alexandrov LB, Bauer MJ, Fu B et al (2012) Genome sequencing and analysis of the tasmanian devil and its transmissible cancer. Cell 148(4):780–791PubMedCrossRefGoogle Scholar
  44. Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J et al (2011) Tumour evolution inferred by single-cell sequencing. Nature 472(7341):90–94PubMedCrossRefGoogle Scholar
  45. Neilsen PM, Noll JE, Suetani RJ, Schulz RB, Al-Ejeh F, Evdokiou A et al (2011) Mutant p53 uses p63 as a molecular chaperone to alter gene expression and induce a pro-invasive secretome. Oncotarget 2(12):1203–1217PubMedGoogle Scholar
  46. Nguyen DX, Massagué J (2007) Genetic determinants of cancer metastasis. Nat Rev Genet 8(5):341–352PubMedCrossRefGoogle Scholar
  47. Padua D, Massagué J (2009) Roles of TGFbeta in metastasis. Cell Res 19(1):89–102PubMedCrossRefGoogle Scholar
  48. Pertovaara L, Kaipainen A, Mustonen T, Orpana A, Ferrara N, Saksela O et al (1994) Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells. J Biol Chem 269(9):6271–6274PubMedGoogle Scholar
  49. Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9(4):265–273PubMedCrossRefGoogle Scholar
  50. Redston MS, Caldas C, Seymour AB, Hruban RH, da Costa L, Yeo CJ et al (1994) p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res 54(11):3025–3033PubMedGoogle Scholar
  51. Riley T, Sontag E, Chen P, Levine A (2008) Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol 9(5):402–412PubMedCrossRefGoogle Scholar
  52. Schubbert S, Shannon K, Bollag G (2007) Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 7(4):295–308PubMedCrossRefGoogle Scholar
  53. Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK et al (1997) Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res 57(15):3126–3130PubMedGoogle Scholar
  54. Siegel PM, Massagué J (2003) Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer 3(11):807–821PubMedCrossRefGoogle Scholar
  55. Sohn TA, Yeo CJ, Cameron JL, Koniaris L, Kaushal S, Abrams RA et al (2000) Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 4(6):567–579PubMedCrossRefGoogle Scholar
  56. Stathis A, Moore MJ (2010) Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol 7(3):163–172PubMedCrossRefGoogle Scholar
  57. Su GH, Hilgers W, Shekher MC, Tang DJ, Yeo CJ, Hruban RH et al (1998) Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. Cancer Res 58(11):2339–2342PubMedGoogle Scholar
  58. Su GH, Hruban RH, Bansal RK, Bova GS, Tang DJ, Shekher MC et al (1999) Germline and somatic mutations of the STK11/LKB1 Peutz–Jeghers gene in pancreatic and biliary cancers. Am J Pathol 154(6):1835–1840PubMedCrossRefGoogle Scholar
  59. Subarsky P, Hill RP (2003) The hypoxic tumour microenvironment and metastatic progression. Clin Exp Metastasis 20(3):237–250PubMedCrossRefGoogle Scholar
  60. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M (2011) Pancreatic cancer. Lancet 378(9791):607–620PubMedCrossRefGoogle Scholar
  61. Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408(6810):307–310PubMedCrossRefGoogle Scholar
  62. Wilentz RE, Geradts J, Maynard R, Offerhaus GJ, Kang M, Goggins M et al (1998) Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression. Cancer Res 58(20):4740–4744PubMedGoogle Scholar
  63. Winter JM, Cameron JL, Campbell KA, Arnold MA, Chang DC, Coleman J et al (2006) 1423 Pancreaticoduodenectomies for pancreatic cancer: a single-institution experience. J Gastrointest Surg 10(9):1199–1210, discussion 1210–1PubMedCrossRefGoogle Scholar
  64. Winter JM, Brennan MF, Tang LH, D’Angelica MI, Dematteo RP, Fong Y et al (2012) Survival after resection of pancreatic adenocarcinoma: results from a single institution over three decades. Ann Surg Oncol 19(1):169–175PubMedCrossRefGoogle Scholar
  65. Yachida S, Iacobuzio-Donahue CA (2009) The pathology and genetics of metastatic pancreatic cancer. Arch Pathol Lab Med 133(3):413–422PubMedGoogle Scholar
  66. Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B et al (2010) Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467(7319):1114–1117PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  1. 1.Department of PathologyJohns Hopkins Medical InstitutionsBaltimoreUSA

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