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Critical Reviews™ in Oncogenesis
SJR: 0.631 SNIP: 0.503 CiteScore™: 2

ISSN 印刷: 0893-9675
ISSN オンライン: 2162-6448

Critical Reviews™ in Oncogenesis

DOI: 10.1615/CritRevOncog.2019030929
pages 119-132

Cytogenetic, Molecular, and Translational Applications in Pancreatic Ductal Adenocarcinoma: Current Evidence and Future Concepts

Rama Rao Malla
Cancer Biology Lab, Department of Biochemistry and Bioinformatics, Institute of Science, GITAM (Deemed to be University), Visakhapatnam, India
Seema Kumari
Cancer Biology Lab, Department of Biochemistry and Bioinformatics, Institute of Science, GITAM (Deemed to be University), Visakhapatnam, India

要約

Pancreatic cancer or pancreatic ductal carcinoma is one of the most destructive human malignancies; it is frequently diagnosed at advanced and incurable metastatic stages. In contempt of the voluminous research in the recent past, it became resistant to currently existing, clinically approved therapeutic regimens. Recent advances in cytogenetic, molecular, and translational applications for understanding the pathophysiological and molecular mechanisms of this disease have opened up new avenues for novel therapeutic strategies. In this review, we present current literature on the cytogenetic, molecular, and translational applications in pancreatic ductal carcinoma, and we emphasize current evidence and future concepts for the development of novel diagnostic and therapeutic approaches and their clinical implications.

参考

  1. Delpu Y, Hanoun N, Lulka H, Sicard F, Selves J, Buscail L, Torrisani J, Cordelier P. Genetic and epigenetic alterations in pancreatic carcinogenesis. Curr Genom. 2011;12:15-24.

  2. De La Cruz MS, Young AP, Ruffin MT. Diagnosis and management of pancreatic cancer. Am Fam Phys. 2014;89:626-32.

  3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30.

  4. von Ahrens D, Bhagat TD, Nagrath D, Maitra A, Verma A. The role of stromal cancer-associated fibroblasts in pancreatic cancer. J Hematol Oncol. 2017;10:76.

  5. Barrett MT, Deiotte R, Lenkiewicz E, Malasi S, Holley T, Evers L, Posner RG, Jones T, Han H, Sausen M, Velculescu VE, Drebin J, O'Dwyer P, Jameson G, Ramanathan RK, Von HoffDD. Clinical study of genomic drivers in pancreatic ductal adenocarcinoma. Br J Cancer. 2017;117:572-82.

  6. Schneider G, Schmid RM. Pathogenesis of the ductal pancreatic adenocarcinoma: implications for future therapies? Der Internist. 2005;46:157-65.

  7. Feldmann G, Maitra A. Molecular genetics of pancreatic ductal adenocarcinomas and recent implications for translational efforts. J Mol Diagn. 2008;10:111-22.

  8. Schneider G, Siveke JT, Eckel F, Schmid RM. Pancreatic cancer: basic and clinical aspects. Gastroenterology. 2005;128:1606-25.

  9. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11-30.

  10. Sirivatanauksorn V, Sirivatanauksorn Y, Gorman PA, Davidson JM, Sheer D, Moore PS, Scarpa A, Edwards PA, Lemoine NR. Non-random chromosomal rearrangements in pancreatic cancer cell lines identified by spectral karyotyping. Int J Cancer. 2001;91:350-58.

  11. Griffin CA, Hruban RH, Morsberger LA, Ellingham T, Long PP, Jaffee EM, Hauda KM, Bohlander SK, Yeo CJ. Consistent chromosome abnormalities in adenocarcinoma of the pancreas. Cancer Res. 1995;55:2394-99.

  12. Lo KW, Teo PM, Hui AB, To KF, Tsang YS, Chan SY, Mak KF, Lee JC, Huang DP. High resolution allelotype of microdissected primary nasopharyngeal carcinoma. Cancer Res. 2000;60:3348-53.

  13. Iacobuzio-Donahue CA, van der Heijden MS, Baumgartner MR, Troup WJ, Romm JM, Doheny K, Pugh E, Yeo CJ, Goggins MG, Hruban RH, Kern SE. Large-scale allelotype of pancreaticobiliary carcinoma provides quantitative estimates of genome-wide allelic loss. Cancer Res. 2004;64:871-75.

  14. Xin W, Yun KJ, Ricci F, Zahurak M, Qiu W, Su GH, Yeo CJ, Hruban RH, Kern SE, Iacobuzio-Donahue CA. MAP2K4/MKK4 expression in pancreatic cancer: genetic validation of immunohistochemistry and relationship to disease course. Clin Cancer Res. 2004;10:8516-20.

  15. Samuel N, Say ad A, Wilson G, Lemire M, Brown KR, Muthuswamy L, Hudson TJ, Moffat J. Integrated genomic, transcriptomic, and RNA-interference analysis of genes in somatic copy number gains in pancreatic ductal adenocarcinoma. Pancreas. 2013;42:1016-26.

