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Genomic Applications in Pancreatic and Gastric Tumors

  • Fátima Carneiro
  • Ralph H. HrubanEmail author
Chapter

Abstract

Next-generation sequencing has expanded our understanding of the molecular alterations that occur in tumors of the pancreas and stomach, and it is now becoming clear that new histologic and molecular-based classification systems are possible. These systems do not replace, but instead complement, the morphologic classification systems that have been developed and tested by pathologists over many decades. Importantly, new classification systems integrate morphology and molecular findings into cohesive systems with significant prognostic and therapeutic implications.

Keywords

Pancreatic tumors Pancreas Gastric tumors Stomach Pathogenesis Genomics Molecular pathology Intratumor heterogeneity Prognosis Targeted therapy 

Notes

Conflict of Interest

Ralph Hruban receives royalty payments from Myriad Genetics for the PALB2 invention.

Fátima Carneiro has no conflicts of interest.

Glossary

MLH1

MUT L homologue 1

MSH

MUT S homologue

MSI-H

High-grade microsatellite instability

TERT

Telomerase RT component

References

  1. 1.
    Abraham SC, Klimstra DS, Wilentz RE, Wu TT, Cameron JL, Yeo CJ, Hruban RH. Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations. Am J Pathol. 2002;160:1361–9.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Adsay NV, Merati K, Andea A, Sarkar F, Hruban RH, Wilentz RE, Goggins M, Iocobuzio-Donahue C, Longnecker DS, Klimstra DS. The dichotomy in the preinvasive neoplasia to invasive carcinoma sequence in the pancreas: differential expression of MUC1 and MUC2 supports the existence of two separate pathways of carcinogenesis. Mod Pathol. 2002;15:1087–95.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ahn S, Lee SJ, Kim Y, Kim A, Shin N, Choi KU, Lee CH, Huh GY, Kim KM, Setia N, Lauwers GY, Park DY. High-throughput protein and mRNA expression-based classification of gastric cancers can identify clinically distinct subtypes, concordant with recent molecular classifications. Am J Surg Pathol. 2017;41:106–15.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Ajani JA, Lee J, Sano T, Janjigian YY, Fan D, Song S. Gastric adenocarcinoma. Nat Rev Dis Primers. 2017;3:17036.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Alsina M, Gullo I, Carneiro F. Intratumoral heterogeneity in gastric cancer: a new challenge to face. Ann Oncol. 2017;28:912–3.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Amato E, Molin MD, Mafficini A, Yu J, Malleo G, Rusev B, Fassan M, Antonello D, Sadakari Y, Castelli P, Zamboni G, Maitra A, Salvia R, Hruban RH, Bassi C, Capelli P, Lawlor RT, Goggins M, Scarpa A. Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas. J Pathol. 2014;233:217–27.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, Miller DK, Christ AN, Bruxner TJ, Quinn MC, Nourse C, Murtaugh LC, Harliwong I, Idrisoglu S, Manning S, Nourbakhsh E, Wani S, Fink L, Holmes O, Chin V, Anderson MJ, Kazakoff S, Leonard C, Newell F, Waddell N, Wood S, Xu Q, Wilson PJ, Cloonan N, Kassahn KS, Taylor D, Quek K, Robertson A, Pantano L, Mincarelli L, Sanchez LN, Evers L, Wu J, Pinese M, Cowley MJ, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chantrill LA, Mawson A, Humphris J, Chou A, Pajic M, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Lovell JA, Merrett ND, Toon CW, Epari K, Nguyen NQ, Barbour A, Zeps N, Moran-Jones K, Jamieson NB, Graham JS, Duthie F, Oien K, Hair J, Grutzmann R, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Rusev B, Capelli P, Salvia R, Tortora G, Mukhopadhyay D, Petersen GM, I. Australian Pancreatic Cancer Genome, Munzy DM, Fisher WE, Karim SA, Eshleman JR, Hruban RH, Pilarsky C, Morton JP, Sansom OJ, Scarpa A, Musgrove EA, Bailey UH, Hofmann O, Sutherland RL, Wheeler DA, Gill AJ, Gibbs RA, Pearson JV, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531(7592):47–52.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang YK. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet (London, England). 2010;376:687–97.CrossRefGoogle Scholar
  9. 9.
    Banville N, Geraghty R, Fox E, Leahy DT, Green A, Keegan D, Geoghegan J, O'Donoghue D, Hyland J, Sheahan K. Medullary carcinoma of the pancreas in a man with hereditary nonpolyposis colorectal cancer due to a mutation of the MSH2 mismatch repair gene. Hum Pathol. 2006;37:1498–502.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Basturk O, Hong SM, Wood LD, Adsay NV, Albores-Saavedra J, Biankin AV, Brosens L, Fukushima N, Goggins M, Hruban RH, Kato Y, Klimstra D, Klöppel G, Krasinskas AM, Longnecker D, Matthaei H, Offerhaus GJ, Shimizu M, Takaori K, Terris B, Yachida S, Esposito I, Furukawa T. A revised classification system and recommendations from the Baltimore consensus meeting for neoplastic precursor lesions in the pancreas. Am J Surg Pathol. 2015;39(12):1730–41.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    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, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491:399–405.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Blackford A, Parmigiani G, Kensler TW, Wolfgang C, Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Eshleman JR, Goggins M, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Klein A, Cameron JL, Olino K, Schulick R, Winter J, Vogelstein B, Velculescu VE, Kinzler KW, Hruban RH. Genetic mutations associated with cigarette smoking in pancreatic cancer. Cancer Res. 2009a;69:3681–8.