Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The pancreatic cancer genome revisited

Abstract

Pancreatic cancer is a genetic disease, and the recurrent genetic alterations characteristic of pancreatic cancer indicate the cellular processes that are targeted for malignant transformation. In addition to somatic alterations in the most common driver genes (KRAS, CDKN2A, TP53 and SMAD4), large-scale studies have revealed major roles for genetic alterations of the SWI/SNF and COMPASS complexes, copy number alterations in GATA6 and MYC that partially define phenotypes of pancreatic cancer, and the role(s) of polyploidy and chromothripsis as factors contributing to pancreatic cancer biology and progression. Germline variants that increase the risk of pancreatic cancer continue to be discovered along with a greater appreciation of the features of pancreatic cancers with mismatch repair deficiencies and homologous recombination deficiencies that confer sensitivity to therapeutic targeting. Wild-type KRAS pancreatic cancers, some of which are driven by alternative oncogenic events affecting NRG1 or NTRK1 — for which targeted therapies exist — further underscore that pancreatic cancer is formally entering the era of precision medicine. Given the vast developments within this field, here we review the wide-ranging and most current information related to pancreatic cancer genomics with the goal of integrating this information into a unifying description of the life history of pancreatic cancer.

Key Points

  • The natural history of pancreatic cancer is characterized by both genetic and epigenetic alterations that contribute to its formation, progression and resistance to therapy.

  • Most pancreatic cancers arise due to the accumulation of somatic alterations in a recurrent set of genes; however, some patients might develop pancreatic cancer owing to a genetic predisposition.

  • Rare subsets of pancreatic cancers arise in association with a genetic alteration that is targetable.

  • The pancreatic cancer stroma, inclusive of the immune system, acts as a dynamic selective pressure to which the neoplasm continuously adapts.

  • Distinct genomic events are associated with pancreatic cancer phenotypes that are differentially sensitive to currently available therapies.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: The most commonly altered driver genes in pancreatic cancer organized by molecular function.
Fig. 2: Revised genetic progression model of pancreatic cancer of the most commonly altered genes.
Fig. 3: Schematic of the clonal dynamics associated with pancreatic cancer formation and progression.

References

  1. 1.

    Rawla, P., Sunkara, T. & Gaduputi, V. Epidemiology of pancreatic cancer: global trends, etiology and risk factors. World J. Oncol. 10, 10–27 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Grossberg, A. J. et al. Multidisciplinary standards of care and recent progress in pancreatic ductal adenocarcinoma. CA Cancer J. Clin. 70, 375–403 (2020).

    PubMed  Article  Google Scholar 

  3. 3.

    Conroy, T. et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N. Engl. J. Med. 379, 2395–2406 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Von Hoff, D. D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369, 1691–1703 (2013).

    Article  CAS  Google Scholar 

  5. 5.

    Hendifar, A. et al. Influence of body mass index and albumin on perioperative morbidity and clinical outcomes in resected pancreatic adenocarcinoma. PLoS ONE 11, e0152172 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. 6.

    Lomberk, G., Dusetti, N., Iovanna, J. & Urrutia, R. Emerging epigenomic landscapes of pancreatic cancer in the era of precision medicine. Nat. Commun. 10, 3875 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  7. 7.

    Makohon-Moore, A. & Iacobuzio-Donahue, C. A. Pancreatic cancer biology and genetics from an evolutionary perspective. Nat. Rev. Cancer 16, 553–565 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Biankin, A. V. et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491, 399–405 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Witkiewicz, A. K. et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat. Commun. 6, 6744 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Raphael, B. J. et al. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 32, 185–203 (2017).

    Article  CAS  Google Scholar 

  12. 12.

    Waddell, N. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518, 495–501 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Notta, F. et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature 538, 378–382 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Connor, A. A. et al. Integration of genomic and transcriptional features in pancreatic cancer reveals increased cell cycle progression in metastases. Cancer Cell 35, 267–282 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

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

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Waters, A. M. & Der, C. J. KRAS: the critical driver and therapeutic target for pancreatic cancer. Cold Spring Harb. Perspect. Med. 8, a031435 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. 17.