  16. Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J, Chang DK, Cowley MJ, Gardiner BB, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Pajic M, Scarlett CJ, Gill AJ, Pinho AV, Rooman I, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu Q, Nones K, Fink JL, Christ A, Bruxner T, Cloonan N, Kolle G, Newell F, Pinese M, Mead RS, Humphris JL, Kaplan W, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chou A, Chin VT, Chantrill LA, Mawson A, Samra JS, Kench JG, Lovell JA, Daly RJ, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N, Kakkar N, Zhao F, Wu YQ, Wang M, Muzny DM, Fisher WE, Brunicardi FC, Hodges SE, Reid JG, Drummond J, Chang K, Han Y, Lewis LR, Dinh H, Buhay CJ, Beck T, Timms L, Sam M, Begley K, Brown A, Pai D, Panchal A, Buchner N, De Borja R, Denroche RE, Yung CK, Serra S, Onetto N, Mukhopadhyay D, Tsao MS, Shaw PA, Petersen GM, Gallinger S, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Lawlor RT, Capelli P, Corbo V, Scardoni M, Tortora G, Tempero MA, Mann KM, Jenkins NA, Perez-Mancera PA, Adams DJ, Largaespada DA, Wessels LF, Rust AG, Stein LD, Tuveson DA, Copeland NG, Musgrove EA, Scarpa A, Eshleman JR, Hudson TJ, Sutherland RL, Wheeler DA, Pearson JV, McPherson JD, Gibbs RA, Grimmond SM. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491:399-405.

  17. Yang ZM, Han XP, Wu SF, Yin YF, Wang K, Gao J, Liang ZY, Zeng X. Analysis of chromosomal abnormalities in pancreatic cancer by spectral karyotyping. Zhonghua Bing Li Xue Za Zhi. 2010;39:767-71 (in Chinese).

  18. Stoecklein NH, Luebke AM, Erbersdobler A, Knoefel WT, Schraut W, Verde PE, Stern F, Scheunemann P, Peiper M, Eisenberger CF, Izbicki JR, Klein CA, Hosch SB. Copy number of chromosome 17 but not HER2 amplification predicts clinical outcome of patients with pancreatic ductal adenocarcinoma. J Clin Oncol. 2004;22:4737-45.

  19. Schleger C, Arens N, Zentgraf H, Bleyl U, Verbeke C. Identification of frequent chromosomal aberrations in ductal adenocarcinoma of the pancreas by comparative genomic hybridization (CGH). J Pathol. 2000;191:27-32.

  20. Harada T, Chelala C, Crnogorac-Jurcevic T, Lemoine NR. Genome-wide analysis of pancreatic cancer using microarray-based techniques. Pancreatology. 2009;9:13-24.

  21. Harada T, Chelala C, Bhakta V, Chaplin T, Caulee K, Baril P, Young BD, Lemoine NR. Genome-wide DNA copy number analysis in pancreatic cancer using high-density single nucleotide polymorphism arrays. Oncogene. 2008;27:1951-60.

  22. Harada T, Okita K, Shiraishi K, Kusano N, Furuya T, Oga A, Kawauchi S, Kondoh S, Sasaki K. Detection of genetic alterations in pancreatic cancers by comparative genomic 32. hybridization coupled with tissue microdissection and degenerate oligonucleotide primed polymerase chain reaction. Oncology. 2002;62:251-58.

  23. Lee JH, Giovannetti E, Hwang JH, Petrini I, Wang Q, Voortman J, Wang Y, Steinberg SM, Funel N, Meltzer PS, Wang Y, Giaccone G. Loss of 18q22.3 involving the carboxypeptidase of glutamate-like gene is associated with poor prognosis in resected pancreatic cancer. Clin Cancer Res. 2012;18:524-33.

  24. Tsiambas E, Karameris A, Lazaris AC, Talieri M, Triantafillidis JK, Cheracakis P, Manaios L, Gerontopoulos K, Patsouris E, Lygidakis NJ. EGFR alterations in pancreatic ductal adenocarcinoma: a chromogenic in situ hybridization analysis based on tissue microarrays. Hepatogastroenterology. 2006;53:452-57.

  25. Tsiambas E, Karameris A, Dervenis C, Lazaris AC, Giannakou N, Gerontopoulos K, Patsouris E. HER2/neu expression and gene alterations in pancreatic ductal adenocarcinoma: a comparative immunohistochemistry and chromogenic in situ hybridization study based on tissue microarrays and computerized image analysis. J Pancreas. 2006;7:283-94.

  26. Schleger C, Verbeke C, Hildenbrand R, Zentgraf H, Bleyl U. c-MYC activation in primary and metastatic ductal adenocarcinoma of the pancreas: incidence, mechanisms, and clinical significance. Mod Pathol. 2002;15:462-69.

  27. Islam HK, Fujioka Y, Tomidokoro T, Sugiura H, Takahashi T, Kondo S, Katoh H. Immunohistochemical study of genetic alterations in intraductal and invasive ductal tumors of the pancreas. Hepatogastroenterology. 2001;48:879-83.

  28. Ulrich CD, 2nd. Growth factors, receptors, and molecular alterations in pancreatic cancer. Putting it all together. Med Clin North Am. 2000;84:697-705, xi-xii.

  29. Fritz S, Fernandez-del Castillo C, Iafrate AJ, Mino-Kenudson M, Neyhard N, LaFemina J, Stirman A, Warshaw AL, Thayer SP. Novel xenograft and cell line derived from an invasive intraductal papillary mucinous neoplasm of the pancreas give new insights into molecular mechanisms. Pancreas. 2010;39:308-14.

