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Pancreatic Cancer: Genetic Conditions and Epigenetic Alterations

  • Review Article
  • Published:
Journal of Gastrointestinal Surgery

Abstract

Background

Pancreatic cancer is a lethal proliferative disease driven by multiple genetic and epigenetic alterations. Microarrays and omics-based sequencing techniques are potent tools that have facilitated a broader understanding of the complex biological processes that drive pancreatic ductal adenocarcinoma (PDAC). In turn, these tools have resulted in the identification of novel disease markers, prognostic factors, and therapeutic targets. Herein, we provide a review of the genetic and epigenetic drivers of PDAC relative to recent discoveries that impact patient management.

Methods

A review of PubMed, Medline, Clinical Key, and Index Medicus was conducted to identify literature from January 1995 to July 2022 that is related to PDAC genetics and epigenetics. Articles in Spanish and English were considered during selection.

Results

Molecular, genetic, and epigenetic diagnostic tools, novel biomarkers, and promising therapeutic targets have emerged in the treatment of pancreatic cancer. The implementation of microarray technology and application of large omics-based data repositories have facilitated recent discoveries in PDAC. Multiple molecular analyses based on RNA interference have been instrumental in the identification of novel therapeutic targets for patients with PDAC. Moreover, microarrays and next-generation omics-based discoveries have been instrumental in the characterization of subtypes of pancreatic cancer, thereby improving prognostication and refining patient selection for available targeted therapies.

Conclusion

Advances in molecular biology, genetics, and epigenetics have ushered in a new era of discovery in the pathobiology of PDAC. Current efforts are underway to translate these findings into clinical tools and therapies to improve outcomes in patients with PDAC.

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References

  1. Porta, M. et al. Exocrine pancreatic cancer: symptoms at presentation and their relation to tumour site and stage. Clin. Transl. Oncol. 7, 189–97 (2005).

    Article  PubMed  Google Scholar 

  2. Stark, A. et al. Long-term survival in patients with pancreatic ductal adenocarcinoma. Surgery. 159 (6) 1520-1527 (2016)

    Article  PubMed  Google Scholar 

  3. van Vliet, J., Oates, N. A. & Whitelaw, E. Epigenetic mechanisms in the context of complex diseases. Cell. Mol. Life Sci. 64, 1531–8 (2007).

    Article  PubMed  Google Scholar 

  4. Feinberg, A. P., Ohlsson, R. & Henikoff, S. The epigenetic progenitor origin of human cancer. Nat. Rev. Genet. 7, 21–33 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Venter, J. C. et al. The Sequence of the Human Genome. Science (80-. ). 291, 1304–1351 (2001).

  6. Schena, M., Shalon, D., Davis, R. W. & Brown, P. O. Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270, 467–70 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Kresse, S. H. et al. DNA copy number changes in high-grade malignant peripheral nerve sheath tumors by array CGH. Mol. Cancer 7, 48 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Stears, R. L., Martinsky, T. & Schena, M. Trends in microarray analysis. Nat. Med. 9, 140–5 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Singhi AD, Wood LD. Early detection of pancreatic cancer using DNA-based molecular approaches. Nat Rev Gastroenterol Hepatol. Jul;18(7):457–468 (2021)

  10. Wang S, et al. The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives. Signal Transduct Target Ther. Jul 5;6(1):249 (2021)

  11. Ho, J. et al. Translational genomics in pancreatic ductal adenocarcinoma: A review with re-analysis of TCGA dataset. Semin. Cancer Biol. 55, 70–77 (2019).

    Article  CAS  PubMed  Google Scholar 

  12. Wu H. et al Advances in biomarkers and techniques for pancreatic cancer diagnosis. Cancer Cell Int. Jun 28;22(1):220. (2022)

  13. Hruban, R. H., Iacobuzio-Donahue, C., Wilentz, R. E., Goggins, M. & Kern, S. E. Molecular pathology of pancreatic cancer. Cancer J. 7, 251–8 (2001).

