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The molecular and cellular heterogeneity of pancreatic ductal adenocarcinoma

Nature Reviews Gastroenterology & Hepatology volume 9, pages 77–87 (2012)Cite this article

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Abstract

Current standard therapies for pancreatic ductal adenocarcinoma have failed to attenuate the aggressiveness of this disease or confer notable improvements in survival. Previous molecular research into pancreatic cancers, along with advances in sequencing technologies, have identified many altered genes in patients with pancreatic cancer and revealed the marked genetic heterogeneity of individual tumors. Thus, the lack of success of conventional empiric therapy can be partly attributed to the underlying heterogeneity of pancreatic tumors. The genetic alterations that have been detected in pancreatic cancer range from simple mutations at the level of base pairs to complex chromosomal structural changes and rearrangements. The identification of molecular changes that are unique to an individual patient's tumors, and the subsequent development of strategies to target the tumors in a personalized approach to therapeutics, is a necessary advance to improve therapy for patients with this disease.

Key Points

  • Pancreatic cancer is a lethal malignancy; the treatment of patients with this disease is a therapeutic challenge

  • Current therapies confer only modest increases in survival, often as little as a few months

  • Molecular and genomic research into pancreatic cancer has demonstrated marked heterogeneity among tumors that might underlie differing responses to standard therapy

  • Improved therapeutic outcomes might be realized in some patients through a personalized approach to targeting patient-specific genetic alterations in tumors

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Figure 1: Genetic alterations in pancreatic cancer.
Figure 2: Alterations in cellular pathways and processes in pancreatic cancer.

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References

  1. Yeo, T. P. et al. Pancreatic cancer. Curr. Probl. Cancer 26, 176–275 (2002).

    Article  PubMed  Google Scholar 

  2. Jemal, A., Seigel, R., Xu, J. & Ward, E. Cancer statistics, 2010. CA Cancer J. Clin. 60, 277–300 (2010).

    Article  PubMed  Google Scholar 

  3. Hezel, A. F., Kimmelman, A. C., Stanger, B. Z., Bardeesy, N. & DePinho, R. A. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 20, 1218–1249 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Feldmann, G. & Maitra, A. Molecular genetics of pancreatic ductal adenocarcinomas and recent implications for translational efforts. J. Mol. Diagn. 10, 111–122 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gräntzdörffer, I., Carl-McGrath, S., Ebert, M. P. & Röcken, C. Proteomics of pancreatic cancer. Pancreas 36, 329–336 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Li, D., Xie, K., Wolff, R. & Abbruzzese, J. L. Pancreatic cancer. Lancet 363, 1049–1057 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Klöppel, G., Solcia, E., Longnecker, D. S., Capella, C. & Sobin, L. H. in International Histological Classification of Tumours 2nd edn 1–61 (Springer/World Health Organization, Berlin, 1998).

    Google Scholar 

  8. Hruban, R. H., Goggins, M., Parsons, J. & Kern, S. E. Progression model for pancreatic cancer. Clin. Cancer Res. 6, 2969–2972 (2000).

    CAS  PubMed  Google Scholar 

  9. Buchholz, M. et al. Transcriptome analysis of microdissected pancreatic intraepithelial neoplastic lesions. Oncogene 24, 6626–6636 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Olive, K. P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chu, G. C., Kimmelman, A. C., Hezel, A. F. & DePinho, R. A. Stromal biology of pancreatic cancer. J. Cell. Biochem. 101, 887–907 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Neesse, A. et al. Stromal biology and therapy in pancreatic cancer. Gut 60, 861–868 (2011).

    Article  PubMed  Google Scholar 

  13. Wang, Z. et al. Pancreatic cancer: understanding and overcoming chemoresistance. Nat. Rev. Gastroenterol. Hepatol. 8, 27–33 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Wang, Z. et al. Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res. 69, 2400–2407 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shah, A. N. et al. Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann. Surg. Oncol. 14, 3629–3637 (2007).