    Ruscetti, M. et al. Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer. Cell 181, 424–441 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Moffitt, R. A. et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat. Genet. 47, 1168–1178 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52 (2016).

    CAS  Article  Google Scholar 

  21. 21.

    Chan-Seng-Yue, M. et al. Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution. Nat. Genet. 52, 231–240 (2020).

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Hayashi, A. et al. A unifying paradigm for transcriptional heterogeneity and squamous features in pancreatic ductal adenocarcinoma. Nat. Cancer 1, 59–74 (2020).

    Article  Google Scholar 

  23. 23.

    O’Reilly, E. M. & Hechtman, J. F. Tumour response to TRK inhibition in a patient with pancreatic adenocarcinoma harbouring an NTRK gene fusion. Ann. Oncol. 30, VIII36–VIII40 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Hayashi, A. et al. Evolutionary dynamics of non-coding regions in pancreatic ductal adenocarcinoma. Preprint at bioRxiv https://doi.org/10.1101/2020.09.11.294389 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Tokheim, C. & Karchin, R. CHASMplus reveals the scope of somatic missense mutations driving human cancers. Cell Syst. 9, 9–23 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Tokheim, C. J., Papadopoulos, N., Kinzler, K. W., Vogelstein, B. & Karchin, R. Evaluating the evaluation of cancer driver genes. Proc. Natl Acad. Sci. USA 113, 14330–14335 (2016).

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Vogelstein, B. et al. Cancer genome landscapes. Science 340, 1546–1558 (2013).

    Article  CAS  Google Scholar 

  28. 28.

    Garraway, L. A. & Lander, E. S. Lessons from the cancer genome. Cell 153, 17–37 (2013).

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Reiter, J. G. et al. Minimal functional driver gene heterogeneity among untreated metastases. Science 361, 1033–1037 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Rheinbay, E. et al. Analyses of non-coding somatic drivers in 2,658 cancer whole genomes. Nature 578, 102–111 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Shuai, S. et al. Combined burden and functional impact tests for cancer driver discovery using DriverPower. Nat. Commun. 11, 734 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Chakravarty, D. et al. OncoKB: a precision oncology knowledge base. JCO Precis. Oncol. 2017, PO.17.00011 (2017).

    Google Scholar 

  33. 33.

    Kurosaki, T., Popp, M. W. & Maquat, L. E. Quality and quantity control of gene expression by nonsense-mediated mRNA decay. Nat. Rev. Mol. Cell Biol. 20, 406–420 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Cherry, S. & Lynch, K. W. Alternative splicing and cancer: insights, opportunities, and challenges from an expanding view of the transcriptome. Genes Dev. 34, 1005–1016 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Luksza, M. et al. A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. Nature 551, 517–520 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Balachandran, V. P. et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551, S12–S16 (2017).

    Article  CAS  Google Scholar 

  38. 38.

    Kryklyva, V. et al. Medullary pancreatic carcinoma due to somatic POLE mutation: a distinctive pancreatic carcinoma with marked long-term survival. Pancreas 49, 999–1003 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Humphris, J. L. et al. Hypermutation in pancreatic cancer. Gastroenterology 152, 68–74 (2017).

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Feigin, M. E. et al. Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma. Nat. Genet. 49, 825–833 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Whittle, M. C. et al. RUNX3 controls a metastatic switch in pancreatic ductal adenocarcinoma. Cell 161, 1345–1360 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Karmakar, S. et al. MicroRNA regulation of K-Ras in pancreatic cancer and opportunities for therapeutic intervention. Semin. Cancer Biol. 54, 63–71 (2019).

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Wu, J. et al. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc. Natl Acad. Sci. USA 108, 21188–21193 (2011).

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Bozic, I. et al. Accumulation of driver and passenger mutations during tumor progression. Proc. Natl Acad. Sci. USA 107, 18545–18550 (2010).