    CAS  PubMed  Google Scholar 

  14. Iacobuzio-Donahue, C. A. et al. Exploration of Global Gene Expression Patterns in Pancreatic Adenocarcinoma Using cDNA Microarrays. Am. J. Pathol. 162, 1151–1162 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Grützmann, R. et al. Meta-analysis of microarray data on pancreatic cancer defines a set of commonly dysregulated genes. Oncogene 24, 5079–88 (2005).

    Article  PubMed  Google Scholar 

  16. Lowe, A. W. et al. Gene expression patterns in pancreatic tumors, cells and tissues. PLoS One 2, e323 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Giulietti, M., Occhipinti, G., Principato, G. & Piva, F. Weighted gene co-expression network analysis reveals key genes involved in pancreatic ductal adenocarcinoma development. Cell. Oncol. 39, 379–388 (2016).

    Article  CAS  Google Scholar 

  18. Michl, P., Ripka, S., Gress, T. & Buchholz, M. Screening Technologies for Target Identification in Pancreatic Cancer. Cancers (Basel). 3, 79–90 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Di Marco, M. et al. Characterization of pancreatic ductal adenocarcinoma using whole transcriptome sequencing and copy number analysis by single-nucleotide polymorphism array. Mol. Med. Rep. 12, 7479–84 (2015).

    Article  PubMed  Google Scholar 

  20. Shen, Q. et al. Possible Molecular Markers for the Diagnosis of Pancreatic Ductal Adenocarcinoma. Med. Sci. Monit. 24, 2368–2376 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Chang, V. H. S. et al. Krüppel-like factor 10 expression as a prognostic indicator for pancreatic adenocarcinoma. Am. J. Pathol. 181, 423–30 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. C, Dutruel F, Bergmann I, Rooman M, Zucknick D, Weichenhan L, Geiselhart T, Kaffenberger P S, Rachakonda A, Bauer N, Giese C, Hong H, Xie J F, Costello J, Hoheisel R, Kumar M, Rehli P, Schirmacher J, Werner C, Plass O, Popanda P, Schmezer (2014) Early epigenetic downregulation of WNK2 kinase during pancreatic ductal adenocarcinoma development. Oncogene 33(26) 3401-3410 https://doi.org/10.1038/onc.2013.312

  23. Rogers, C. D. et al. Differentiating pancreatic lesions by microarray and QPCR analysis of pancreatic juice RNAs. Cancer Biol. Ther. 5, 1383–9 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Singh K. et al. Kras mutation rate precisely orchestrates ductal derived pancreatic intraepithelial neoplasia and pancreatic cancer. Lab Invest. Feb;101(2):177–192. (2021)

  25. Qian Y. et al. Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma. J Hematol Oncol. Oct 2;13(1):130. (2020)

  26. Sharma, S., Kelly, T. K. & Jones, P. A. Epigenetics in cancer. Carcinogenesis 31, 27–36 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Eissa, Maryam A L et al. “Promoter methylation of ADAMTS1 and BNC1 as potential biomarkers for early detection of pancreatic cancer in blood.” Clinical epigenetics vol. 11,1 59. 5 Apr. (2019)

  28. Matsubayashi, H. et al. Methylation of Cyclin D2 Is Observed Frequently in Pancreatic Cancer but Is Also an Age-related Phenomenon in Gastrointestinal Tissues. Clin. Cancer Res. 9, (2003).

  29. T, U. et al. Aberrant CpG island methylation in cancer cell lines arises in the primary cancers from which they were derived. Oncogene 21, 2114–2117 (2002).

  30. N, F. et al. Diagnosing pancreatic cancer using methylation specific PCR analysis of pancreatic juice. Cancer Biol. Ther. 2, 78–83 (2003).

  31. Dutruel, C. et al. Early epigenetic downregulation of WNK2 kinase during pancreatic ductal adenocarcinoma development. Oncogene 33, 3401–3410 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Nodin, B., Hedner, C., Uhlén, M. & Jirström, K. Expression of the global regulator SATB1 is an independent factor of poor prognosis in high grade epithelial ovarian cancer. J. Ovarian Res. 5, 24 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ali, S., Saleh, H., Sethi, S., Sarkar, F. H. & Philip, P. A. MicroRNA profiling of diagnostic needle aspirates from patients with pancreatic cancer. Br. J. Cancer 107, 1354–60 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Anting Liu, Carlsen Maiken Thyregod, Joergensen Steen, Knudsen Ove B. Schaffalitzky, de Muckadell Niels H. H., Heegaard (2013) Cell-Free Plasma MicroRNA in Pancreatic Ductal Adenocarcinoma and Disease Controls. Pancreas 42(7) 1107-1113 https://doi.org/10.1097/MPA.0b013e318296bb34