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Blackford A, Serrano OK, Wolfgang CL, Parmigiani G, Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Eshleman JR, Goggins M, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Cameron JL, Olino K, Schulick R, Winter J, Herman JM, Laheru D, Klein AP, Vogelstein B, Kinzler KW, Velculescu VE, Hruban RH. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res. 2009b;15:4674–9.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Boger C, Behrens HM, Mathiak M, Kruger S, Kalthoff H, Rocken C. PD-L1 is an independent prognostic predictor in gastric cancer of Western patients. Oncotarget. 2016;7:24269–83.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Boyd CA, Benarroch-Gampel J, Sheffield KM, Cooksley CD, Riall TS. 415 patients with adenosquamous carcinoma of the pancreas: a population-based analysis of prognosis and survival. J Surg Res. 2012;174:12–9.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Bray F, Jemal A, Grey N, Ferlay J, Forman D. Global cancer transitions according to the human development index (2008-2030): a population-based study. Lancet Oncol. 2012;13:790–801.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Brody JR, Costantino CL, Potoczek M, Cozzitorto J, McCue P, Yeo CJ, Hruban RH, Witkiewicz AK. Adenosquamous carcinoma of the pancreas harbors KRAS2, DPC4 and TP53 molecular alterations similar to pancreatic ductal adenocarcinoma. Mod Pathol. 2009;22(5):651–9.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nature Genet. 1994;8:27–32.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Carneiro F. Stomach cancer, pp. 383–391. In: Stewart BW, Wild CP, editors. World cancer report 2014. Lyon: International Agency for Research on Cancer; 2014.Google Scholar
  20. 20.
    Carneiro F, Grabsch HI. Pathogenesis of gastric cancer, pp. 61–72. In: Kukar M, Hochwald SN, editors. Minimally invasive foregut surgery for malignancy: principles and practice. Cham: Springer International Publishing; 2015.Google Scholar
  21. 21.
    Carvalho B, Buffart TE, Reis RM, Mons T, Moutinho C, Silva P, van Grieken NC, Grabsch H, van de Velde CJ, Ylstra B, Meijer GA, Carneiro F. Mixed gastric carcinomas show similar chromosomal aberrations in both their diffuse and glandular components. Cell Oncol. 2006;28:283–94.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Chmielecki J, Hutchinson KE, Frampton GM, Chalmers ZR, Johnson A, Shi C, Elvin J, Ali SM, Ross JS, Basturk O, Balasubramanian S, Lipson D, Yelensky R, Pao W, Miller VA, Klimstra DS, Stephens PJ. Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes. Cancer Discov. 2014;4:1398–405.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Collisson EA, Sadanandam A, Olson P, Gibb WJ, Truitt M, Gu S, Cooc J, Weinkle J, Kim GE, Jakkula L, Feiler HS, Ko AH, Olshen AB, Danenberg KL, Tempero MA, Spellman PT, Hanahan D, Gray JW. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med. 2011;17:500–3.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Correa P. Human gastric carcinogenesis: a multistep and multifactorial process–first American Cancer Society award lecture on cancer epidemiology and prevention. Cancer Res. 1992;52:6735–40.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Correa P. The biological model of gastric carcinogenesis. IARC Sci Publ. 2004;150:301–10.Google Scholar
  26. 26.
    Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, Liu J, Yue YG, Wang J, Yu K, Ye XS, Do IG, Liu S, Gong L, Fu J, Jin JG, Choi MG, Sohn TS, Lee JH, Bae JM, Kim ST, Park SH, Sohn I, Jung SH, Tan P, Chen R, Hardwick J, Kang WK, Ayers M, Hongyue D, Reinhard C, Loboda A, Kim S, Aggarwal A. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21:449–56.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Das K, Chan XB, Epstein D, Teh BT, Kim KM, Kim ST, Park SH, Kang WK, Rozen S, Lee J, Tan P. NanoString expression profiling identifies candidate biomarkers of RAD001 response in metastatic gastric cancer. ESMO Open. 2016;1:e000009.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Deng N, Goh LK, Wang H, Das K, Tao J, Tan IB, Zhang S, Lee M, Wu J, Lim KH, Lei Z, Goh G, Lim QY, Tan AL, Sin Poh DY, Riahi S, Bell S, Shi MM, Linnartz R, Zhu F, Yeoh KG, Toh HC, Yong WP, Cheong HC, Rha SY, Boussioutas A, Grabsch H, Rozen S, Tan P. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut. 2012;61:673–84.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Derks S, Liao X, Chiaravalli AM, Xu X, Camargo MC, Solcia E, Sessa F, Fleitas T, Freeman GJ, Rodig SJ, Rabkin CS, Bass AJ. Abundant PD-L1 expression in Epstein-Barr virus-infected gastric cancers. Oncotarget. 2016;7:32925–32.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Dong M, Wang HY, Zhao XX, Chen JN, Zhang YW, Huang Y, Xue L, Li HG, Du H, Wu XY, Shao CK. Expression and prognostic roles of PIK3CA, JAK2, PD-L1, and PD-L2 in Epstein-Barr virus-associated gastric carcinoma. Hum Pathol. 2016;53:25–34.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Donner I, Kiviluoto T, Ristimaki A, Aaltonen LA, Vahteristo P. Exome sequencing reveals three novel candidate predisposition genes for diffuse gastric cancer. Familial Cancer. 2015;14:241–6.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Endoh Y, Tamura G, Motoyama T, Ajioka Y, Watanabe H. Well-differentiated adenocarcinoma mimicking complete-type intestinal metaplasia in the stomach. Hum Pathol. 1999;30:826–32.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.CrossRefGoogle Scholar
