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Molecular Subtyping of Pancreatic Cancer

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Textbook of Pancreatic Cancer

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Abstract

Pancreatic cancer has become the third leading cause of cancer related death, with little improvement in outcomes despite decades of research. Cancers with similar morphological appearance such as pancreatic cancer often have dramatically different clinical features, with variable therapeutic response and a spectrum of survival outcomes.

Accumulating molecular data are defining subgroups of patients with pancreatic cancer with distinct biology and potential subtype-specific therapeutic vulnerabilities, providing an opportunity to define a de novo clinically applicable molecular taxonomy.

This chapter summarizes current knowledge concerning the molecular subtyping performed in pancreatic cancer and explores rationale for using a molecular taxonomy to guide therapeutic development, personalised therapy and selection for surgery, with the overall goal of improving outcomes for this disease.

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References

  1. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503–11.

    Article  CAS  PubMed  Google Scholar 

  2. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52.

    Article  CAS  PubMed  Google Scholar 

  3. Collisson EA, Bailey P, Chang DK, Biankin AV. Molecular subtypes of pancreatic cancer. Nat Rev Gastroenterol Hepatol. 2019;16(4):207–20.

    Article  PubMed  Google Scholar 

  4. Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531(7592):47–52.

    Article  CAS  PubMed  Google Scholar 

  5. Collisson EA, Sadanandam A, Olson P, Gibb WJ, Truitt M, Gu S, et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med. 2011;17(4):500–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Moffitt RA, Marayati R, Flate EL, Volmar KE, Loeza SG, Hoadley KA, et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet. 2015;47(10):1168–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Humphris JL, Patch AM, Nones K, Bailey PJ, Johns AL, McKay S, et al. Hypermutation in pancreatic cancer. Gastroenterology. 2017;152(1):68–74.e2.

    Article  CAS  PubMed  Google Scholar 

  8. Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518(7540):495–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Biankin AV, Maitra A. Subtyping pancreatic cancer. Cancer Cell. 2015;28(4):411–3.

    Article  CAS  PubMed  Google Scholar 

  10. Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491(7424):399–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hoadley KA, Yau C, Wolf DM, Cherniack AD, Tamborero D, Ng S, et al. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell. 2014;158(4):929–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Witkiewicz AK, McMillan EA, Balaji U, Baek G, Lin WC, Mansour J, et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun. 2015;6:6744.

    Article  CAS  PubMed  Google Scholar 

  13. Hayashi A, Fan J, Chen R, Ho Y-j, Makohon-Moore AP, Lecomte N, et al. A unifying paradigm for transcriptional heterogeneity and squamous features in pancreatic ductal adenocarcinoma. Nat Cancer. 2020;1(1):59–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  15. Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST, et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature. 2015;527(7579):472–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015;527(7579):525–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Maurer C, Holmstrom SR, He J, Laise P, Su T, Ahmed A, et al. Experimental microdissection enables functional harmonisation of pancreatic cancer subtypes. Gut. 2019;68:953–4.

    Article  Google Scholar 

  18. Candido JB, Morton JP, Bailey P, Campbell AD, Karim SA, Jamieson T, et al. CSF1R(+) macrophages sustain pancreatic tumor growth through T cell suppression and maintenance of key gene programs that define the squamous subtype. Cell Rep. 2018;23(5):1448–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Puleo F, Nicolle R, Blum Y, Cros J, Marisa L, Demetter P, et al. Stratification of pancreatic ductal adenocarcinomas based on tumor and microenvironment features. Gastroenterology. 2018;155(6):1999–2013.e3.

    Article  PubMed  Google Scholar 

  20. Zhang Y, Velez-Delgado A, Mathew E, Li D, Mendez FM, Flannagan K, et al. Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer. Gut. 2017;66(1):124–36.

    Article  CAS  PubMed  Google Scholar 

  21. Jiang H, Hegde S, Knolhoff BL, Zhu Y, Herndon JM, Meyer MA, et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med. 2016;22(8):851–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Xu Z, Vonlaufen A, Phillips PA, Fiala-Beer E, Zhang X, Yang L, et al. Role of pancreatic stellate cells in pancreatic cancer metastasis. Am J Pathol. 2010;177(5):2585–96.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ikushima H, Miyazono K. TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer. 2010;10(6):415–24.