  35. Amy L., Collins Sylwia, Wojcik James, Liu Wendy L., Frankel Hansjuerg, Alder Lianbo, Yu Thomas D., Schmittgen Carlo M., Croce Mark, Bloomston (2014) A Differential MicroRNA Profile Distinguishes Cholangiocarcinoma from Pancreatic Adenocarcinoma. Annals of Surgical Oncology 21(1) 133-138 https://doi.org/10.1245/s10434-013-3240-y

  36. Dong, Q. et al. MicroRNA-891b is an independent prognostic factor of pancreatic cancer by targeting Cbl-b to suppress the growth of pancreatic cancer cells. Oncotarget 7, 82338–82353 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Elisa, Giovannetti Niccola, Funel Godefridus J., Peters Marco, Del Chiaro Leyla A., Erozenci Enrico, Vasile Leticia G., Leon Luca E., Pollina Annemieke, Groen Alfredo, Falcone Romano, Danesi Daniela, Campani Henk M., Verheul Ugo, Boggi (2010) (2010) MicroRNA-21 in Pancreatic Cancer: Correlation with Clinical Outcome and Pharmacologic Aspects Underlying Its Role in the Modulation of Gemcitabine Activity. Cancer Research 70(11) 4528-4538 https://doi.org/10.1158/0008-5472.CAN-09-4467

  38. Jamieson, N. B. et al. MicroRNA Molecular Profiles Associated with Diagnosis, Clinicopathologic Criteria, and Overall Survival in Patients with Resectable Pancreatic Ductal Adenocarcinoma. Diagnosis (2012). https://doi.org/10.1158/1078-0432.CCR-11-0679

    Article  Google Scholar 

  39. Long R., Jiao Adam E., Frampton Jimmy, Jacob Loredana, Pellegrino Jonathan, Krell Georgios, Giamas Nicole, Tsim Panagiotis, Vlavianos Patrizia, Cohen Raida, Ahmad Andreas, Keller Nagy A., Habib Justin, Stebbing Leandro, Castellano Marc, Tjwa (2012) MicroRNAs Targeting Oncogenes Are Down-Regulated in Pancreatic Malignant Transformation from Benign Tumors. PLoS ONE 7(2) e32068-10.1371/journal.pone.0032068 https://doi.org/10.1371/journal.pone.0032068

  40. Qing, Ji Xinbao, Hao Min, Zhang Wenhua, Tang Meng, Yang Ling, Li Debing, Xiang Jeffrey T., DeSano Guido T., Bommer Daiming, Fan Eric R., Fearon Theodore S., Lawrence Liang, Xu Eric J., Bernhard (2009) MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells. PLoS ONE 4(8) e6816. https://doi.org/10.1371/journal.pone.0006816

  41. Lai, X. et al. A microRNA signature in circulating exosomes is superior to exosomal glypican-1 levels for diagnosing pancreatic cancer. Cancer Lett. 393, 86–93 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ang, Li Noriyuki, Omura Seung-Mo, Hong Audrey, Vincent Kimberly, Walter Margaret, Griffith Michael, Borges Michael, Goggins (2010) (2010) Cancer Research 70(13) 5226-5237 https://doi.org/10.1158/0008-5472.CAN-09-4227

  43. Liu, P. F. et al. Integrated microRNA-mRNA analysis of pancreatic ductal adenocarcinoma. Genet. Mol. Res. 14, 10288–10297 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Liu, Q. et al. Putative Tumor Suppressor Gene SEL1L Was Downregulated by Aberrantly Upregulated hsa-mir-155 in Human Pancreatic Ductal Adenocarcinoma. Mol Carcinog 53, 711–721 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Lubezky, N. et al. MicroRNA expression signatures in intraductal papillary mucinous neoplasm of the pancreas. Surgery 153, 663–672 (2013).