  30. Dewald GW, Smyrk TC, Thorland EC, McWilliams RR, Van Dyke DL, Keefe JG, Belongie KJ, Smoley SA, Knutson DL, Fink SR, Wiktor AE, Petersen GM. Fluorescence in situ hybridization to visualize genetic abnormalities in interphase cells of acinar cell carcinoma, ductal adenocarcinoma, and islet cell carcinoma of the pancreas. Mayo Clin Proc. 2009;84:801-10.

  31. Yamanaka S, Sunamura M, Furukawa T, Sun L, Lefter LP, Abe T, Yatsuoka T, Fujimura H, Shibuya E, Kotobuki N, Oshimura M, Sakurada A, Sato M, Kondo T, Matsuno S, Horii A. Chromosome 12, frequently deleted in human pancreatic cancer, may encode a tumor-suppressor gene that suppresses angiogenesis. Lab Invest. 2004;84:1339-51.

  32. Sunamura M, Lefter LP, Duda DG, Morita R, Inoue H, Yokoyama T, Yatsuoka T, Abe T, Egawa S, Furukawa T, Fukushige S, Oshimura M, Horii A, Matsuno S. The role of chromosome 18 abnormalities in the progression of pancreatic adenocarcinoma. Pancreas. 2004;28:311-16.

  33. Moskovitz AH, Linford NJ, Brentnall TA, Bronner MP, Storer BE, Potter JD, Bell RH, Jr, Rabinovitch PS. Chromosomal instability in pancreatic ductal cells from patients with chronic pancreatitis and pancreatic adenocarcinoma. Genes Chromo Cancer. 2003;37:201-6.

  34. Moore PS, Beghelli S, Zamboni G, Scarpa A. Genetic abnormalities in pancreatic cancer. Mol Cancer. 2003;2:7.

  35. Sato N, Fukushima N, Matsubayashi H, Iacobuzio- Donahue CA, Yeo CJ, Goggins M. Aberrant methylation of Reprimo correlates with genetic instability and predicts poor prognosis in pancreatic ductal adenocarcinoma. Cancer. 2006;107:251-57.

  36. Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, Rustgi AK, Chang S, Tuveson DA. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005;7:469-83.

  37. Stratford JK, Yan F, Hill RA, Major MB, Graves LM, Der CJ, Yeh JJ. Genetic and pharmacological inhibition of TTK impairs pancreatic cancer cell line growth by inducing lethal chromosomal instability. PLoS One. 2017;12:e0174863.

  38. Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 2013;144:1252-61.

  39. von Figura G, Fukuda A, Roy N, Liku ME, Morris Iv JP, Kim GE, Russ HA, Firpo MA, Mulvihill SJ, Dawson DW, Ferrer J, Mueller WF, Busch A, Hertel KJ, Hebrok M. The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma. Nat Cell Biol. 2014;16:255-67.

  40. Kang R, Xie Y, Zhang Q, Hou W, Jiang Q, Zhu S, Liu J, Zeng D, Wang H, Bartlett DL, Billiar TR, Zeh HJ, 3rd, Lotze MT, Tang D. Intracellular HMGB1 as a novel tumor suppressor of pancreatic cancer. Cell Res. 2017;27:916-32.

  41. Genovese G, Carugo A, Tepper J, Robinson FS, Li L, Svelto M, Nezi L, Corti D, Minelli R, Pettazzoni P, Gutschner T, Wu CC, Seth S, Akdemir KC, Leo E, Amin S, Molin MD, Ying H, Kwong LN, Colla S, Takahashi K, Ghosh P, Giuliani V, Muller F, Dey P, Jiang S, Garvey J, Liu CG, Zhang J, Heffernan TP, Toniatti C, Fleming JB, Goggins MG, Wood LD, Sgambato A, Agaimy A, Maitra A, Roberts CW, Wang H, Viale A, DePinho RA, Draetta GF, Chin L. Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer. Nature. 2017;542:362-66.

  42. Zhang Q, Zhang Y, Parsels JD, Lohse I, Lawrence TS, 53. Pasca di Magliano M, Sun Y, Morgan MA. Fbxw7 Deletion accelerates kras(G12D)-driven pancreatic tumorigenesis via yap accumulation. Neoplasia (New York, NY). 2016;18:666-73.

  43. Wartenberg M, Centeno I, Haemmig S, Vassella E, Zlobec I, Galvan JA, Neuenschwander M, Schlup C, Gloor B, Lugli A, Perren A, Karamitopoulou E. PTEN alterations of the stromal cells characterise an aggressive subpopulation of pancreatic cancer with enhanced metastatic potential. Eur J Cancer. 2016;65:80-90.

  44. Lee JC, Shin J, Baek KH. Trisomy of the Dscr1 gene suppresses early progression of pancreatic intraepithelial neoplasia driven by oncogenic Kras. Biochem Biophys 56. Res Commun. 2013;440:50-55.

  45. Luo Y, Tian L, Feng Y, Yi M, Chen X, Huang Q. The predictive role of p16 deletion, p53 deletion, and polysomy 9 and 17 in pancreatic ductal adenocarcinoma. 57. Pathol Oncol Res. 2013;19:35-40.

  46. Luebke AM, Baudis M, Matthaei H, Vashist YK, Verde PE, Hosch SB, Erbersdobler A, Klein CA, Izbicki JR, Knoefel WT, Stoecklein NH. Losses at chromosome 4q are associated with poor survival in operable ductal pancreatic adenocarcinoma. Pancreatology. 2012;12:16-22.