  34. 34.
    Garcia-Carracedo D, Chen ZM, Qiu W, Huang AS, Tang SM, Hruban RH, Su GH. PIK3CA mutations in mucinous cystic neoplasms of the pancreas. Pancreas. 2014;43:245–9.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Goggins M, Offerhaus GJ, Hilgers W, Griffin CA, Shekher M, Tang D, Sohn TA, Yeo CJ, Kern SE, Hruban RH. Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology. Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+. Am J Pathol. 1998;152:1501–7.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Grabsch H, Sivakumar S, Gray S, Gabbert HE, Muller W. HER2 expression in gastric cancer: rare, heterogeneous and of no prognostic value – conclusions from 924 cases of two independent series. Cell Oncol. 2010;32:57–65.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Grogg KL, Lohse CM, Pankratz VS, Halling KC, Smyrk TC. Lymphocyte-rich gastric cancer: associations with Epstein-Barr virus, microsatellite instability, histology, and survival. Mod Pathol. 2003;16:641–51.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Gullo I, Gonçalves G, Pinto ML, Almeida GM, Oliveira C, Carneiro F. Gastric carcinoma with lymphoid stroma: a study of Epstein-Barr virus, microsatellite instability, tumor immune microenvironment and PD-L1 expression. Virchows Archiv (An International Journal of Pathology). 2016;469(Suppl 1):S3–4.Google Scholar
  39. 39.
    Gupta R, Arora R, Das P, Singh MK. Deeply eosinophilic cell variant of signet-ring type of gastric carcinoma: a diagnostic dilemma. Int J Clin Oncol. 2008;13:181–4.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science (New York, NY). 1996;271:350–3.CrossRefGoogle Scholar
  41. 41.
    Hansford S, Kaurah P, Li-Chang H, Woo M, Senz J, Pinheiro H, Schrader KA, Schaeffer DF, Shumansky K, Zogopoulos G, Santos TA, Claro I, Carvalho J, Nielsen C, Padilla S, Lum A, Talhouk A, Baker-Lange K, Richardson S, Lewis I, Lindor NM, Pennell E, MacMillan A, Fernandez B, Keller G, Lynch H, Shah SP, Guilford P, Gallinger S, Corso G, Roviello F, Caldas C, Oliveira C, Pharoah PD, Huntsman DG. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol. 2015;1:23–32.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Heaphy CM, de Wilde RF, Jiao Y, Klein AP, 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 (New York, NY). 2011;333:425.CrossRefGoogle Scholar
  43. 43.
    Hosoda W, Chianchiano P, Griffin JF, Pittman ME, Brosens LA, Noe M, Yu J, Shindo K, Suenaga M, Rezaee N, Yonescu R, Ning Y, Albores-Saavedra J, Yoshizawa N, Harada K, Yoshizawa A, Hanada K, Yonehara S, Shimizu M, Uehara T, Samra JS, Gill AJ, Wolfgang CL, Goggins MG, Hruban RH, Wood LD. Genetic analyses of isolated high-grade pancreatic intraepithelial neoplasia (HG-PanIN) reveal paucity of alterations in TP53 and SMAD4. J Pathol. 2017;242:16–23.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Hruban RH, Pitman MB, Klimstra DS. Tumors of the pancreas. Atlas of tumor pathology, vol. Fourth Series, Fascicle 6. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2007.Google Scholar
  45. 45.
    Hruban RH, van Mansfeld ADM, Offerhaus GJ, van Weering DHJ, Allison DC, Goodman SN, Kensler TW, Bose KK, Cameron JL, Bos JL. K- ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol. 1993;143:545–54.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Humphris JL, Patch AM, Nones K, Bailey PJ, Johns AL, McKay S, Chang DK, Miller DK, Pajic M, Kassahn KS, Quinn MC, Bruxner TJ, Christ AN, Harliwong I, Idrisoglu S, Manning S, Nourse C, Nourbakhsh E, Stone A, Wilson PJ, Anderson M, Fink JL, Holmes O, Kazakoff S, Leonard C, Newell F, Waddell N, Wood S, Mead RS, Xu Q, Wu J, Pinese M, Cowley MJ, Jones MD, Nagrial AM, Chin VT, Chantrill LA, Mawson A, Chou A, Scarlett CJ, Pinho AV, Rooman I, Giry-Laterriere M, Samra JS, Kench JG, Merrett ND, Toon CW, Epari K, Nguyen NQ, Barbour A, Zeps N, Jamieson NB, McKay CJ, Carter CR, Dickson EJ, Graham JS, Duthie F, Oien K, Hair J, Morton JP, Sansom OJ, Grutzmann R, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Lawlor RT, Rusev B, Corbo V, Salvia R, Cataldo I, Tortora G, Tempero MA, I. Australian Pancreatic Cancer Genome, Hofmann O, Eshleman JR, Pilarsky C, Scarpa A, Musgrove EA, Gill AJ, Pearson JV, Grimmond SM, Waddell N, Biankin AV. Hypermutation in pancreatic cancer. Gastroenterology. 2017;152:68–74.e62.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Infante MH, Sato N, Tonascia J, Klein AP, Riall TS, Yeo CJ, Iacobuzio-Donahue CA, Goggins M. Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. J Clin Oncol. 2007;25:319–25.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    JGCA. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011;14:101–12.CrossRefGoogle Scholar
  50. 50.
    Jiao Y, Yonescu R, Offerhaus GJ, Klimstra DS, Maitra A, Eshleman JR, Herman JG, Poh W, Pelosof L, Wolfgang CL, Vogelstein B, Kinzler KW, Hruban RH, Papadopoulos N, Wood LD. Whole-exome sequencing of pancreatic neoplasms with acinar differentiation. J Pathol. 2014;232:428–35.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang LH, Wolfgang CL, Choti MA, Velculescu VE, Diaz LA Jr, Vogelstein B, Kinzler KW, Hruban RH, Papadopoulos N. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science (New York, NY). 2011;331:1199–203.CrossRefGoogle Scholar