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Connor, A. A. et al. Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma. JAMA Oncol. 3, 774–783 (2017).

    PubMed  Article  Google Scholar 

  48. 48.

    Sakamoto, H. et al. The evolutionary origins of recurrent pancreatic cancer. Cancer Discov. 10, 792–805 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Iodice, S., Gandini, S., Maisonneuve, P. & Lowenfels, A. B. Tobacco and the risk of pancreatic cancer: a review and meta-analysis. Langenbeck’s Arch. Surg. 393, 535–545 (2008).

    Article  Google Scholar 

  50. 50.

    Lynch, S. M. et al. Cigarette smoking and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium. Am. J. Epidemiol. 170, 403–413 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Hu, Z. I. et al. Evaluating mismatch repair deficiency in pancreatic adenocarcinoma: challenges and recommendations. Clin. Cancer Res. 24, 1326–1336 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Helleday, T., Eshtad, S. & Nik-Zainal, S. Mechanisms underlying mutational signatures in human cancers. Nat. Rev. Genet. 15, 585–598 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Suspène, R. et al. Somatic hypermutation of human mitochondrial and nuclear DNA by APOBEC3 cytidine deaminases, a pathway for DNA catabolism. Proc. Natl Acad. Sci. USA 108, 4858–4863 (2011).

    PubMed  Article  Google Scholar 

  54. 54.

    Landry, S., Narvaiza, I., Linfesty, D. C. & Weitzman, M. D. APOBEC3A can activate the DNA damage response and cause cell-cycle arrest. EMBO Rep. 12, 444–450 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Campbell, P. J. et al. Pan-cancer analysis of whole genomes. Nature 578, 82–93 (2020).

    Article  CAS  Google Scholar 

  56. 56.

    Evans, M. D., Dizdaroglu, M. & Cooke, M. S. Oxidative DNA damage and disease: induction, repair and significance. Mutat. Res. Rev. Mutat. Res. 567, 1–61 (2004).

    CAS  Article  Google Scholar 

  57. 57.

    Al-Tassan, N. et al. Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors. Nat. Genet. 30, 227–232 (2002).

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Georgeson, P. et al. Evaluating the utility of tumour mutational signatures for identifying hereditary colorectal cancer and polyposis syndrome carriers. Gut https://doi.org/10.1136/gutjnl-2019-320462 (2021).

    Article  PubMed  Google Scholar 

  59. 59.

    Bielski, C. M. et al. Genome doubling shapes the evolution and prognosis of advanced cancers. Nat. Genet. 50, 1189–1195 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Cortés-Ciriano, I. et al. Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing. Nat. Genet. 52, 331–341 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  62. 62.

    Maley, C. C. et al. Classifying the evolutionary and ecological features of neoplasms. Nat. Rev. Cancer 17, 605–619 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Reiter, J. G. & Iacobuzio-Donahue, C. A. Pancreatic cancer: pancreatic carcinogenesis–several small steps or one giant leap? Nat. Rev. Gastroenterol. Hepatol. 14, 7–8 (2017).

    CAS  Article  Google Scholar 

  64. 64.

    Storz, P. & Crawford, H. C. Carcinogenesis of pancreatic ductal adenocarcinoma. Gastroenterology 158, 2072–2081 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Buscail, L., Bournet, B. & Cordelier, P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat. Rev. Gastroenterol. Hepatol. 17, 153–168 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Hart, P. A. et al. Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer. Lancet Gastroenterol. Hepatol. 1, 226–237 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Yadav, D. et al. Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies: rationale and study design for PROCEED from the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer. Pancreas 47, 1229–1238 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Grabocka, E. & Bar-Sagi, D. Mutant KRAS enhances tumor cell fitness by upregulating stress granules. Cell 167, 1803–1813 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Zhao, Y. et al. Oncogene-induced senescence limits the progression of pancreatic neoplasia through production of activin A. Cancer Res. 80, 3359–3371 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  70. 70.