  47. Gutierrez ML, Munoz-Bellvis L, Abad Mdel M, 58. Bengoechea O, Gonzalez-Gonzalez M, Orfao A, Sayagues JM. Association between genetic subgroups of pancreatic ductal adenocarcinoma defined by high density 500 K SNP-arrays and tumor histopathology. PLoS One. 2011;6:e22315.

  48. Rowley M, Ohashi A, Mondal G, Mills L, Yang L, Zhang L, Sundsbak R, Shapiro V, Muders MH, Smyrk T, Couch FJ. Inactivation of Brca2 promotes Trp53-associated but inhibits KrasG12D-dependent pancreatic cancer development in mice. Gastroenterology. 2011;140:1303-13.e1-3.

  49. Tsiambas E, Karameris A, Stamatelopoulos A, Baltayiannis N, Manaios L, Gerontopoulos K, Talieri M, Athanassiou AE, Patsouris E. Chromogenic in situ hybridization analysis of chromosomes 7, 9, and 17 in pancreatic ductal adenocarcinoma based on tissue microarrays. J BUON. 2006;11:205-11.

  50. Tsiambas E, Kravvaritis C, Tsounis D, Salemis NS, Niotis A, Niotis TH, Rigopoulos DN, Karameris A, Athanasiou AE, Patsouris E, Karakitsos P. Correlation between different p53 expression patterns and chromosome 17 imbalances in pancreatic ductal adenocarcinoma based on tissue microarray analysis. J BUON. 2010;15:94-100.

  51. Syren P, Andersson R, Bauden M, Ansari D. Epigenetic alterations as biomarkers in pancreatic ductal adenocarcinoma. Scand J Gastroenterol. 2017;52:668-73.

  52. Lomberk GA, Iovanna J, Urrutia R. The promise of epigenomic therapeutics in pancreatic cancer. Epigenomics. 2016;8:831-42.

  53. Botezatu A, Bleotu C, Nastase A, Anton G, Bacalbasa N, Duda D, Dima SO, Popescu I. Epigenetic silencing of GNMT gene in pancreatic adenocarcinoma. Cancer Genom Proteom. 2015;12:21-30.

  54. Paradise BD, Barham W, Fernandez-Zapico ME. Targeting epigenetic aberrations in pancreatic cancer, a new path to improve patient outcomes? Cancers (Basel). 2018;10.

  55. Erichsen L, Ghanjati F, Beermann A, Poyet C, Hermanns T, Schulz WA, Seifert HH, Wild PJ, Buser L, Kroning A, Braunstein S. Aberrant methylated key genes of methyl group metabolism within the molecular etiology of urothelial carcinogenesis. Sci Rep. 2018;8(1):3477.

  56. Lomberk GA, Urrutia R. The triple-code model for pancreatic cancer: cross talk among genetics, epigenetics, and nuclear structure. Surg Clin North Am. 2015;95:935-52.

  57. Dutruel C, Bergmann F, Rooman I, Zucknick M, Weichenhan D, Geiselhart L, Kaffenberger T, Rachakonda PS, Bauer A, Giese N, Hong C, Xie H, Costello JF, Hoheisel J, Kumar R, Rehli M, Schirmacher P, Werner J, Plass C, Popanda O, Schmezer P. Early epigenetic downregulation of WNK2 kinase during pancreatic ductal adenocarcinoma development. Oncogene. 2014;33:3401-10.

  58. Tinari N, De Tursi M, Grassadonia A, Zilli M, Stuppia L, Iacobelli S, Natoli C. An epigenetic approach to pancreatic cancer treatment: the prospective role of histone deacetylase inhibitors. Curr Cancer Drug Targets. 2012;12:439-52.

  59. McCleary-Wheeler AL, Lomberk GA, Weiss FU, Schneider G, Fabbri M, Poshusta TL, Dusetti NJ, Baumgart S, Iovanna JL, Ellenrieder V, Urrutia R, Fernandez-Zapico ME. Insights into the epigenetic mechanisms controlling pancreatic carcinogenesis. Cancer Lett. 2013;328:212-21.

  60. Carrer A, Trefely S, Zhao S, Campbell SL, Norgard RJ, Schultz KC, Sidoli S, Parris JL, Affronti HC, Sivanand S, Egolf S. Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis. Cancer Discov. 2019 Mar 1;9(3):416-35.

  61. Watanabe S, Shimada S, Akiyama Y, Ishikawa Y, Ogura T, Ogawa K, Ono H, Mitsunori Y, Ban D, Kudo A, Yamaoka S. Loss of KDM6A characterizes a poor prognostic subtype of human pancreatic cancer and potentiates HDAC inhibitor lethality. Int J Cancer. 2019 Jul 1;145(1):192-205.

  62. Guo S, Fesler A, Wang H, Ju J. microRNA based prognostic biomarkers in pancreatic cancer. Biomarker Res. 2018;6:18.

  63. Gailhouste L, Liew LC, Hatada I, Nakagama H, Ochiya T. Epigenetic reprogramming using 5-azacytidine promotes an anti-cancer response in pancreatic adenocarcinoma cells. Cell Death Dis. 2018;9:468.