  52. 52.
    Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, Lin JC, Palmisano E, Brune K, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Parmigiani G, Kern SE, Velculescu VE, Kinzler KW, Vogelstein B, Eshleman JR, Goggins M, Klein AP. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science (New York, NY). 2009;324:217.CrossRefGoogle Scholar
  53. 53.
    Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science (New York, NY). 2008;321:1801–6.CrossRefGoogle Scholar
  54. 54.
    Joo M, Han SH. Gastric-type extremely well-differentiated adenocarcinoma of the stomach: a challenge for preoperative diagnosis. J Pathol Transl Med. 2016;50:71–4.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Kakiuchi M, Nishizawa T, Ueda H, Gotoh K, Tanaka A, Hayashi A, Yamamoto S, Tatsuno K, Katoh H, Watanabe Y, Ichimura T, Ushiku T, Funahashi S, Tateishi K, Wada I, Shimizu N, Nomura S, Koike K, Seto Y, Fukayama M, Aburatani H, Ishikawa S. Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat Genet. 2014;46:583–7.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Kanda M, Sadakari Y, Borges M, Topazian M, Farrell J, Syngal S, Lee J, Kamel I, Lennon AM, Knight S, Fujiwara S, Hruban RH, Canto MI, Goggins M. Mutant TP53 in duodenal samples of pancreatic juice from patients with pancreatic cancer or high-grade dysplasia. Clin Gastroenterol Hepatol. 2013a;11:719–730.e715.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Kanda M, Knight S, Topazian M, Syngal S, Farrell J, Lee J, Kamel I, Lennon AM, Borges M, Young A, Fujiwara S, Seike J, Eshleman J, Hruban RH, Canto MI, Goggins M. Mutant GNAS detected in duodenal collections of secretin-stimulated pancreatic juice indicates the presence or emergence of pancreatic cysts. Gut. 2013b;62:1024–33.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Kaneda A, Matsusaka K, Aburatani H, Fukayama M. Epstein-Barr virus infection as an epigenetic driver of tumorigenesis. Cancer Res. 2012;72:3445–50.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Kawazoe A, Kuwata T, Kuboki Y, Shitara K, Nagatsuma AK, Aizawa M, Yoshino T, Doi T, Ohtsu A, Ochiai A. Clinicopathological features of programmed death ligand 1 expression with tumor-infiltrating lymphocyte, mismatch repair, and Epstein-Barr virus status in a large cohort of gastric cancer patients. Gastric Cancer. 2017;20:407–15.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Kim H, An JY, Noh SH, Shin SK, Lee YC, Kim H. High microsatellite instability predicts good prognosis in intestinal-type gastric cancers. J Gastroenterol Hepatol. 2011;26:585–92.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Kim HS, Shin SJ, Beom SH, Jung M, Choi YY, Son T, Kim HI, Cheong JH, Hyung WJ, Noh SH, Chung H, Park JC, Shin SK, Lee SK, Lee YC, Koom WS, Lim JS, Chung HC, Rha SY, Kim H. Comprehensive expression profiles of gastric cancer molecular subtypes by immunohistochemistry: implications for individualized therapy. Oncotarget. 2016;7:44608–20.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Koorstra JB, Maitra A, Morsink FH, Drillenburg P, Ten Kate FJ, Hruban RH, Offerhaus JA. Undifferentiated Carcinoma with Osteoclastic Giant Cells (UCOCGC) of the pancreas associated with the Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM). Am J Surg Pathol. 2008;32:1905–9.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson KA, Byars A, Sahmoud T, Franz DN. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363:1801–11.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Laurén P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand. 1965;64:31–49.Google Scholar
  65. 65.
    Lauwers GY, Carneiro F, Graham DY, Curado M-P, Franceschi S, Montgomery E, Tatematsu M, Hattori T. Gastric Cancer. 4th ed. Lyon: IARC; 2010.Google Scholar
  66. 66.
    Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science (New York, NY). 2017;357(6349):409–13.CrossRefGoogle Scholar
  68. 68.
    Lee WA. Gastric extremely well differentiated adenocarcinoma of gastric phenotype: as a gastric counterpart of adenoma malignum of the uterine cervix. World J Surg Oncol. 2005;3:28.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Lee YS, Cho YS, Lee GK, Lee S, Kim YW, Jho S, Kim HM, Hong SH, Hwang JA, Kim SY, Hong D, Choi IJ, Kim BC, Kim BC, Kim CH, Choi H, Kim Y, Kim KW, Kong G, Kim HL, Bhak J, Lee SH, Lee JS. Genomic profile analysis of diffuse-type gastric cancers. Genome Biol. 2014;15(4):R55.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Lei Z, Tan IB, Das K, Deng N, Zouridis H, Pattison S, Chua C, Feng Z, Guan YK, Ooi CH, Ivanova T, Zhang S, Lee M, Wu J, Ngo A, Manesh S, Tan E, Teh BT, So JB, Goh LK, Boussioutas A, Lim TK, Flotow H, Tan P, Rozen SG. Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil. Gastroenterology. 2013;145:554–65.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Lennon AM, Wolfgang CL, Canto MI, Klein AP, Herman JM, Goggins M, Fishman EK, Kamel I, Weiss MJ, Diaz LA, Papadopoulos N, Kinzler KW, Vogelstein B, Hruban RH. The early detection of pancreatic cancer: what will it take to diagnose and treat curable pancreatic neoplasia? Cancer Res. 2014;74:3381–9.