    Article  PubMed  Google Scholar 

  16. Hermann, P. C. et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1, 313–323 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Hong, S. P., Wen, J., Bang, S., Park, S. & Song, S. Y. CD44-positive cells are responsible for gemcitabine resistance in pancreatic cancer cells. Int. J. Cancer 125, 2323–2331 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Campbell, P. J. et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467, 1109–1113 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Biankin, A. V. & Hudson, T. J. Somatic variation and cancer: therapies lost in the mix. Hum. Genet. 130, 79–91 (2011).

    Article  PubMed  Google Scholar 

  20. Hong, S. M., Park, J. Y., Hruban, R. H. & Goggins, M. Molecular signatures of pancreatic cancer. Arch. Pathol. Lab. Med. 135, 716–727 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Harris, T. J. & McCormick, F. The molecular pathology of cancer. Nat. Rev. Clin. Oncol. 7, 251–265 (2010).

    Article  CAS  PubMed  Google Scholar 

  22. Lynch, H. T. et al. Familial pancreatic cancer: a review. Semin. Oncol. 23, 251–275 (1996).

    CAS  PubMed  Google Scholar 

  23. Bignell, G. R. et al. Signatures of mutation and selection in the cancer genome. Nature 463, 893–898 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bardeesy, N. & DePinho, R. A. Pancreatic cancer biology and genetics. Nat. Rev. Cancer 2, 897–909 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Hansel, D. E., Kern, S. E. & Hruban, R. H. Molecular pathogenesis of pancreatic cancer. Annu. Rev. Genomics Hum. Genet. 4, 237–256 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Baumgart, M., Heinmöller, E., Horstmann, O., Becker, H. & Ghadimi, B. M. The genetic basis of sporadic pancreatic cancer. Cell. Oncol. 27, 3–13 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Wong, H. H. & Lemoine, N. R. Pancreatic cancer: molecular pathogenesis and new therapeutic targets. Nat. Rev. Gastroenterol. Hepatol. 6, 412–422 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Klimstra, D. S. & Longnecker, D. S. K-ras mutations in pancreatic ductal proliferative lesions. Am. J. Pathol. 145, 1547–1550 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Rozenblum, E. et al. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res. 57, 1731–1734 (1997).

    CAS  PubMed  Google Scholar 

  30. Rachagani, S. et al. Activated KrasG12D is associated with invasion and metastasis of pancreatic cancer cells through inhibition of E-cadherin. Br. J. Cancer 104, 1038–1048 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pugliese, V. et al. Pancreatic intraductal sampling during ERCP in patients with chronic pancreatitis and pancreatic cancer: cytologic studies and k-ras-2 codon 12 molecular analysis in 47 cases. Gastrointest. Endosc. 54, 595–599 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Van Laethem, J. L. et al. Relative contribution of Ki-ras gene analysis and brush cytology during ERCP for the diagnosis of biliary and pancreatic diseases. Gastrointest. Endosc. 47, 479–485 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Luttges, J. et al. The K-ras mutation pattern in pancreatic ductal adenocarcinoma usually is identical to that in associated normal, hyperplastic, and metaplastic ductal epithelium. Cancer 85, 1703–1710 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Hruban, R. H., Wilentz, R. & Kern, S. E. Genetic progression in the pancreatic ducts. Am. J. Pathol. 156, 1821–1825 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Calhoun, E. S. et al. BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets. Am. J. Pathol. 163, 1255–1260 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cheng, J. Q. et al. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc. Natl Acad. Sci. USA 93, 3636–3641 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ruggeri, B. A., Huang, L., Wood, M., Cheng, J. Q. & Testa, J. R. Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol. Carcinog. 21, 81–86 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Wallrapp, C. et al. Characterization of a high copy number amplification at 6q24 in pancreatic cancer identifies c-myb as a candidate oncogene. Cancer Res. 57, 3135–3139 (1997).

    CAS  PubMed  Google Scholar 

  39. Caldas, C. et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat. Genet. 8, 27–32 (1994).

    Article  CAS  PubMed  Google Scholar 

  40. Ruggeri, B. A. et al. Human pancreatic carcinomas and cell lines reveal frequent and multiple alterations in the p53 and Rb-1 tumor-suppressor genes. Oncogene 7, 1503–1511 (1992).