  64. Roe JS, Hwang CI, Somerville TDD, Milazzo JP, Lee EJ, Da Silva B, Maiorino L, Tiriac H, Young CM, Miyabayashi K, Filippini D, Creighton B, Burkhart RA, Buscaglia JM, Kim EJ, Grem JL, Lazenby AJ, Grunkemeyer JA, Hollingsworth MA, Grandgenett PM, Egeblad M, Park Y, Tuveson DA, Vakoc CR. Enhancer reprogramming promotes pancreatic cancer metastasis. 76. Cell. 2017;170:875-88.e20.

  65. Kanno S, Nosho K, Ishigami K, Yamamoto I, Koide H, Kurihara H, Mitsuhashi K, Shitani M, Motoya M, Sasaki S, Tanuma T, Maguchi H, Hasegawa T, Kimura 77. Y, Takemasa I, Shinomura Y, Nakase H. MicroRNA-196b is an independent prognostic biomarker in patients with pancreatic cancer. Carcinogenesis. 2017;38:425-31.

  66. Rajabpour A, Rajaei F, Teimoori-Toolabi L. Molecular alterations contributing to pancreatic cancer 78. chemoresistance. Pancreatology. 2017;17:310-20.

  67. Iguchi E, Safgren SL, Marks DL, Olson RL, Fernandez- Zapico ME. Pancreatic cancer, a mis-interpreter of the epigenetic language. Yale J Biol Med. 2016;89:575-90.

  68. Huang Y, Nahar S, Nakagawa A, Fernandez-Barrena 79. MG, Mertz JA, Bryant BM, Adams CE, Mino-Kenudson M, Von Alt KN, Chang K, Conery AR, Hatton C, Sims RJ, 3rd, Fernandez-Zapico ME, Wang X, Lillemoe KD, Fernandez-Del Castillo C, Warshaw AL, Thayer SP, Liss AS. Regulation of GLI underlies a role for BET bromodomains in pancreatic cancer growth and the tumor microenvironment. Clin Cancer Res. 2016;22:4259-70.

  69. Amato E, Barbi S, Fassan M, Luchini C, Vicentini C, Brunelli M, Malleo G, Scarpa A, Malpeli G. RASSF1 tumor suppressor gene in pancreatic ductal adenocarcinoma: correlation of expression, chromosomal status and epigenetic changes. BMC Cancer. 2016;16:11.

  70. van Heek NT, Meeker AK, Kern SE, Yeo CJ, Lillemoe KD, Cameron JL, Offerhaus GJ, Hicks JL, Wilentz RE, Goggins MG, De Marzo AM, Hruban RH, Maitra A. 81. Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia. Am J Pathol. 2002;161:1541-47.

  71. Cowan RW, Maitra A. Genetic progression of pancreatic cancer. Cancer J. 2014;20:80-84.

  72. Heaphy CM, de Wilde RF, Jiao Y, KleinAP, Edil BH, Shi C, Bettegowda C, Rodriguez FJ, Eberhart CG, Hebbar S, Offerhaus GJ, McLendon R, Rasheed BA, He Y, Yan H, Bigner DD, Oba-Shinjo SM, Marie SK, Riggins GJ, Kinzler KW, Vogelstein B, Hruban RH, Maitra A, Papadopoulos N, Meeker AK. Altered telomeres in tumors with ATRX and DAXX mutations. Science. 2011;333:425.

  73. Carew JS, Huang P. Mitochondrial defects in cancer. Mol Cancer. 2002;1:9.

  74. Hopkins JF, Denroche RE, Aguiar JA, Notta F, Connor AA, Wilson JM, Stein LD, Gallinger S, Boutros PC. Mutations in mitochondrial DNA from pancreatic ductal adenocarcinomas associate with survival times of patients and accumulate as tumors progress. Gastroenterology. 2018;154:1620-4.e5.

  75. Jones JB, Song JJ, Hempen PM, Parmigiani G, Hruban RH, Kern SE. Detection of mitochondrial DNA mutations in pancreatic cancer offers a "mass"-ive advantage over detection of nuclear DNA mutations. Cancer Res. 2001;61:1299-304.

  76. Katsiougiannis S, Chia D, Kim Y, Singh RP, Wong DT. Saliva exosomes from pancreatic tumor-bearing mice modulate NK cell phenotype and antitumor cytotoxicity. FASEB J. 2017;31:998-1010.

  77. Antwi SO, Eckert EC, Sabaque CV, Leof ER, Hawthorne KM, Bamlet WR, Chaffee KG, Oberg AL, Petersen GM. Exposure to environmental chemicals and heavy metals, and risk of pancreatic cancer. Cancer Causes Control. 2015 Nov 1;26(11):1583-91.

  78. Frese KK, Neesse A, Cook N, Bapiro TE, Lolkema MP, Jodrell DI, Tuveson DA. nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov. 2012;2:260-69.

  79. Kato A, Naiki-Ito A, Naitoh I, Hayashi K, Nakazawa T, Shimizu S, Nishi Y, Okumura F, Inoue T, Takada H, Kondo H, Yoshida M, Takahashi S, Joh T. The absence of class III beta-tubulin is predictive of a favorable response to nab-paclitaxel and gemcitabine in patients with unresectable pancreatic ductal adenocarcinoma. Hum Pathol. 2018;74:92-98.

  80. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W. 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. 2007;25:1960-66.

  81. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378:607-20.