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Li J, Woods SL, Healey S, Beesley J, Chen X, Lee JS, Sivakumaran H, Wayte N, Nones K, Waterfall JJ, Pearson J, Patch AM, Senz J, Ferreira MA, Kaurah P, Mackenzie R, Heravi-Moussavi A, Hansford S, Lannagan TR, Spurdle AB, Simpson PT, da Silva L, Lakhani SR, Clouston AD, Bettington M, Grimpen F, Busuttil RA, Di Costanzo N, Boussioutas A, Jeanjean M, Chong G, Fabre A, Olschwang S, Faulkner GJ, Bellos E, Coin L, Rioux K, Bathe OF, Wen X, Martin HC, Neklason DW, Davis SR, Walker RL, Calzone KA, Avital I, Heller T, Koh C, Pineda M, Rudloff U, Quezado M, Pichurin PN, Hulick PJ, Weissman SM, Newlin A, Rubinstein WS, Sampson JE, Hamman K, Goldgar D, Poplawski N, Phillips K, Schofield L, Armstrong J, Kiraly-Borri C, Suthers GK, Huntsman DG, Foulkes WD, Carneiro F, Lindor NM, Edwards SL, French JD, Waddell N, Meltzer PS, Worthley DL, Schrader KA, Chenevix-Trench G. Point mutations in exon 1B of APC reveal gastric adenocarcinoma and proximal polyposis of the stomach as a familial adenomatous polyposis variant. Am J Hum Genet. 2016a;98:830–42.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Li X, Wu WK, Xing R, Wong SH, Liu Y, Fang X, Zhang Y, Wang M, Wang J, Li L, Zhou Y, Tang S, Peng S, Qiu K, Chen L, Chen K, Yang H, Zhang W, Chan MT, Lu Y, Sung JJ, Yu J. Distinct subtypes of gastric Cancer defined by molecular characterization include novel mutational signatures with prognostic capability. Cancer Res. 2016b;76:1724–32.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Li Z, Lai Y, Sun L, Zhang X, Liu R, Feng G, Zhou L, Jia L, Huang X, Kang Q, Lin D, Gao J, Shen L. PD-L1 expression is associated with massive lymphocyte infiltration and histology in gastric cancer. Hum Pathol. 2016c;55:182–9.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Lim H, Park YS, Lee JH, Son DH, Ahn JY, Choi KS, Kim DH, Choi KD, Song HJ, Lee GH, Jung HY, Kim JH, Yook JH, Kim BS. Features of gastric carcinoma with lymphoid stroma associated with Epstein-Barr virus. Clinical Gastroenterol Hepatol. 2015;13:1738–1744.e1732.CrossRefGoogle Scholar
  76. 76.
    Liu C, Karam R, Zhou Y, Su F, Ji Y, Li G, Xu G, Lu L, Wang C, Song M, Zhu J, Wang Y, Zhao Y, Foo WC, Zuo M, Valasek MA, Javle M, Wilkinson MF, Lu Y. The UPF1 RNA surveillance gene is commonly mutated in pancreatic adenosquamous carcinoma. Nat Med. 2014a;20:596–8.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Liu W, Shia J, Gonen M, Lowery MA, O’Reilly EM, Klimstra DS. DNA mismatch repair abnormalities in acinar cell carcinoma of the pancreas: frequency and clinical significance. Pancreas. 2014b;43:1264–70.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Liu X, Meltzer SJ. Gastric Cancer in the era of precision medicine. Cell Mol Gastroenterol Hepatol. 2017;3:348–58.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Lowery MA, Kelsen DP, Stadler ZK, Yu KH, Janjigian YY, Ludwig E, D’Adamo DR, Salo-Mullen E, Robson ME, Allen PJ, Kurtz RC, O'Reilly EM. An emerging entity: pancreatic adenocarcinoma associated with a known BRCA mutation: clinical descriptors, treatment implications, and future directions. Oncologist. 2011;16:1397–402.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Lu BJ, Lai M, Cheng L, Xu JY, Huang Q. Gastric medullary carcinoma, a distinct entity associated with microsatellite instability-H, prominent intraepithelial lymphocytes and improved prognosis. Histopathology. 2004;45:485–92.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Ma C, Patel K, Singhi AD, Ren B, Zhu B, Shaikh F, Sun W. Programmed death-ligand 1 expression is common in gastric cancer associated with Epstein-Barr virus or microsatellite instability. Am J Surg Pathol. 2016;40:1496–506.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Machado JC, Soares P, Carneiro F, Rocha A, Beck S, Blin N, Berx G, Sobrinho-Simoes M. E-cadherin gene mutations provide a genetic basis for the phenotypic divergence of mixed gastric carcinomas. Lab Investig. 1999;79:459–65.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Mafficini A, Amato E, Fassan M, Simbolo M, Antonello D, Vicentini C, Scardoni M, Bersani S, Gottardi M, Rusev B, Malpeli G, Corbo V, Barbi S, Sikora KO, Lawlor RT, Tortora G, Scarpa A. Reporting tumor molecular heterogeneity in histopathological diagnosis. PLoS One. 2014;9:e104979.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Majewski IJ, Kluijt I, Cats A, Scerri TS, de Jong D, Kluin RJ, Hansford S, Hogervorst FB, Bosma AJ, Hofland I, Winter M, Huntsman D, Jonkers J, Bahlo M, Bernards R. An alpha-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer. J Pathol. 2013;229:621–9.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Moffitt RA, Marayati R, Flate EL, Volmar KE, Loeza SG, Hoadley KA, Rashid NU, Williams LA, Eaton SC, Chung AH, Smyla JK, Anderson JM, Kim HJ, Bentrem DJ, Talamonti MS, Iacobuzio-Donahue CA, Hollingsworth MA, Yeh JJ. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet. 2015;47:1168–78.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Nakata B, Wang YQ, Yashiro M, Ohira M, Ishikawa T, Nishino H, Seki S, Hirakawa K. Negative hMSH2 protein expression in pancreatic carcinoma may predict a better prognosis of patients. Oncol Rep. 2003;10:997–1000.