    Article  CAS  PubMed  Google Scholar 

  24. Martens S, Lefesvre P, Nicolle R, Biankin AV, Puleo F, Van Laethem JL, et al. Different shades of pancreatic ductal adenocarcinoma, different paths towards precision therapeutic applications. Ann Oncol. 2019;30(9):1428–36.

    Article  CAS  PubMed  Google Scholar 

  25. The Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell. 2017;32(2):185–203.e13.

    Article  PubMed Central  Google Scholar 

  26. Noll EM, Eisen C, Stenzinger A, Espinet E, Muckenhuber A, Klein C, et al. CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma. Nat Med. 2016;22(3):278–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Knudsen ES, Balaji U, Mannakee B, Vail P, Eslinger C, Moxom C, et al. Pancreatic cancer cell lines as patient-derived avatars: genetic characterisation and functional utility. Gut. 2018;67(3):508–20.

    Article  CAS  PubMed  Google Scholar 

  28. Steele CW, Karim SA, Leach JD, Bailey P, Upstill-Goddard R, Rishi L, et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell. 2016;29(6):832–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kalimuthu SN, Wilson GW, Grant RC, Seto M, O’Kane G, Vajpeyi R, et al. Morphological classification of pancreatic ductal adenocarcinoma that predicts molecular subtypes and correlates with clinical outcome. Gut. 2020;69(2):317–28.

    Article  Google Scholar 

  30. Aguirre AJ, Nowak JA, Camarda ND, Moffitt RA, Ghazani AA, Hazar-Rethinam M, et al. Real-time genomic characterization of advanced pancreatic cancer to enable precision medicine. Cancer Discov. 2018; https://doi.org/10.1158/2159-8290.CD-18-0275.

  31. Karasinska JM, Topham JT, Kalloger SE, Jang GH, Denroche RE, Culibrk L, et al. Altered gene expression along the glycolysis-cholesterol synthesis axis is associated with outcome in pancreatic cancer. Clin Cancer Res. 2020;26(1):135–46.

    Article  CAS  PubMed  Google Scholar 

  32. Kuzu OF, Noory MA, Robertson GP. The role of cholesterol in cancer. Cancer Res. 2016;76(8):2063–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Baek G, Tse YF, Hu Z, Cox D, Buboltz N, McCue P, et al. MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies. Cell Rep. 2014;9(6):2233–49.

    Article  CAS  PubMed  Google Scholar 

  34. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008;7(1):11–20.

    Article  CAS  PubMed  Google Scholar 

  35. Chan-Seng-Yue M, Kim JC, Wilson GW, Ng K, Figueroa EF, O’Kane GM, et al. Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution. Nat Genet. 2020;2(2):231–40.

    Article  Google Scholar 

  36. Dreyer SB, Jamieson NB, Upstill-Goddard R, Bailey PJ, McKay CJ, Australian Pancreatic Cancer Genome Initiative, et al. Defining the molecular pathology of pancreatic body and tail adenocarcinoma. Br J Surg. 2018;105(2):e183–91.

    Article  CAS  PubMed  Google Scholar 

  37. Mackay TM, van Erning FN, van der Geest LGM, de Groot JWB, Haj Mohammad N, Lemmens VE, et al. Association between primary origin (head, body and tail) of metastasised pancreatic ductal adenocarcinoma and oncologic outcome: a population-based analysis. Eur J Cancer. 2018;106:99–105.

    Article  PubMed  Google Scholar 

  38. Artinyan A, Soriano PA, Prendergast C, Low T, Ellenhorn JD, Kim J. The anatomic location of pancreatic cancer is a prognostic factor for survival. HPB (Oxford). 2008;10(5):371–6.

    Article  Google Scholar 

  39. Sohn TA, Yeo CJ, Cameron JL, Koniaris L, Kaushal S, Abrams RA, et al. Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg. 2000;4(6):567–79.

    Article  CAS  PubMed  Google Scholar 

  40. Brennan MF, Moccia RD, Klimstra D. Management of adenocarcinoma of the body and tail of the pancreas. Ann Surg. 1996;223(5):506–11; discussion 11–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Notta F, Chan-Seng-Yue M, Lemire M, Li Y, Wilson GW, Connor AA, et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature. 2016;538(7625):378–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, et al. Tracking the evolution of non-small-cell lung cancer. N Engl J Med. 2017;376(22):2109–21.