  82. Heinemann V, Haas M, Boeck S. Systemic treatment of advanced pancreatic cancer. Cancer Treat Rev. 2012;38:843-53.

  83. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, Bennouna J, Bachet JB, Khemissa-Akouz F, Pere-Verge D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817-25.

  84. Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, Innocenti F, Mulcahy MF, O'Reilly E, Wozniak TF, Picus J, Bhargava P, Mayer RJ, Schilsky RL, Goldberg RM. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the cancer and leukemia group B (CALGB 80303). J Clin Oncol. 2010;28:3617-22.

  85. Costello E, Greenhalf W, Neoptolemos JP. New biomarkers and targets in pancreatic cancer and their application to treatment. Nat Rev Gastroenterol Hepatol. 2012;9:435-44.

  86. Kruger S, Haas M, Ormanns S, Bachmann S, Siveke JT, Kirchner T, Heinemann V, Boeck S. Translational research in pancreatic ductal adenocarcinoma: current evidence and future concepts. World J Gastroenterol. 2014;20:10769-77.

  87. Suda K, Tomizawa K, Mitsudomi T. Biological and clinical significance of KRAS mutations in lung cancer: an oncogenic driver that contrasts with EGFR mutation. Cancer Meta Rev. 2010;29:49-60.

  88. Kim ST, Lim DH, Jang KT, Lim T, Lee J, Choi YL, Jang 97. HL, Yi JH, Baek KK, Park SH, Park YS, Lim HY, Kang WK, Park JO. Impact of KRAS mutations on clinical outcomes in pancreatic cancer patients treated with first-line gemcitabine-based chemotherapy. Mol Cancer 98. Ther. 2011;10:1993-99.

  89. Shin SH, Kim SC, Hong SM, Kim YH, Song KB, Park KM, Lee YJ. Genetic alterations of K-ras, p53, c-erbB-2, and DPC4 in pancreatic ductal adenocarcinoma and their correlation with patient survival. Pancreas. 99. 2013;42:216-22.

  90. Ogura T, Yamao K, Hara K, Mizuno N, Hijioka S, Imaoka H, Sawaki A, Niwa Y, Tajika M, Kondo S, Tanaka T, Shimizu Y, Bhatia V, Higuchi K, Hosoda W, Yatabe Y. Prognostic value of K-ras mutation status and subtypes in endoscopic ultrasound-guided fine-needle aspiration specimens from patients with unresectable pancreatic cancer. J Gastroenterol. 2013;48:640-46.

  91. Nakano Y, Kitago M, Matsuda S, Nakamura Y, Fujita Y, Imai S, Shinoda M, Yagi H, Abe Y, Hibi T, Fujii-Nishimura Y, Takeuchi A, Endo Y, Itano O, Kitagawa Y. KRAS mutations in cell-free DNA from preoperative and postoperative sera as a pancreatic cancer marker: a retrospective study. Br J Cancer. 2018;118:662-69.

  92. Boeck S, Jung A, Laubender RP, Neumann J, Egg R, Goritschan C, Ormanns S, Haas M, Modest DP, Kirchner T, Heinemann V. KRAS mutation status is not predictive for objective response to anti-EGFR treatment with erlotinib in patients with advanced pancreatic cancer. J Gastroenterol. 2013;48:544-48.

  93. Lee J, Jang KT, Ki CS, Lim T, Park YS, Lim HY, Choi DW, Kang WK, Park K, Park JO. Impact of epidermal growth factor receptor (EGFR) kinase mutations, EGFR gene amplifications, and KRAS mutations on survival of pancreatic adenocarcinoma. Cancer. 2007;109:1561-69.

  94. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes 103. R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocakova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023-34.

  95. Massarelli E, Varella-Garcia M, Tang X, Xavier AC, Ozburn NC, Liu DD, Bekele BN, Herbst RS, Wistuba, II. KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin Cancer Res. 2007;13:2890-96.

  96. da Cunha Santos G, Dhani N, Tu D, Chin K, Ludkovski O, Kamel-Reid S, Squire J, Parulekar W, Moore MJ, Tsao MS. Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3. Cancer. 2010;116:5599-607.

  97. Oliveira-Cunha M, Hadfield KD, Siriwardena AK, Newman W. EGFR and KRAS mutational analysis and their correlation to survival in pancreatic and periampullary cancer. Pancreas. 2012;41:428-34.

  98. Muta Y, Oneda H, Inouye K. Anomalous pH- dependence of the activity of human matrilysin (matrix metalloproteinase-7) as revealed by nitration and amination of its tyrosine residues. Biochem J. 2005;386:263-70.

  99. Iacobuzio-Donahue CA, Fu B, Yachida S, Luo M, Abe H, Henderson CM, Vilardell F, Wang Z, Keller JW, Banerjee P, Herman JM, Cameron JL, Yeo CJ, Halushka MK, Eshleman JR, Raben M, Klein AP, Hruban RH, Hidalgo M, Laheru D. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;27:1806-13.

  100. Oshima M, Okano K, Muraki S, Haba R, Maeba T, Suzuki Y, Yachida S. Immunohistochemically detected expression of 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4) strongly predicts survival in patients with resectable pancreatic cancer. Ann Surg. 2013;258:336-46.