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Oliveira C, Pinheiro H, Figueiredo J, Seruca R, Carneiro F. Familial gastric cancer: genetic susceptibility, pathology, and implications for management. Lancet Oncol. 2015;16:e60–70.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Osaka H, Yashiro M, Nishino H, Nakata B, Ohira M, Hirakawa K. A case of osteoclast-type giant cell tumor of the pancreas with high-frequency microsatellite instability. Pancreas. 2004;29:239–41.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Park CK, Park JS, Kim HS, Rha SY, Hyung WJ, Cheong JH, Noh SH, Lee SK, Lee YC, Huh YM, Kim H. Receptor tyrosine kinase amplified gastric cancer: clinicopathologic characteristics and proposed screening algorithm. Oncotarget. 2016;7:72099–112.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Park S, Choi MG, Kim KM, Kim HS, Jung SH, Lee JH, Noh JH, Sohn TS, Bae JM, Kim S. Lymphoepithelioma-like carcinoma: a distinct type of gastric cancer. J Surg Res. 2015;194:458–63.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Park SY, Kook MC, Kim YW, Cho NY, Kim TY, Kang GH. Mixed-type gastric cancer and its association with high-frequency CpG island hypermethylation. Virchows Arch. 2010;456:625–33.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 2006;118:3030–44.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Redston MS, Caldas C, Seymour AB, Hruban RH, da Costa L, Yeo CJ, Kern SE. p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res. 1994;54:3025–33.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Roberts NJ, Jiao Y, Yu J, Kopelovich L, Petersen GM, Bondy ML, Gallinger S, Schwartz AG, Syngal S, Cote ML, Axilbund J, Schulick R, Ali SZ, Eshleman JR, Velculescu VE, Goggins M, Vogelstein B, Papadopoulos N, Hruban RH, Kinzler KW, Klein AP. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012;2:41–6.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Roberts NJ, Norris AL, Petersen GM, Bondy ML, Brand R, Gallinger S, Kurtz RC, Olson SH, Rustgi AK, Schwartz AG, Stoffel E, Syngal S, Zogopoulos G, Ali SZ, Axilbund J, Chaffee KG, Chen YC, Cote ML, Childs EJ, Douville C, Goes FS, Herman JM, Iacobuzio-Donahue C, Kramer M, Makohon-Moore A, McCombie RW, McMahon KW, Niknafs N, Parla J, Pirooznia M, Potash JB, Rhim AD, Smith AL, Wang Y, Wolfgang CL, Wood LD, Zandi PP, Goggins M, Karchin R, Eshleman JR, Papadopoulos N, Kinzler KW, Vogelstein B, Hruban RH, Klein AP. Whole genome sequencing defines the genetic heterogeneity of familial pancreatic cancer. Cancer Discov. 2016;6:166–75.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Ruschoff J, Dietel M, Baretton G, Arbogast S, Walch A, Monges G, Chenard MP, Penault-Llorca F, Nagelmeier I, Schlake W, Hofler H, Kreipe HH. HER2 diagnostics in gastric cancer-guideline validation and development of standardized immunohistochemical testing. Virchows Arch. 2010;457:299–307.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Samdani RT, Hechtman JF, O'Reilly E, DeMatteo R, Sigel CS. EBV-associated lymphoepithelioma-like carcinoma of the pancreas: case report with targeted sequencing analysis. Pancreatology. 2015;15:302–4.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Sausen M, Phallen J, Adleff V, Jones S, Leary RJ, Barrett MT, Anagnostou V, Parpart-Li S, Murphy D, Kay Li Q, Hruban CA, Scharpf R, White JR, O’Dwyer PJ, Allen PJ, Eshleman JR, Thompson CB, Klimstra DS, Linehan DC, Maitra A, Hruban RH, Diaz LA Jr, Von Hoff DD, Johansen JS, Drebin JA, Velculescu VE. Clinical implications of genomic alterations in the tumor and circulation of pancreatic cancer patients. Nat Commun. 2015;6:7686.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Seidel G, Zahurak M, Iacobuzio-Donahue CA, Sohn TA, Adsay NV, Yeo CJ, Lillemoe KD, Cameron JL, Hruban RH, Wilentz RE. Almost all infiltrating colloid carcinomas of the pancreas and periampullary region arise from in situ papillary neoplasms: a study of 39 cases. Am J Surg Pathol. 2002;26:56–63.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Setia N, Agoston AT, Han HS, Mullen JT, Duda DG, Clark JW, Deshpande V, Mino-Kenudson M, Srivastava A, Lennerz JK, Hong TS, Kwak EL, Lauwers GY. A protein and mRNA expression-based classification of gastric cancer. Modern Pathol. 2016;29:772–84.CrossRefGoogle Scholar
  101. 101.
    Smit VTHBM, Boot AJM, Smits AMM, Fleuren GJ, Cornelisse CJ, Bos JL. K- ras codon 12 mutations occur very frequently in pancreatic adenocarcinomas. Nucleic Acids Res. 1988;16:7773–82.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Solcia E, Klersy C, Mastracci L, Alberizzi P, Candusso ME, Diegoli M, Tava F, Riboni R, Manca R, Luinetti O. A combined histologic and molecular approach identifies three groups of gastric cancer with different prognosis. Virchows Arch. 2009;455:197–211.CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Speck O, Tang W, Morgan DR, Kuan PF, Meyers MO, Dominguez RL, Martinez E, Gulley ML. Three molecular subtypes of gastric adenocarcinoma have distinct histochemical features reflecting Epstein-Barr virus infection status and neuroendocrine differentiation. Appl Immunohistochem Mol Morphol. 2015;23:633–45.