    CAS  PubMed  Google Scholar 

  41. Scarpa, A. et al. Pancreatic adenocarcinomas frequently show p53 gene mutations. Am. J. Pathol. 142, 1534–1543 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Hahn, S. A. et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271, 350–353 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Vogelstein, B. & Kinzler, K. W. Cancer genes and the pathways they control. Nat. Med. 10, 789–799 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Maitra, A. & Hruban, R. H. Pancreatic cancer. Annu. Rev. Pathol. 3, 157–188 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wu, X. et al. HOXB7 homeodomain protein is overexpressed in breast cancer and confers epithelial-mesenchymal transition. Cancer Res. 66, 9527–9534 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Chen, H. et al. Hoxb7 inhibits transgenic HER-2/neu-induced mouse mammary tumor onset but promotes progression and lung metastasis. Cancer Res. 68, 3637–3644 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. De Souza Setubal Destro, M. F. et al. Overexpression of HOXB7 homebox gene in oral cancer induces ceullar proliferation and is associated with poor prognosis. Int. J. Oncol. 36, 141–149 (2010).

    PubMed  Google Scholar 

  48. Kim, Y. S., Gum, J. R. Jr, Crawley, S. C., Deng G. & Ho, J. J. Mucin gene and antigen expression in biliopancreatic carcinogenesis. Ann. Oncol. 10 (Suppl. 4), 51–55 (1999).

    Article  PubMed  Google Scholar 

  49. Kim, G. E. et al. Aberrant expression of MUC5AC and MUC6 gastric mucins and sialyl Tn antigen in intraepithelial neoplasms of the pancreas. Gastroenterology 123, 1052–1060 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Monges, G. M. et al. Differential MUC1 expression in normal and neoplastic human pancreatic tissue. An immunohistochemical study of 60 samples. Am. J. Clin. Pathol. 112, 635–640 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Besmer, D. M. et al. Pancreatic ductal adenocarcinoma (PDA) mice lacking mucin 1 have a profound defect in tumor growth and metastasis. Cancer Res. 71, 4434–4442 (2011).

    Article  CAS  Google Scholar 

  52. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

  53. Ding, L. et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069–1075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

  55. Varela, I. et al. Exome sequencing identifies frequent mutations of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wood, L. D. et al. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108–1113 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Morris, J. P. 4th, Wang, S. C. & Hebrok, M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat. Rev. Cancer 10, 683–695 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Stuart, D. & Sellers, W. R. Linking somatic genetic alterations to cancer therapeutics. Curr. Opin. Cell Biol. 21, 304–310 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. International Cancer Genome Consortium. International network of cancer genome projects. Nature 464, 993–998 (2010).

  61. Suzuki, A. et al. Identification of SMURF1 as a possible target for 7q21.3–221 amplification detected in a pancreatic cancer cell line by in-house array-based comparative genomic hybridization. Cancer Sci. 99, 986–994 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Fu, B., Luo, M., Lakkur, S., Lucito, R. & Iacobuzio-Donahue, C. A. Frequent genomic copy number gain and overexpression of GATA-6 in pancreatic carcinoma. Cancer Biol. Ther. 7, 1593–1601 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Heidenblad, M. et al. Genome-wide array-based comparative genomic hybridization reveals multiple amplification targets and novel homozygous deletions in pancreatic carcinoma cell lines. Cancer Res. 64, 3052–3059 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Holzmann, K. et al. Genomic DNA-chip hybridization reveals a higher incidence of genomic amplifications in pancreatic cancer than conventional comparative genomic hybridization and leads to the identification of novel candidate genes. Cancer Res. 64, 4428–4433 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Kitoh, H. et al. Comparative genomic hybridization analysis for pancreatic cancer specimens obtained by endoscopic ultrasonography-guided fine-needle aspiration. J. Gastroenterol. 40, 511–517 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Loukopoulous, P. et al. Genome-wide array-based comparative genomic hybridization analysis of pancreatic adenocarcinome: identification of genetic indicators that predict patient outcome. Cancer Sci. 98, 392–400 (2007).

    Article  CAS  Google Scholar 

  67. Zhong, Y. et al. GATA6 activates Wnt signaling in pancreatic cancer by negatively regulating the Wnt antagonist Dickkopf-1. PLoS ONE 6, e22129 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Genomic Health. Oncotype DX [online], (2010).