  101. Boone BA, Sabbaghian S, Zenati M, Marsh JW, Moser AJ, Zureikat AH, Singhi AD, Zeh HJ, 3rd, Krasinskas AM. Loss of SMAD4 staining in pre-operative cell blocks is associated with distant metastases following pancreaticoduodenectomy with venous resection for pancreatic cancer. J Surg Oncol. 2014;110:171-75.

  102. Bachet JB, Marechal R, Demetter P, Bonnetain F, Couvelard A, Svrcek M, Bardier-Dupas A, Hammel P, Sauvanet A, Louvet C, Paye F, Rougier P, Penna C, Vaillant JC, Andre T, Closset J, Salmon I, Emile JF, Van Laethem JL. Contribution of CXCR4 and SMAD4 in predicting disease progression pattern and benefit from adjuvant chemotherapy in resected pancreatic adenocarcinoma. Ann Oncol. 2012;23:2327-35.

  103. Petrushnko W, Gundara JS, De Reuver PR, O'Grady G, Samra JS, Mittal A. Systematic review of peri-operative prognostic biomarkers in pancreatic ductal adenocarcinoma. HPB (Oxford). 2016;18:652-63.

  104. Wang WQ, Liu L, Xu HX, Wu CT, Xiang JF, Xu J, Liu C, Long J, Ni QX, Yu XJ. Infiltrating immune cells and gene mutations in pancreatic ductal adenocarcinoma. Br J Surg. 2016;103:1189-99.

  105. Dempe S, Stroh-Dege AY, Schwarz E, Rommelaere J, 118. Dinsart C. SMAD4: a predictive marker of PDAC cell permissiveness for oncolytic infection with parvovirus H-1PV. Int J Cancer. 2010;126:2914-27.

  106. Lippitz BE. Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol. 2013;14: e218-28.

  107. Kryczek I, Wei S, Keller E, Liu R, Zou W. Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis. Am J Physiol Cell Physiol. 2007;292:C987-95.

  108. Marechal R, Demetter P, Nagy N, Berton A, Decaestecker C, Polus M, Closset J, Deviere J, Salmon I, Van Laethem JL. High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma. Br J Cancer. 2009;100:1444-51.

  109. Gebauer F, Tachezy M, Effenberger K, von Loga K, Zander H, Marx A, Kaifi JT, Sauter G, Izbicki JR, Bockhorn M. Prognostic impact of CXCR4 and CXCR7 expression in pancreatic adenocarcinoma. J Surg Oncol. 2011;104:140-45.

  110. Nixon AB, Pang H, Starr MD, Friedman PN, Bertagnolli MM, Kindler HL, Goldberg RM, Venook AP, Hurwitz HI. Prognostic and predictive blood-based biomarkers in patients with advanced pancreatic cancer: results from CALGB80303 (Alliance). Clin Cancer Res. 2013;19:6957-66.

  111. Ding Y, Du Y. Clinicopathological significance and prognostic role of chemokine receptor CXCR4 expression in pancreatic ductal adenocarcinoma, a meta-analysis and literature review. Int J Surg. 2019;65:32-38.

  112. Krieg A, Riemer JC, Telan LA, Gabbert HE, Knoefel WT. CXCR4-A prognostic and clinicopathological biomarker for pancreatic ductal adenocarcinoma: a meta-analysis. PLoS One. 2015;10:e0130192.

  113. Marechal R, Van Laethem JL. Towards a tailored therapy in pancreatic cancer. Acta Gastroenterol Belg. 2013;76:49-56.

  114. Liang JJ, Zhu S, Bruggeman R, Zaino RJ, Evans DB, Fleming JB, Gomez HF, Zander DS, Wang H. High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma. Cancer Epidemiol 125. Biomarkers Prev. 2010;19:2598-604.

  115. Kure S, Matsuda Y, Hagio M, Ueda J, Naito Z, Ishiwata T. Expression of cancer stem cell markers in pancreatic intraepithelial neoplasias and pancreatic ductal adenocarcinomas. Int J Oncol. 2012;41:1314-24.

  116. Matsuda Y, Kure S, Ishiwata T. Nestin and other putative cancer stem cell markers in pancreatic cancer. Med Mol Morphol. 2012;45:59-65.

  117. Yamamoto S, Tomita Y, Hoshida Y, Morooka T, Nagano H, Dono K, Umeshita K, Sakon M, Ishikawa O, Ohigashi H, Nakamori S, Monden M, Aozasa K. Prognostic significance of activated Akt expression in pancreatic ductal adenocarcinoma. Clin Cancer Res. 2004;10:2846-50.

  118. Chadha KS, Khoury T, Yu J, Black JD, Gibbs JF, Kuvshinoff BW, Tan D, Brattain MG, Javle MM. Activated Akt and Erk expression and survival after surgery in pancreatic carcinoma. Ann Surg Oncol. 2006;13:933-39.

  119. Javle MM, Gibbs JF, Iwata KK, Pak Y, Rutledge P, Yu J, Black JD, Tan D, Khoury T. Epithelial-mesenchymal transition (EMT) and activated extracellular signal-regulated kinase (p-Erk) in surgically resected pancreatic cancer. Ann Surg Oncol. 2007;14:3527-33.

  120. Ratushny V, Astsaturov I, Burtness BA, Golemis EA, Silverman JS. Targeting EGFR resistance networks in head and neck cancer. Cell Signal. 2009;21:1255-68.