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Springer S, Wang Y, Molin MD, Masica DL, Jiao Y, Kinde I, Blackford A, Raman SP, Wolfgang CL, Tomita T, Niknafs N, Douville C, Ptak J, Dobbyn L, Allen PJ, Klimstra DS, Schattner MA, Schmidt MC, Yip-Schneider M, Cummings OW, Brand RE, Zeh HJ, Singhi AD, Scarpa A, Salvia R, Malleo G, Zamboni G, Falconi M, Jang JY, Kim SW, Kwon W, Hong SM, Song KB, Kim SC, Swan N, Murphy J, Geoghegan J, Brugge W, Fernandez-Del Castillo C, Mino-Kenudson M, Schulick R, Edil BH, Adsay V, Paulino J, van Hooft J, Yachida S, Nara S, Hiraoka N, Yamao K, Hijioka S, van der Merwe S, Goggins M, Canto MI, Ahuja N, Hirose K, Makary M, Weiss MJ, Cameron J, Pittman M, Eshleman JR, Diaz LA Jr, Papadopoulos N, Kinzler KW, Karchin R, Hruban RH, Vogelstein B, Lennon AM. A combination of molecular markers and clinical features improve the classification of pancreatic cysts. Gastroenterology. 2015;149:1501–10.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Tan IB, Ivanova T, Lim KH, Ong CW, Deng N, Lee J, Tan SH, Wu J, Lee MH, Ooi CH, Rha SY, Wong WK, Boussioutas A, Yeoh KG, So J, Yong WP, Tsuburaya A, Grabsch H, Toh HC, Rozen S, Cheong JH, Noh SH, Wan WK, Ajani JA, Lee JS, Tellez MS, Tan P. Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. Gastroenterology. 2011;141:476–85, 485.e471-411.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    TCGA. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–9.CrossRefGoogle Scholar
  107. 107.
    Thompson ED, Zahurak M, Murphy A, Cornish T, Cuka N, Abdelfatah E, Yang S, Duncan M, Ahuja N, Taube JM, Anders RA, Kelly RJ. Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma. Gut. 2017;66:794–801.CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Tsukashita S, Kushima R, Bamba M, Sugihara H, Hattori T. MUC gene expression and histogenesis of adenocarcinoma of the stomach. Int J Cancer. 2001;94:166–70.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Ushiku T, Arnason T, Ban S, Hishima T, Shimizu M, Fukayama M, Lauwers GY. Very well-differentiated gastric carcinoma of intestinal type: analysis of diagnostic criteria. Modern Pathol. 2013;26:1620–31.CrossRefGoogle Scholar
  110. 110.
    Valente P, Garrido M, Gullo I, Baldaia H, Marques M, Baldaque-Silva F, Lopes J, Carneiro F. Epithelial dysplasia of the stomach with gastric immunophenotype shows features of biological aggressiveness. Gastric Cancer. 2015;18:720–8.CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    van der Post RS, Vogelaar IP, Carneiro F, Guilford P, Huntsman D, Hoogerbrugge N, Caldas C, Schreiber KE, Hardwick RH, Ausems MG, Bardram L, Benusiglio PR, Bisseling TM, Blair V, Bleiker E, Boussioutas A, Cats A, Coit D, DeGregorio L, Figueiredo J, Ford JM, Heijkoop E, Hermens R, Humar B, Kaurah P, Keller G, Lai J, Ligtenberg MJ, O'Donovan M, Oliveira C, Pinheiro H, Ragunath K, Rasenberg E, Richardson S, Roviello F, Schackert H, Seruca R, Taylor A, Ter Huurne A, Tischkowitz M, Joe ST, van Dijck B, van Grieken NC, van Hillegersberg R, van Sandick JW, Vehof R, van Krieken JH, Fitzgerald RC. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet. 2015;52:361–74.CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Vogelstein B, Kinzler KW. The path to cancer – three strikes and You’re out. N Engl J Med. 2015;373:1895–8.CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–703.CrossRefGoogle Scholar
  114. 114.
    Voong KR, Davison J, Pawlik TM, Uy MO, Hsu CC, Winter J, Hruban RH, Laheru D, Rudra S, Swartz MJ, Nathan H, Edil BH, Schulick R, Cameron JL, Wolfgang CL, Herman JM. Resected pancreatic adenosquamous carcinoma: clinicopathologic review and evaluation of adjuvant chemotherapy and radiation in 38 patients. Hum Pathol. 2010;41:113–22.CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, Johns AL, Miller D, Nones K, Quek K, Quinn MC, Robertson AJ, Fadlullah MZ, Bruxner TJ, Christ AN, Harliwong I, Idrisoglu S, Manning S, Nourse C, Nourbakhsh E, Wani S, Wilson PJ, Markham E, Cloonan N, Anderson MJ, Fink JL, Holmes O, Kazakoff SH, Leonard C, Newell F, Poudel B, Song S, Taylor D, Wood S, Xu Q, Wu J, Pinese M, Cowley MJ, Lee HC, Jones MD, Nagrial AM, Humphris J, Chantrill LA, Chin V, Steinmann AM, Mawson A, Humphrey ES, Colvin EK, Chou A, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Pettitt JA, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N, Jamieson NB, Graham JS, Niclou SP, Bjerkvig R, Grutzmann R, Aust D, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Falconi M, Zamboni G, Tortora G, Tempero MA, Gill AJ, Eshleman JR, Pilarsky C, Scarpa A, Musgrove EA, Pearson JV, Biankin AV, Grimmond SM. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518:495–501.CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Wang HH, Wu MS, Shun CT, Wang HP, Lin CC, Lin JT. Lymphoepithelioma-like carcinoma of the stomach: a subset of gastric carcinoma with distinct clinicopathological features and high prevalence of Epstein-Barr virus infection. Hepato-Gastroenterology. 1999;46:1214–9.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Wang K, Yuen ST, Xu J, Lee SP, Yan HH, Shi ST, Siu HC, Deng S, Chu KM, Law S, Chan KH, Chan AS, Tsui WY, Ho SL, Chan AK, Man JL, Foglizzo V, Ng MK, Chan AS, Ching YP, Cheng GH, Xie T, Fernandez J, Li VS, Clevers H, Rejto PA, Mao M, Leung SY. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet. 2014;46:573–82.CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Westra WH, Sturm PJ, Drillenburg P, Choti MA, Klimstra DS, Abores-Saavedra J, Montag A, Offerhaus GJ, Hruban RH. K-ras oncogene mutations in osteoclast-like giant cell tumors of the pancreas and liver: genetic evidence to support origin from the duct epithelium. Am J Surg Pathol. 