    Article  CAS  PubMed  Google Scholar 

  43. Birnbaum DJ, Finetti P, Birnbaum D, Mamessier E, Bertucci F. Validation and comparison of the molecular classifications of pancreatic carcinomas. Mol Cancer. 2017;16(1):168.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Aung KL, Fischer SE, Denroche RE, Jang GH, Dodd A, Creighton S, et al. Genomics-driven precision medicine for advanced pancreatic cancer: early results from the COMPASS trial. Clin Cancer Res. 2018;24(6):1344–54.

    Article  CAS  PubMed  Google Scholar 

  45. Brennan MF, Kattan MW, Klimstra D, Conlon K. Prognostic nomogram for patients undergoing resection for adenocarcinoma of the pancreas. Ann Surg. 2004;240(2):293–8.

    Article  PubMed  PubMed Central  Google Scholar 

  46. van Roessel S, Strijker M, Steyerberg EW, Groen JV, Mieog JS, Groot VP, et al. International validation and update of the Amsterdam model for prediction of survival after pancreatoduodenectomy for pancreatic cancer. Eur J Surg Oncol. 2020;46(5):796–803.

    Article  PubMed  Google Scholar 

  47. Strijker M, Chen JW, Mungroop TH, Jamieson NB, van Eijck CH, Steyerberg EW, et al. Systematic review of clinical prediction models for survival after surgery for resectable pancreatic cancer. Br J Surg. 2019;106(4):342–54.

    Article  CAS  PubMed  Google Scholar 

  48. Biankin AV, Kench JG, Colvin EK, Segara D, Scarlett CJ, Nguyen NQ, et al. Expression of S100A2 calcium-binding protein predicts response to pancreatectomy for pancreatic cancer. Gastroenterology. 2009;137(2):558–68. 68.e1–11.

    Article  PubMed  Google Scholar 

  49. Dreyer SB, Pinese M, Jamieson NB, Scarlett CJ, Colvin EK, Pajic M, et al. Precision oncology in surgery: patient selection for operable pancreatic cancer. Ann Surg. 2018; https://doi.org/10.1097/SLA.0000000000003143.

  50. Fei F, Qu J, Zhang M, Li Y, Zhang S. S100A4 in cancer progression and metastasis: a systematic review. Oncotarget. 2017;8(42):73219–39.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Dreyer SB, Jamieson NB, Morton JP, Sansom OJ, Biankin AV, Chang DK. Pancreatic cancer: from genome discovery to PRECISION-Panc. Clin Oncol (R Coll Radiol). 2020;32(1):5–8.

    Article  CAS  Google Scholar 

  52. Dreyer SB, Jamieson NB, Cooke SL, Valle JW, McKay CJ, Biankin AV, et al. PRECISION-Panc: the next generation therapeutic development platform for pancreatic cancer. Clin Oncol (R Coll Radiol). 2020;32(1):1–4.

    Article  CAS  Google Scholar 

  53. Dreyer SB, Jamieson NB, Evers L, Duthie F, Cooke S, Marshall J, et al. Feasibility and clinical utility of endoscopic ultrasound guided biopsy of pancreatic cancer for next-generation molecular profiling. Chin Clin Oncol. 2019;8(2):16.

    Article  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK

    Stephan B. Dreyer, Nigel B. Jamieson, David K. Chang & Andrew V. Biankin

  2. University Department of Surgery, Glasgow Royal Infirmary, University of Glasgow, Glasgow, UK

    Stephan B. Dreyer, Nigel B. Jamieson, David K. Chang & Andrew V. Biankin

  3. West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK

    Stephan B. Dreyer, Nigel B. Jamieson, David K. Chang & Andrew V. Biankin

Authors
  1. Stephan B. Dreyer
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  2. Nigel B. Jamieson
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  3. David K. Chang
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  4. Andrew V. Biankin
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Correspondence to Stephan B. Dreyer .

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Editors and Affiliations

  1. Stavanger University Hospital, The University of Bergen, Bergen, Norway

    Kjetil Søreide

  2. Chirurgie (VTT), Innsbruck Medical University, Innsbruck, Tirol, Austria

    Stefan Stättner

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Dreyer, S.B., Jamieson, N.B., Chang, D.K., Biankin, A.V. (2021). Molecular Subtyping of Pancreatic Cancer. In: Søreide, K., Stättner, S. (eds) Textbook of Pancreatic Cancer. Springer, Cham. https://doi.org/10.1007/978-3-030-53786-9_21

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  • DOI: https://doi.org/10.1007/978-3-030-53786-9_21

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