  69. Collisson, E. A. et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat. Med. 17, 500–503 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Chelala, C. et al. Pancreatic expression database: a generic model for the organization, integration and mining of complex cancer datasets. BMC Genomics 8, 439 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  71. International Cancer Genome Consortium Data Coordination Center. Data Portal [online], (2011).

  72. Vincent, A. et al. Genome-wide analysis of promoter methylation associated with gene expression profile in pancreatic adenocarcinoma. Clin. Cancer Res. 17, 4341–4354 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Bloomston, M. et al. MircoRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 297, 1901–1908 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Dillhoff, M., Lieu, J., Frankel, W., Croce, C. & Bloomston, M. MicroRNA-21 is overexpressed in pancreatic cancer and a potential predictor of survival. J. Gastrointest. Surg. 12, 2171–2176 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Lee, E. J. et al. Expression profiling identifies microRNA signature in pancreatic cancer. Int. J. Cancer 120, 1046–1054 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Szafranska, A. E. et al. MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene 26, 4442–4452 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Zhang, Y. et al. Profiling of 95 microRNAs in pancreatic cancer cell lines and surgical specimens by real-time PCR analysis. World J. Surg. 33, 698–709 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Kent, O. A. et al. A resource for analysis of microRNA expression and function in pancreatic ductal adenocarcinoma cells. Cancer Biol. Ther. 8, 2013–2024 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Burris, H. A. 3rd et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol. 15, 2403–2413 (1997).

    Article  CAS  PubMed  Google Scholar 

  80. Moore, M. J. et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a Phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 25, 1960–1966 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Conroy, T. et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364, 1817–1825 (2011).

    Article  CAS  PubMed  Google Scholar 

  82. Stratton, M. R. Exploring the genomes of cancer cells: progress and promise. Science 33, 1553–1558 (2011).

    Article  CAS  Google Scholar 

  83. Esteva, F. J., Yu, D., Hung., M. C. & Horobagyi, G. N. Molecular predictors of response to trastuzumab and lapatinib in breast cancer. Nat. Rev. Clin. Oncol. 7, 98–107 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Genentech. FDA Approves Zelboraf (Vemurafenib) and Companion Diagnostic for BRAF Mutation-Positive Metastatic Melanoma, a Deadly Form of Skin Cancer [online], (2011).

  85. Villarroel, M. C. 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. 10, 3–8 (2011).

    Article  CAS  PubMed  Google Scholar 

  86. Xia, B. et al. Control of BRAC2 cellular and clinical functions by a nuclear partner, PALB2. Mol. Cell 22, 719–729 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Jones, S. et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 324, 217 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Couch, F. J. et al. The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol. Biomarkers Prev. 16, 342–346 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Iacobuzio-Donahue, C. A. et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J. Clin. Oncol. 27, 1806–1813 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Armstrong, M. D. et al. An effective personalized approach to a rare tumor: prolonged survival in metastatic pancreatic acinar cell carcinoma based on genetic analysis and cell line development. J. Cancer 2, 142–152 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Solinas-Toldo, S. et al. Mapping of chromosomal imbalances in pancreatic carcinoma by comparative genomic hybridization. Cancer Res. 56, 3803–3807 (1996).

    CAS  PubMed  Google Scholar 

  92. Mahlamäki, E. H. et al. Comparative genomic hybridization reveals frequent gains of 20q, 8q, 11q, 12p, and 17q and losses of 18q, 9p and 15q in pancreatic cancer. Genes Chromosomes Cancer 20, 383–391 (1997).

    Article  PubMed  Google Scholar 

  93. Fukushige, S. et al. Frequent gain of copy number on the long arm of chromosome 20 in human pancreatic adenocarcinoma. Genes Chromosomes Cancer 19, 161–169 (1997).

    Article  CAS  PubMed  Google Scholar 

  94. Curtis, L. J. et al. Amplification of DNA sequences from chromosome 19q31.1 in human pancreatic cell line. Genomics 53, 42–55 (1998).