  121. Bianco R, Shin I, Ritter CA, Yakes FM, Basso A, Rosen N, Tsurutani J, Dennis PA, Mills GB, Arteaga CL. Loss of PTEN/MMAC1 /TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene. 2003;22:2812-22.

  122. Ardito CM, Gruner BM, Takeuchi KK, Lubeseder-Martellato C, Teichmann N, Mazur PK, Delgiorno KE, Carpenter ES, Halbrook CJ, Hall JC, Pal D, Briel T, Herner A, Trajkovic-Arsic M, Sipos B, Liou GY, Storz P, Murray NR, Threadgill DW, Sibilia M, Washington MK, Wilson CL, Schmid RM, Raines EW, Crawford HC, Siveke JT. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell. 2012;22:304-17.

  123. Liang WS, Craig DW, Carpten J, Borad MJ, Demeure MJ, Weiss GJ, Izatt T, Sinari S, Christoforides A, Aldrich J, Kurdoglu A, Barrett M, Phillips L, Benson H, Tembe W, Braggio E, Kiefer JA, Legendre C, Posner R, Hostetter GH, Baker A, Egan JB, Han H, Lake D, Stites EC, Ramanathan RK, Fonseca R, Stewart AK, Von Hoff D. Genome-wide characterization of pancreatic adenocarcinoma patients using next generation sequencing. PLoS One. 2012;7:e43192.

  124. Liu Q, Chen J, Mai B, Amos C, Killary AM, Sen S, Wei C, Frazier ML. A single-nucleotide polymorphism in tumor suppressor gene SEL1L as a predictive and prognostic marker for pancreatic ductal adenocarcinoma in Caucasians. Mol Carcinog. 2012;51:433-38.

  125. Murakawa M, Aoyama T, Miyagi Y, Kobayashi S, Ueno M, Morimoto M, Numata M, Yamamoto N, Tamagawa H, Yukawa N, Rino Y, Masuda M, Morinaga S. The impact of SPARC expression on the survival of pancreatic ductal adenocarcinoma patients after curative resection. J Cancer. 2019;10:627-33.

  126. Shintakuya R, Kondo N, Murakami Y, Uemura K, Nakagawa N, Okano K, Takahashi S, Sueda T. The high stromal SPARC expression is independently associated with poor survival of patients with resected pancreatic ductal adenocarcinoma treated with adjuvant gemcitabine in combination with S-1 or adjuvant gemcitabine alone. Pancreatology. 2018;18:191-97.

  127. Fan P, Zhao J, Meng Z, Wu H, Wang B, Wu H, Jin X. Overexpressed histone acetyltransferase 1 regulates cancer immunity by increasing programmed death-ligand 1 expression in pancreatic cancer. J Exp Clin Cancer Res. 2019;38:47.

  128. Rieser CJ, Zenati M, Hamad A, Al Abbas AI, Bahary N, Zureikat AH, Zeh HJ, 3rd, Hogg ME. CA19-9 on postoperative surveillance in pancreatic ductal adenocarcinoma: predicting recurrence and changing prognosis over time. Ann Surg Oncol. 2018;25:3483-91.

  129. Asaoka T, Miyamoto A, Maeda S, Hama N, Tsujie M, Ikeda M, Sekimoto M, Nakamori S. CA19-9 level determines therapeutic modality in pancreatic cancer patients with para-aortic lymph node metastasis. Hepatobiliary Pancreat Dis Int. 2018;17:75-80.

  130. Li S, Xu H, Wu C, Wang W, Jin W, Gao H, Li H, Zhang S, Xu J, Zhang W, Xu S. Prognostic value of y-glutamyltransferase-to-albumin ratio in patients with pancreatic ductal adenocarcinoma following radical surgery. Cancer Med. 2019 Feb;8(2):572-84.

  131. Peng HY, Chang MC, Hu CM, Yang HI, Lee WH, Chang YT. Thrombospondin-2 is a highly specific diagnostic marker and is associated with prognosis in pancreatic cancer. Ann Surg Oncol. 2019;26:807-14.

  132. Tesfaye AA, Azmi AS, Philip PA. miRNA and gene expression in pancreatic ductal adenocarcinoma. Am J Pathol. 2019;189:58-70.

  133. Isohookana J, Haapasaari KM, Soini Y, Leppanen J, Karihtala P. Proteins of the retinoblastoma pathway, FEN1 and MGMT are novel potential prognostic biomarkers in pancreatic adenocarcinoma. Pathol Res Pract. 2018;214:840-47.

  134. Gao HL, Liu L, Qi ZH, Xu HX, Wang WQ, Wu CT, Zhang SR, Xu JZ, Ni QX, Yu XJ. The clinicopathological and prognostic significance ofPD-L1 expression in pancreatic cancer: A meta-analysis. Hepatobiliary Pancreat Dis Int. 2018;17:95-100.

  135. Liu WJ, Zhou L, Liang ZY, Zhou WX, You L, Zhang TP, Zhao YP. High expression of GRK3 is associated with favorable prognosis in pancreatic ductal adenocarcinoma. Pathol Res Pract. 2018;214:228-32.

  136. Felix K, Hinz U, Dobiasch S, Hackert T, Bergmann F, Neumuller M, Gronowitz S, Bergqvist M, Strobel O. Preoperative serum thymidine kinase activity as novel monitoring, prognostic, and predictive biomarker in pancreatic cancer. Pancreas. 2018;47:72-79.