    Commisso, C. et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497, 633–637 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    Shi, C. et al. KRAS2 mutations in human pancreatic acinar-ductal metaplastic lesions are limited to those with PanIN: implications for the human pancreatic cancer cell of origin. Mol. Cancer Res. 7, 230–236 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Kanda, M. et al. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology 142, 730–733 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Burgess, M. R. et al. KRAS allelic imbalance enhances fitness and modulates MAP kinase dependence in cancer. Cell 168, 817–829 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Mueller, S. et al. Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. Nature 554, 62–68 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Heining, C. et al. NRG1 fusions in KRAS wild-type pancreatic cancer. Cancer Discov. 8, 1087–1095 (2018).

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Jones, M. R. et al. NRG1 gene fusions are recurrent, clinically actionable gene rearrangements in KRAS wild-type pancreatic ductal adenocarcinoma. Clin. Cancer Res. 25, 4674–4681 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Gil, J. & Peters, G. Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat. Rev. Mol. Cell Biol. 7, 667–677 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78.

    Kim, W. Y. & Sharpless, N. E. The regulation of INK4/ARF in cancer and aging. Cell 127, 265–275 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  79. 79.

    Schutte, M. et al. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res. 57, 3126–3130 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Yachida, S. et al. Clinical significance of the genetic landscape of pancreatic cancer and implications for identification of potential long-term survivors. Clin. Cancer Res. 18, 6339–6347 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Klein, W. M., Hruban, R. H., Klein-Szanto, A. J. P. & Wilentz, R. E. Direct correlation between proliferative activity and dysplasia in pancreatic intraepithelial neoplasia (panIN): additional evidence for a recently proposed model of progression. Mod. Pathol. 15, 441–447 (2002).

    PubMed  Article  PubMed Central  Google Scholar 

  82. 82.

    Yachida, S. et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114–1117 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Hosoda, W. et al. Genetic analyses of isolated high-grade pancreatic intraepithelial neoplasia (HG-PanIN) reveal paucity of alterations in TP53 and SMAD4. J. Pathol. 242, 16–23 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Makohon-Moore, A. P. et al. Precancerous neoplastic cells can move through the pancreatic ductal system. Nature 561, 201–205 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Vogelstein, B., Lane, D. & Levine, A. J. Surfing the p53 network. Nature 408, 307–310 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  86. 86.

    Morton, J. P. et al. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc. Natl Acad. Sci. USA 107, 246–251 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  87. 87.

    Morton, J. P., Klimstra, D. S., Mongeau, M. E. & Lewis, B. C. Trp53 deletion stimulates the formation of metastatic pancreatic tumors. Am. J. Pathol. 172, 1081–1087 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Hayashi, A. et al. Genetic and clinical correlates of entosis in pancreatic ductal adenocarcinoma. Mod. Pathol. 33, 1822–1831 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Florey, O., Kim, S. & Overholtzer, M. Entosis: cell-in-cell formation that kills through entotic cell death. Curr. Mol. Med. 15, 861–866 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. 90.

    Shu, Z., Row, S. & Deng, W. M. Endoreplication: the good, the bad, and the ugly. Trends Cell Biol. 28, 465–474 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    David, C. J. & Massagué, J. Contextual determinants of TGFβ action in development, immunity and cancer. Nat. Rev. Mol. Cell Biol. 19, 419–435 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

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

    CAS  PubMed  Article  Google Scholar 

  93. 93.

    Togashi, Y. et al. Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer. Mol. Cancer 13, 126 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  94. 94.

    Su, G. H. et al. ACVR1B (ALK4, activin receptor type 1B) gene mutations in pancreatic carcinoma. Proc. Natl Acad. Sci. USA 98, 3254–3257 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  95. 95.

    Hempen, P. M. et al. Evidence of selection for clones having genetic inactivation of the activin A type II receptor (ACVR2) gene in gastrointestinal cancers. Cancer Res. 63, 994–999 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Ryu, B. & Kern, S. E. The essential similarity of TGFβ and activin receptor transcriptional responses in cancer cells. Cancer Biol. Ther. 2, 164–170 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  97. 97.