    Article  PubMed  Google Scholar 

  46. Johanna B., Munding Alex T., Adai Abdelouahid, Maghnouj Aleksandra, Urbanik Hannah, Zöllner Sven T., Liffers Ansgar M., Chromik Waldemar, Uhl Anna E., Szafranska-Schwarzbach Andrea, Tannapfel Stephan A., Hahn (2012) Global microRNA expression profiling of microdissected tissues identifies miR-135b as a novel biomarker for pancreatic ductal adenocarcinoma. International Journal of Cancer 131(2) E86-E95 https://doi.org/10.1002/ijc.26466

  47. Yuichi, Nagao Masanori, Hisaoka Atsuji, Matsuyama Shuichi, Kanemitsu Tetsuo, Hamada Tokihiko, Fukuyama Ryuji, Nakano Akihiko, Uchiyama Masahiko, Kawamoto Koji, Yamaguchi Hiroshi, Hashimoto (2012) Association of microRNA-21 expression with its targets PDCD4 and TIMP3 in pancreatic ductal adenocarcinoma. Modern Pathology 25(1) 112-121 S0893395222020683 https://doi.org/10.1038/modpathol.2011.142

  48. Junghyun, Namkung Wooil, Kwon Yonwhan, Choi Sung Gon, Yi Sangjo, Han Mee Joo, Kang Sun-Whe, Kim Taesung, Park Jin-Young, Jang (2016) Molecular subtypes of pancreatic cancer based on miRNA expression profiles have independent prognostic value. Journal of Gastroenterology and Hepatology 31(6) 1160-1167 https://doi.org/10.1111/jgh.13253

  49. Panarelli, N. C., Chen, Y.-T., Zhou, X. K., Kitabayashi, N. & Yantiss, R. K. MicroRNA Expression Aids the Preoperative Diagnosis of Pancreatic Ductal Adenocarcinoma. Pancreas 41(5), 685 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Anna E, Szafranska Martina, Doleshal Hayward S, Edmunds Stuart, Gordon Jutta, Luttges Johanna B, Munding Richard J, Barth Edward J, Gutmann Arief A, Suriawinata J, Marc Pipas Andrea, Tannapfel Murray, Korc Stephan A, Hahn Emmanuel, Labourier Gregory J, Tsongalis (2008) (2008) Analysis of MicroRNAs in Pancreatic Fine-Needle Aspirates Can Classify Benign and Malignant Tissues. Clinical Chemistry 54(10) 1716-1724 https://doi.org/10.1373/clinchem.2008.109603

  51. Remotti, H. Tissue microarrays: construction and use. Methods Mol. Biol. 980, 13–28 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Curia, M. C. et al. High methylation levels of PCDH10 predict poor prognosis in patients with pancreatic ductal adenocarcinoma. BMC Cancer 19, 452 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Nagao, Y. et al. Association of microRNA-21 expression with its targets, PDCD4 and TIMP3, in pancreatic ductal adenocarcinoma. Mod. Pathol. 25, 112–121 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. An, Y. et al. Novel serum microRNAs panel on the diagnostic and prognostic implications of hepatocellular carcinoma. World J. Gastroenterol. 24, 2596–2604 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Tanaka, M. et al. EVI1 oncogene promotes KRAS pathway through suppression of microRNA-96 in pancreatic carcinogenesis. Oncogene 33, 2454–63 (2014).

    Article  CAS  PubMed  Google Scholar 

  56. Kung, J. T. Y., Colognori, D. & Lee, J. T. Long noncoding RNAs: past, present, and future. Genetics 193, 651–69 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Tahira, A. C. et al. Long noncoding intronic RNAs are differentially expressed in primary and metastatic pancreatic cancer. Molecular cancer. 10(1): 1-9 (2011).

    Article  Google Scholar 

  58. Zhou, M. et al. Construction and analysis of dysregulated lncRNA-associated ceRNA network identified novel lncRNA biomarkers for early diagnosis of human pancreatic cancer. Oncotarget 7, (2016).

  59. Li, J. et al. Long non-coding RNAs expressed in pancreatic ductal adenocarcinoma and lncRNA BC008363 an independent prognostic factor in PDAC. Pancreatology 14, 385–390 (2014).