    Article  CAS  PubMed  Google Scholar 

  95. Ghadimi, M. B. et al. Specific chromosomal aberrations and amplification of the AIB1 nuclear receptor coactivator gene in pancreatic carcinomas. Am. J. Pathol. 154, 525–536 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Schleger, C., Arens, N., Zentraf, H., Bleyl, U. & Verbeke, C. Identification of frequent chromosomal aberrations in ductal adenocarcinoma of the pancreas by comparative genomic hybridization (CGH). J. Pathol. 191, 27–32 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Shiraishi, K. et al. A comparison of DNA copy number changes detected by comparative genomic hybridization in malignancies of the liver, biliary tract and pancreas. Oncology 60, 151–161 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Harada, T. et al. Detection of genetic alterations in pancreatic cancers by comparative genomic hybridization coupled with tissue microdissection and degenerate oligonucleotide primed polymerase chain reaction. Oncology 62, 251–258 (2002).

    Article  CAS  PubMed  Google Scholar 

  99. Mahlamäki, E. H. et al. Frequent amplification of 8q24, 11q, 17q and 20q-specific genes in pancreatic cancer. Genes Chromosomes Cancer 35, 353–358 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Lin, M., Cai, D. & Luo, M. Identification of chromosomal imbalances in pancreatic carcinoma using comparative genomic hybridization. Chin. Med. J. (Engl.) 116, 1156–1160 (2003).

    CAS  Google Scholar 

  101. Aguirre, A. J. et al. High resolution characterization of the pancreatic adenocarcinoma genome. Proc. Natl Acad. Sci. USA 101, 9067–9072 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Mahlamäki, E. H. et al. High resolution genomic and expression profiling reveals 105 putative amplification target genes in pancreatic cancer. Neoplasia 6, 432–439 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Bashyam, M. D. et al. Array-based comparative genomic hybridization identifies localized DNA amplifications and homozygous deletions in pancreatic cancer. Neoplasia 7, 556–562 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Gysin, S., Rickert, P., Kastury, K. & McMahon, M. Analysis of genomic DNA alterations and mRNA expression patterns in a panel of human pancreatic cancer cell lines. Genes Chromosomes Cancer 44, 37–51 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Nowak, N. J. et al. Genome-wide aberrations in pancreatic adenocarcinoma. Cancer Genet. Cytogenet. 161, 36–50 (2005).

    Article  CAS  PubMed  Google Scholar 

  106. Harada, T., Chelala, C., Crnogorac-Jurcevic, T. & Lemoine, N. R. Genome-wide analysis of pancreatic cancer using microarray-based techniques. Pancreatology 9, 13–24 (2009).

    Article  CAS  PubMed  Google Scholar 

  107. Calhoun, E. S. et al. Identifying allelic loss and homozygous deletions in pancreatic cancer without matched normals using high-density single-nucleotide polymorphism arrays. Cancer Res. 66, 7920–7928 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Harada, T. et al. Genome-wide DNA copy number analysis in pancreatic cancer using high-density single nucleotide polymorphism arrays. Oncogene 27, 1951–1960 (2008).

    Article  CAS  PubMed  Google Scholar 

  109. Stoecklein, N. H. et al. Copy number of chromosome 17 but not HER2 amplification predicts clinical outcome of patients with pancreatic ductal adenocarincoma. J. Clin. Oncol. 22, 4737–4745 (2004).

    Article  CAS  PubMed  Google Scholar 

  110. Forbes, S. A. et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer Nucleic Acids Res. 39, D945–D950 (2011).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

N. Samuel is supported by an award from the Frank Fletcher Memorial Fund. T. J. Hudson is the recipient of a Senior Investigator Award from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation.

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  1. Department of Molecular Genetics, 1 King's College Circle, Room 4398, University of Toronto, Toronto, M5S 1A8, ON, Canada

    Nardin Samuel

  2. Ontario Institute for Cancer Research, MaRS Centre, South Tower, 101 College Street, Suite 800, Toronto, M5G 0A3, ON, Canada

    Thomas J. Hudson

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Samuel, N., Hudson, T. The molecular and cellular heterogeneity of pancreatic ductal adenocarcinoma. Nat Rev Gastroenterol Hepatol 9, 77–87 (2012). https://doi.org/10.1038/nrgastro.2011.215

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