    Massagué, J. TGFβ in cancer. Cell 134, 215–230 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  98. 98.

    Huang, W. et al. Pattern of invasion in human pancreatic cancer organoids is associated with loss of SMAD4 and clinical outcome. Cancer Res. 80, 2804–2817 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Aung, K. L. et al. Genomics-driven precision medicine for advanced pancreatic cancer: early results from the COMPASS trial. Clin. Cancer Res. 24, 1344–1354 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  100. 100.

    O’Kane, G. M. et al. GATA6 expression distinguishes classical and basal-like subtypes in advanced pancreatic cancer. Clin. Cancer Res. 26, 4901–4910 (2020).

    PubMed  Article  Google Scholar 

  101. 101.

    Centore, R. C., Sandoval, G. J., Mendes Soares, L. M., Kadoch, C. & Chan, H. M. Mammalian SWI/SNF chromatin remodeling complexes: emerging mechanisms and therapeutic strategies. Trends Genet. 36, 936–950 (2020).

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Wang, L. & Shilatifard, A. UTX mutations in human cancer. Cancer Cell 35, 168–176 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 103.

    Shain, A. H. et al. Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer. Proc. Natl Acad. Sci. USA 109, E252–E259 (2012).

    CAS  Article  Google Scholar 

  104. 104.

    Clapier, C. R., Iwasa, J., Cairns, B. R. & Peterson, C. L. Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes. Nat. Rev. Mol. Cell Biol. 18, 407–422 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105.

    Rafati, H. et al. Repressive LTR nucleosome positioning by the BAF complex is required for HIV latency. PLoS Biol. 9, e1001206 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Sze, C. C. & Shilatifard, A. MLL3/MLL4/COMPASS family on epigenetic regulation of enhancer function and cancer. Cold Spring Harb. Perspect. Med. 6, a026427 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  107. 107.

    Somerville, T. D. D. et al. TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma. Cell Rep. 25, 1741–1755 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. 108.

    Somerville, T. D. et al. Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation. eLife 9, e53381 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

    Roe, J. S. et al. Enhancer reprogramming promotes pancreatic cancer metastasis. Cell 170, 875–888 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Andricovich, J. et al. Loss of KDM6A activates super-enhancers to induce gender-specific squamous-like pancreatic cancer and confers sensitivity to BET inhibitors. Cancer Cell 33, 512–526 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Turan, S. & Bastepe, M. GNAS spectrum of disorders. Curr. Osteoporos. Rep. 13, 146–158 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Dumitrescu, C. E. & Collins, M. T. McCune-Albright syndrome. Orphanet J. Rare Dis. 3, 12 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Wu, J. et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci. Transl Med. 3, 2ra66 (2011).

    Article  CAS  Google Scholar 

  114. 114.

    Hao, H. X., Jiang, X. & Cong, F. Control of Wnt receptor turnover by R-spondin-ZNRF3/RNF43 signaling module and its dysregulation in cancer. Cancers 8, 54 (2016).

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  115. 115.

    Hao, H. X. et al. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature 485, 195–202 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  116. 116.

    Springer, S. et al. A combination of molecular markers and clinical features improve the classification of pancreatic cysts. Gastroenterology 149, 1501–1510 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Bradley, C. A. Guiding pancreatic cyst management. Nat. Rev. Gastroenterol. Hepatol. 16, 582–583 (2019).

    CAS  PubMed  Article  Google Scholar 

  118. 118.

    Kwei, K. A. et al. Genomic profiling identifies GATA6 as a candidate oncogene amplified in pancreatobiliary cancer. PLoS Genet. 4, e1000081 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  119. 119.

    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).

    CAS  PubMed  Article  Google Scholar 

  120. 120.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Dang, C. V. MYC on the path to cancer. Cell 149, 22–35 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Baker, N. E. Emerging mechanisms of cell competition. Nat. Rev. Genet. 21, 683–697 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  123. 123.