1998;22:1247–54.CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti MA, Zahurak M, Johnson KA, Tascilar M, Offerhaus GJ, Hruban RH, Kern SE. Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: a newly described and characterized entity. Am J Pathol. 2000;156:1641–51.CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Winter JM, Ting AH, Vilardell F, Gallmeier E, Baylin SB, Hruban RH, Kern SE, Iacobuzio-Donahue CA. Absence of E-cadherin expression distinguishes noncohesive from cohesive pancreatic cancer. Clin Cancer Res. 2008;14:412–8.CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Witkiewicz AK, McMillan EA, Balaji U, Baek G, Lin WC, Mansour J, Mollaee M, Wagner KU, Koduru P, Yopp A, Choti MA, Yeo CJ, McCue P, White MA, Knudsen ES. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun. 2015;6:6744.CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Wong H, Yau T. Molecular targeted therapies in advanced gastric cancer: does tumor histology matter? Ther Adv Gastroenterol. 2013;6:15–31.CrossRefGoogle Scholar
  123. 123.
    Wood LD, Hruban RH. Pathology and molecular genetics of pancreatic neoplasms. Cancer J. 2012;18:492–501.CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, Ballinger DG, Sparks AB, Hartigan J, Smith DR, Suh E, Papadopoulos N, Buckhaults P, Markowitz SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B. The genomic landscapes of human breast and colorectal cancers. Science (New York, NY). 2007;318:1108–13.CrossRefGoogle Scholar
  125. 125.
    Worthley DL, Phillips KD, Wayte N, Schrader KA, Healey S, Kaurah P, Shulkes A, Grimpen F, Clouston A, Moore D, Cullen D, Ormonde D, Mounkley D, Wen X, Lindor N, Carneiro F, Huntsman DG, Chenevix-Trench G, Suthers GK. Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome. Gut. 2012;61:774–9.CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Wu J, Matthaei H, Maitra A, Dal Molin M, Wood LD, Eshleman JR, Goggins M, Canto MI, Schulick RD, Edil BH, Wolfgang CL, Klein AP, Diaz LA Jr, Allen PJ, Schmidt CM, Kinzler KW, Papadopoulos N, Hruban RH, Vogelstein B. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med. 2011a;3:92ra66.CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Wu J, Jiao Y, Dal Molin M, Maitra A, de Wilde RF, Wood LD, Eshleman JR, Goggins MG, Wolfgang CL, Canto MI, Schulick RD, Edil BH, Choti MA, Adsay V, Klimstra DS, Offerhaus GJ, Klein AP, Kopelovich L, Carter H, Karchin R, Allen PJ, Schmidt CM, Naito Y, Diaz LA Jr, Kinzler KW, Papadopoulos N, Hruban RH, Vogelstein B. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc Natl Acad Sci U S A. 2011b;108:21188–93.CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Yachida S, Vakiani E, White CM, Zhong Y, Saunders T, Morgan R, de Wilde RF, Maitra A, Hicks J, Demarzo AM, Shi C, Sharma R, Laheru D, Edil BH, Wolfgang CL, Schulick RD, Hruban RH, Tang LH, Klimstra DS, Iacobuzio-Donahue CA. Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am J Surg Pathol. 2012;36:173–84.CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Yamazawa S, Ushiku T, Shinozaki-Ushiku A, Hayashi A, Iwasaki A, Abe H, Tagashira A, Yamashita H, Seto Y, Aburatani H, Fukayama M. Gastric cancer with primitive enterocyte phenotype: an aggressive subgroup of intestinal-type adenocarcinoma. Am J Surg Pathol. 2017;41(7):989–97.CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Yanaru-Fujisawa R, Nakamura S, Moriyama T, Esaki M, Tsuchigame T, Gushima M, Hirahashi M, Nagai E, Matsumoto T, Kitazono T. Familial fundic gland polyposis with gastric cancer. Gut. 2012;61:1103–4.CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Oberg K. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514–23.CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Yao T, Utsunomiya T, Oya M, Nishiyama K, Tsuneyoshi M. Extremely well-differentiated adenocarcinoma of the stomach: clinicopathological and immunohistochemical features. World J Gastroenterol. 2006;12:2510–6.CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Yu J, Sadakari Y, Shindo K, Suenaga M, Brant A, Almario JA, Borges M, Barkley T, Fesharakizadeh S, Ford M, Hruban RH, Shin EJ, Lennon AM, Canto MI, Goggins M. Digital next-generation sequencing identifies low-abundance mutations in pancreatic juice samples collected from the duodenum of patients with pancreatic cancer and intraductal papillary mucinous neoplasms. Gut. 2016;66(9):1677–87.CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Zhen DB, Rabe KG, Gallinger S, Syngal S, Schwartz AG, Goggins MG, Hruban RH, Cote ML, McWilliams RR, Roberts NJ, Cannon-Albright LA, Li D, Moyes K, Wenstrup RJ, Hartman AR, Seminara D, Klein AP, Petersen GM. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med. 2015;17:569–77.CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Zheng HC, Li XH, Hara T, Masuda S, Yang XH, Guan YF, Takano Y. Mixed-type gastric carcinomas exhibit more aggressive features and indicate the histogenesis of carcinomas. Virchows Arch. 2008;452:525–34.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Ipatimup/i3S, Faculty of Medicine of the University of Porto and Centro Hospitalar São JoãoPortoPortugal
  2. 2.The Sol Goldman Pancreatic Cancer Research Center, Departments of Pathology and OncologyJohns Hopkins University School of MedicineBaltimoreUSA

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