    Article  CAS  PubMed  Google Scholar 

  60. Fu, X.-L. et al. Analysis of long non-coding RNA expression profiles in pancreatic ductal adenocarcinoma. Sci. Rep. 6, 33535 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Yu, X. et al Analysis of distinct long noncoding RNA transcriptional fingerprints in pancreatic ductal adenocarcinoma. Cancer Med. 6, 673–680 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Liang, X. et al. Long non-coding RNA CUDR promotes malignant phenotypes in pancreatic ductal adenocarcinoma via activating AKT and ERK signaling pathways. Int. J. Oncol. 53, 2671–2682 (2018).

    CAS  PubMed  Google Scholar 

  63. Jin, X. et al. Antagonizing circRNA_002581–miR-122–CPEB1 axis alleviates NASH through restoring PTEN–AMPK–mTOR pathway regulated autophagy. Cell Death Dis. 11, 123 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Li, H. et al. Circular RNA Expression Profile of Pancreatic Ductal Adenocarcinoma Revealed by Microarray. Cell. Physiol. Biochem. 40, 1334–1344 (2016).

    Article  CAS  PubMed  Google Scholar 

  65. Cao L. et al. Proteogenomic characterization of pancreatic ductal adenocarcinoma. Cell. 2021 Sep;184(19):5031-5052.e26.

  66. Zakov, S., Kinsella, M. & Bafna, V. An algorithmic approach for breakage-fusion-bridge detection in tumor genomes. Proc. Natl. Acad. Sci. U. S. A. 110, 5546–51 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Donahue, T. R. et al. Integrative Survival-Based Molecular Profiling of Human Pancreatic Cancer. Clin Cancer Res 18, (2012).

  68. Giroux, V., Iovanna, J. & Dagorn, J.-C. Probing the human kinome for kinases involved in pancreatic cancer cell survival and gemcitabine resistance. FASEB J. 20, 1982–1991 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Long R., Jiao Adam E., Frampton Jimmy, Jacob Loredana, Pellegrino Jonathan, Krell Georgios, Giamas Nicole, Tsim Panagiotis, Vlavianos Patrizia, Cohen Raida, Ahmad Andreas, Keller Nagy A., Habib Justin, Stebbing Leandro, Castellano Marc, Tjwa (2012) MicroRNAs Targeting Oncogenes Are Down-Regulated in Pancreatic Malignant Transformation from Benign Tumors. PLoS ONE 7(2) e32068. https://doi.org/10.1371/journal.pone.0032068

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Authors and Affiliations

  1. Hepatopancreatobiliary Clinic, Department of Surgery, Hospital General de México “Dr. Eduardo Liceaga”, Mexico City, Mexico

    Eduardo E. Montalvo-Javé MD PhD FACS

  2. Department of Surgery, Faculty of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico

    Eduardo E. Montalvo-Javé MD PhD FACS

  3. Translational Research Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico

    Natalia Nuño-Lámbarri PhD & Guillermo Nahúm López-Sánchez MD PhD

  4. Department of Surgery, Hospital General de México “Dr. Eduardo Liceaga”, Mexico City, Mexico

    Edwin A. Ayala-Moreno MD

  5. Liver, Pancreas and Motility Laboratory, Unit of Experimental Medicine, Hospital General de México “Dr. Eduardo Liceaga”, Mexico City, Mexico

    Gabriela Gutierrez-Reyes PhD

  6. Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, OH, USA

    Joal Beane MD & Timothy M. Pawlik MD PhD MPH

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  1. Eduardo E. Montalvo-Javé MD PhD FACS
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All authors have contributed with diverse ideas and improved, corrected, and revised the article final version. The content of the manuscript to be published was also agreed and approved.

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Correspondence to Eduardo E. Montalvo-Javé MD PhD FACS.

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Montalvo-Javé, E.E., Nuño-Lámbarri, N., López-Sánchez, G.N. et al. Pancreatic Cancer: Genetic Conditions and Epigenetic Alterations. J Gastrointest Surg 27, 1001–1010 (2023). https://doi.org/10.1007/s11605-022-05553-0

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