    Heger, P., Zheng, W., Rottmann, A., Panfilio, K. A. & Wiehe, T. The genetic factors of bilaterian evolution. eLife 9, e45530 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. 124.

    Ballard, M. S. et al. Mammary stem cell self-renewal is regulated by Slit2/Robo1 signaling through SNAI1 and mINSC. Cell Rep. 13, 290–301 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    Zhang, J. et al. Disease-causing mutations in SF3B1 alter splicing by disrupting interaction with SUGP1. Mol. Cell 76, 82–95 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Jung, J. H., Lee, H., Zeng, S. X. & Lu, H. RBM10, a new regulator of p53. Cells 9, 2107 (2020).

    CAS  PubMed Central  Article  Google Scholar 

  127. 127.

    Matsubayashi, H. et al. Familial pancreatic cancer: concept, management and issues. World J. Gastroenterol. 23, 935–948 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  128. 128.

    Klein, A. P. Identifying people at a high risk of developing pancreatic cancer. Nat. Rev. Cancer 3, 66–74 (2013).

    Article  CAS  Google Scholar 

  129. 129.

    Roberts, N. J. et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2, 41–46 (2012).

    CAS  PubMed  Article  Google Scholar 

  130. 130.

    Roberts, N. J. et al. Whole genome sequencing defines the genetic heterogeneity of familial pancreatic cancer. Cancer Discov. 6, 166–175 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  131. 131.

    Shindo, K. et al. Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma. J. Clin. Oncol. 35, 3382–3390 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Mizukami, K. et al. Genetic characterization of pancreatic cancer patients and prediction of carrier status of germline pathogenic variants in cancer-predisposing genes. EBioMedicine 60, 103033 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    Lowery, M. A. et al. Prospective evaluation of germline alterations in patients with exocrine pancreatic neoplasms. J. Natl Cancer Inst. 110, 1067–3390 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  134. 134.

    Lord, C. J. & Ashworth, A. BRCAness revisited. Nat. Rev. Cancer 16, 110–120 (2016).

    CAS  PubMed  Article  Google Scholar 

  135. 135.

    Kleeff, J. et al. Chronic pancreatitis. Nat. Rev. Dis. Prim. 3, 17060 (2017).

    PubMed  Article  Google Scholar 

  136. 136.

    Shelton, C. A., Umapathy, C., Stello, K., Yadav, D. & Whitcomb, D. C. Hereditary pancreatitis in the United States: survival and rates of pancreatic cancer. Am. J. Gastroenterol. 113, 1376–1384 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  137. 137.

    Tamura, K. et al. Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer. Proc. Natl Acad. Sci. USA 115, 4767–4772 (2018).

    CAS  PubMed  Article  Google Scholar 

  138. 138.

    Tomasetti, C., Vogelstein, B. & Parmigiani, G. Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation. Proc. Natl Acad. Sci. USA 110, 1999–2004 (2013).

    CAS  PubMed  Article  Google Scholar 

  139. 139.

    Yan, L. et al. Molecular analysis to detect pancreatic ductal adenocarcinoma in high-risk groups. Gastroenterology 128, 2124–2130 (2005).

    CAS  PubMed  Article  Google Scholar 

  140. 140.

    Löhr, M. et al. P53 and K-ras mutations in pancreatic juice samples from patients with chronic pancreatitis. Gastrointest. Endosc. 53, 734–743 (2001).

    PubMed  Article  Google Scholar 

  141. 141.

    Martincorena, I. et al. Somatic mutant clones colonize the human esophagus with age. Science 362, 911–917 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    Martincorena, I. et al. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. 143.

    Guerra, C. et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11, 291–302 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  144. 144.

    Kandikattu, H. K., Venkateshaiah, S. U. & Mishra, A. Chronic pancreatitis and the development of pancreatic cancer. Endocrine, Metab. Immune Disord. Drug Targets 20, 1182–1210 (2020).

    CAS  Article  Google Scholar 

  145. 145.

    Wang, L. et al. ATDC is required for the initiation of KRAS-induced pancreatic tumorigenesis. Genes Dev. 33, 641–655 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146.

    Ling, J. et al. Kras G12D-induced IKK2/β/NF-κB activation by IL-1α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell 21, 105–120 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. 147.

    Kopp, J. L. et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 22, 737–750 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. 148.

    Lee, A. Y. L. et al. Cell of origin affects tumour development and phenotype in pancreatic ductal adenocarcinoma. Gut 68, 487–498 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  149. 149.

    Shi, C. et al. Differential cell susceptibilities to KrasG12D in the setting of obstructive chronic pancreatitis. Cell. Mol. Gastroenterol. Hepatol. 8, 579–594 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  150. 150.

    Pylayeva-Gupta, Y. et al. IL35-producing B cells promote the development of pancreatic neoplasia. Cancer Discov. 6, 247–255 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  151. 151.

    Ardito, C. M. et al. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 22, 304–317 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. 152.

    Hermann, P. C. et al. Nicotine promotes initiation and progression of KRAS-induced pancreatic cancer via Gata6-dependent dedifferentiation of acinar cells in mice. Gastroenterology 147, 1119–1133 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  153. 153.

    McAllister, F. et al. Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. Cancer Cell 25, 621–637 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. 154.

    Luo, Y. et al. Oncogenic KRAS reduces expression of FGF21 in acinar cells to promote pancreatic tumorigenesis in mice on a high-fat diet. Gastroenterology 157, 1413–1428 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. 155.

    Daniluk, J. et al. An NF-κB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice. J. Clin. Invest. 122, 1519–1528 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  156. 156.

    Lahouel, K. et al. Revisiting the tumorigenesis timeline with a data-driven generative model. Proc. Natl Acad. Sci. USA 117, 857–864 (2020).

    CAS  PubMed  Article  Google Scholar 

  157. 157.

    Matsuda, Y. et al. The prevalence and clinicopathological characteristics of high-grade pancreatic intraepithelial neoplasia autopsy study evaluating the entire pancreatic parenchyma. Pancreas 46, 658–664 (2017).

    PubMed  Article  Google Scholar 

  158. 158.

    Wangsa, D. et al. Near-tetraploid cancer cells show chromosome instability triggered by replication stress and exhibit enhanced invasiveness. FASEB J. 32, 3502–3517 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. 159.

    Van de Peer, Y., Mizrachi, E. & Marchal, K. The evolutionary significance of polyploidy. Nat. Rev. Genet. 18, 411–424 (2017).

    Article  CAS  Google Scholar 

  160. 160.

    Stromnes, I. M., DelGiorno, K. E., Greenberg, P. D. & Hingorani, S. R. Stromal re-engineering to treat pancreas cancer. Carcinogenesis 35, 1451–1460 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. 161.

    Gurtner, G. C., Werner, S., Barrandon, Y. & Longaker, M. T. Wound repair and regeneration. Nature 35, 314–321 (2008).

    Article  CAS  Google Scholar 

  162. 162.

    Dvorak, H. F. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. 163.

    Hutchings, D. et al. Cancerization of the pancreatic ducts: demonstration of a common and under-recognized process using immunolabeling of paired duct lesions and invasive pancreatic ductal adenocarcinoma for p53 and Smad4 expression. Am. J. Surg. Pathol. 42, 1556–1561 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  164. 164.

    Makohon-Moore, A. P. et al. Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. Nat. Genet. 49, 358–366 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  165. 165.

    Reiter, J. G. et al. An analysis of genetic heterogeneity in untreated cancers. Nat. Rev. Cancer 19, 639–650 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  166. 166.

    Bechard, M. E. et al. Pancreatic cancers suppress negative feedback of glucose transport to reprogram chromatin for metastasis. Nat. Commun. 11, 4055 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  167. 167.

    McDonald, O. G. et al. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat. Genet. 49, 367–376 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  168. 168.

    Pishvaian, M. J. et al. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. Lancet Oncol. 21, 508–518 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. 169.

    O’Reilly, E. M. et al. Randomized, multicenter, phase II trial of gemcitabine and cisplatin with or without veliparib in patients with pancreas adenocarcinoma and a germline BRCA/PALB2 mutation. J. Clin. Oncol. 38, 1378–1388 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  170. 170.

    Golan, T. et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N. Engl. J. Med. 381, 317–327 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  171. 171.

    Hong, D. S. et al. KRAS G12C inhibition with sotorasib in advanced solid tumors. N. Engl. J. Med. 383, 1207–1217 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  172. 172.

    Lito, P., Solomon, M., Li, L. S., Hansen, R. & Rosen, N. Cancer therapeutics: allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science 351, 604–608 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. 173.

    Janes, M. R. et al. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell 172, 578–589 (2018).

    CAS  PubMed  Article  Google Scholar 

  174. 174.

    Chou, A. et al. Clinical and molecular characterization of HER2 amplified-pancreatic cancer. Genome Med. 5, 1–11 (2013).

    Article  CAS  Google Scholar 

  175. 175.

    Wagner, A. D., Özdemir, B. C. & Rüschoff, J. Human epidermal growth factor receptor 2-positive digestive tumors. Curr. Opin. Oncol. 31, 354–361 (2019).

    CAS  PubMed  Article  Google Scholar 

  176. 176.

    Chaturvedi, S., Hoffman, R. M. & Bertino, J. R. Exploiting methionine restriction for cancer treatment. Biochem. Pharmacol. 154, 170–173 (2018).

    CAS  PubMed  Article  Google Scholar 

  177. 177.

    Marjon, K. et al. MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis. Cell Rep. 15, 574–587 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  178. 178.

    Basturk, O. et al. A revised classification system and recommendations from the Baltimore Consensus Meeting for neoplastic precursor lesions in the pancreas. Am. J. Surg. Pathol. 39, 1730–1741 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  179. 179.

    Yachida, S. & Iacobuzio-Donahue, C. A. Evolution and dynamics of pancreatic cancer progression. Oncogene 32, 5253–5260 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  180. 180.

    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 

  181. 181.

    Matthaei, H., Schulick, R. D., Hruban, R. H. & Maitra, A. Cystic precursors to invasive pancreatic cancer. Nat. Rev. Gastroenterol. Hepatol. 8, 141–150 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  182. 182.

    Collisson, E. A., Bailey, P., Chang, D. K. & Biankin, A. V. Molecular subtypes of pancreatic cancer. Nat. Rev. Gastroenterol. Hepatol. 16, 207–220 (2019).

    PubMed  Article  Google Scholar 

  183. 183.

    Juiz, N. et al. Basal-like and classical cells coexist in pancreatic cancer revealed by single-cell analysis on biopsy-derived pancreatic cancer organoids from the classical subtype. FASEB J. 34, 12214–12228 (2020).

    CAS  PubMed  Article  Google Scholar 

  184. 184.

    Miyabayashi, K. et al. Intraductal transplantation models of human pancreatic ductal adenocarcinoma reveal progressive transition of molecular subtypes. Cancer Discov. 10, 1566–1589 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  185. 185.

    Nicolle, R. et al. Establishment of a pancreatic adenocarcinoma molecular gradient (PAMG) that predicts the clinical outcome of pancreatic cancer. EBioMedicine 57, 102858 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

C.A.I.-D. and A.H. contributed to researching data for the article, made a substantial contribution to discussion of content, and wrote and reviewed/edited the manuscript before submission. J.H. wrote and reviewed/edited the manuscript before submission.

Corresponding author

Correspondence to Christine A. Iacobuzio-Donahue.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Gastroenterology & Hepatology thanks A. Biankin and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hayashi, A., Hong, J. & Iacobuzio-Donahue, C.A. The pancreatic cancer genome revisited. Nat Rev Gastroenterol Hepatol (2021). https://doi.org/10.1038/s41575-021-00463-z

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing