J Pathol Transl Med.  2016 Jan;50(1):1-9. 10.4132/jptm.2015.09.10.

Molecular Dimensions of Gastric Cancer: Translational and Clinical Perspectives

• Choi YY
• Noh SH
• Cheong JH

• KMID: 2211395
• DOI: http://doi.org/10.4132/jptm.2015.09.10

Abstract

Gastric cancer is a global health burden and has the highest incidence in East Asia. This disease is complex in nature because it arises from multiple interactions of genetic, local environmental, and host factors, resulting in biological heterogeneity. This genetic intricacy converges on molecular characteristics reflecting the pathophysiology, tumor biology, and clinical outcome. Therefore, understanding the molecular characteristics at a genomic level is pivotal to improving the clinical care of patients with gastric cancer. A recent landmark study, The Cancer Genome Atlas (TCGA) project, showed the molecular landscape of gastric cancer through a comprehensive molecular evaluation of 295 primary gastric cancers. The proposed molecular classification divided gastric cancer into four subtypes: Epstein-Barr virus-positive, microsatellite unstable, genomic stable, and chromosomal instability. This information will be taken into account in future clinical trials and will be translated into clinical therapeutic decisions. To fully realize the clinical benefit, many challenges must be overcome. Rapid growth of high-throughput biology and functional validation of molecular targets will further deepen our knowledge of molecular dimensions of this cancer, allowing for personalized precision medicine.

Keyword

Stomach neoplasms; Translational medical research; Cancer genomics; Cancer genetics; Target therapy

MeSH Terms

Biology
Chromosomal Instability
Classification
Far East
Genome
Humans
Incidence
Microsatellite Repeats
Population Characteristics
Stomach Neoplasms*
Translational Medical Research

Reference

1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 136:E359–86.

2. Jung KW, Won YJ, Kong HJ, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2012. Cancer Res Treat. 2015; 47:127–41.

3. Jung KW, Won YJ, Oh CM, et al. Prediction of cancer incidence and mortality in Korea, 2015. Cancer Res Treat. 2015; 47:142–8.

4. Lee KS, Oh DK, Han MA, et al. Gastric cancer screening in Korea: report on the national cancer screening program in 2008. Cancer Res Treat. 2011; 43:83–8.

5. Suh M, Choi KS, Lee YY, Jun JK. Trends in cancer screening rates among Korean men and women: results from the Korean National Cancer Screening Survey, 2004-2012. Cancer Res Treat. 2013; 45:86–94.

6. Ajani JA, Bentrem DJ, Besh S, et al. Gastric cancer, version 2.2013: featured updates to the NCCN Guidelines. J Natl Compr Canc Netw. 2013; 11:531–46.

7. Waddell T, Verheij M, Allum W, et al. Gastric cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013; 24 Suppl 6:vi57–63.

8. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2010 (ver. 3). Gastric Cancer. 2011; 14:113–23.

9. Songun I, Putter H, Kranenbarg EM, Sasako M, van de Velde CJ. Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol. 2010; 11:439–49.

10. Wu CW, Hsiung CA, Lo SS, et al. Nodal dissection for patients with gastric cancer: a randomised controlled trial. Lancet Oncol. 2006; 7:309–15.

11. Bang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012; 379:315–21.

12. Noh SH, Park SR, Yang HK, et al. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol. 2014; 15:1389–96.

13. Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007; 357:1810–20.

14. Sasako M, Sakuramoto S, Katai H, et al. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 2011; 29:4387–93.

15. Ohtsu A, Shah MA, Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011; 29:3968–76.

16. Bang YJ, Van Cutsem E, Feyereislova A, et al. 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. 2010; 376:687–97.

17. Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO classification of tumours of the digestive system. 4th ed. Lyon: IARC Press;2010.

18. Lauren P. The Two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma: an attempt at a histoclinical classification. Acta Pathol Microbiol Scand. 1965; 64:31–49.

19. Choi YY, Noh SH, Cheong JH. Evolution of gastric cancer treatment: from the golden age of surgery to an era of precision medicine. Yonsei Med J. 2015; 56:1177–85.

20. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014; 513:202–9.

21. Muro K, Bang Y, Shankaran V, et al. A phase 1B study of pembrolizumab (Pembro; MK-3475) in patients (pts) with advanced gastric cancer. Ann Oncol. 2014; 25 Suppl 4:LBA15.

22. Mueller A, Bachmann E, Linnig M, et al. Selective PI3K inhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines. Cancer Chemother Pharmacol. 2012; 69:1601–15.

23. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015; 372:2509–20.

24. Huntsman DG, Carneiro F, Lewis FR, et al. Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations. N Engl J Med. 2001; 344:1904–9.

25. Lordick F, Kang YK, Chung HC, et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013; 14:490–9.

26. Waddell T, Chau I, Cunningham D, et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol. 2013; 14:481–9.

27. Satoh T, Xu RH, Chung HC, et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN: a randomized, phase III study. J Clin Oncol. 2014; 32:2039–49.

28. Lennerz JK, Kwak EL, Ackerman A, et al. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J Clin Oncol. 2011; 29:4803–10.

29. Iveson T, Donehower RC, Davidenko I, et al. Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: an open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study. Lancet Oncol. 2014; 15:1007–18.

30. Doshi S, Gisleskog PO, Zhang Y, et al. Rilotumumab exposure-response relationship in patients with advanced or metastatic gastric cancer. Clin Cancer Res. 2015; 21:2453–61.

31. Amgen announces termination of all amgen-sponsored clinical studies of rilotumumab in advanced gastric cancer [Internet]. New York: PR Newswire Association LLC;2014. [cited 2015 Oct 1]. Available from: http://www.prnewswire.com/news-releases/amgenannounces-termination-of-all-amgen-sponsored-clinical-studiesof-rilotumumab-in-advanced-gastric-cancer-300000103.html.

32. Van Cutsem E, de Haas S, Kang YK, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol. 2012; 30:2119–27.

33. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014; 383:31–9.

34. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014; 15:1224–35.

35. Murphy G, Pfeiffer R, Camargo MC, Rabkin CS. Meta-analysis shows that prevalence of Epstein-Barr virus-positive gastric cancer differs based on sex and anatomic location. Gastroenterology. 2009; 137:824–33.

36. Kaneda A, Matsusaka K, Aburatani H, Fukayama M. Epstein-Barr virus infection as an epigenetic driver of tumorigenesis. Cancer Res. 2012; 72:3445–50.

37. Tan P, Yeoh KG. Genetics and molecular pathogenesis of gastric adenocarcinoma. Gastroenterology. 2015; 149:1153–62. e3.

38. 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.

39. Wang K, Kan J, Yuen ST, et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat Genet. 2011; 43:1219–23.

40. Bitler BG, Aird KM, Garipov A, et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med. 2015; 21:231–8.

41. An JY, Kim H, Cheong JH, Hyung WJ, Kim H, Noh SH. Microsatellite instability in sporadic gastric cancer: its prognostic role and guidance for 5-FU based chemotherapy after R0 resection. Int J Cancer. 2012; 131:505–11.

42. Lee HS, Choi SI, Lee HK, et al. Distinct clinical features and outcomes of gastric cancers with microsatellite instability. Mod Pathol. 2002; 15:632–40.

43. Choi YY, Bae JM, An JY, et al. Is microsatellite instability a prognostic marker in gastric cancer? A systematic review with meta-analysis. J Surg Oncol. 2014; 110:129–35.

44. Cristescu R, Lee J, Nebozhyn M, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015; 21:449–56.

45. Kim SY, Choi YY, An JY, et al. The benefit of microsatellite instability is attenuated by chemotherapy in stage II and stage III gastric cancer: results from a large cohort with subgroup analyses. Int J Cancer. 2015; 137:819–25.

46. Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003; 349:247–57.

47. Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010; 28:3219–26.

48. Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014; 371:2189–99.

49. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology: mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015; 348:124–8.

50. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology (NCCN guidelines): colon cancer, version 2.2015 [Internet]. Fort Washington: National Comprehensive Cancer Network;2014. [cited 2015 Oct 1]. Available from: http://www.tri-kobe.org/nccn/guideline/colorectal/english/colon.pdf.

51. Suraweera N, Duval A, Reperant M, et al. Evaluation of tumor microsatellite instability using five quasimonomorphic mononucleotide repeats and pentaplex PCR. Gastroenterology. 2002; 123:1804–11.

52. Buhard O, Cattaneo F, Wong YF, et al. Multipopulation analysis of polymorphisms in five mononucleotide repeats used to determine the microsatellite instability status of human tumors. J Clin Oncol. 2006; 24:241–51.

53. Corso G, Carvalho J, Marrelli D, et al. Somatic mutations and deletions of the E-cadherin gene predict poor survival of patients with gastric cancer. J Clin Oncol. 2013; 31:868–75.

54. Wang K, Yuen ST, Xu J, et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet. 2014; 46:573–82.

55. Kakiuchi M, Nishizawa T, Ueda H, et al. Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat Genet. 2014; 46:583–7.

56. Ridley AJ, Schwartz MA, Burridge K, et al. Cell migration: integrating signals from front to back. Science. 2003; 302:1704–9.

57. Thumkeo D, Watanabe S, Narumiya S. Physiological roles of Rho and Rho effectors in mammals. Eur J Cell Biol. 2013; 92:303–15.

58. Yao F, Kausalya JP, Sia YY, et al. Recurrent fusion genes in gastric cancer: CLDN18-ARHGAP26 induces loss of epithelial integrity. Cell Rep. 2015; 12:272–85.

59. Hanazono K, Natsugoe S, Stein HJ, Aikou T, Hoefler H, Siewert JR. Distribution of p53 mutations in esophageal and gastric carcinomas and the relationship with p53 expression. Oncol Rep. 2006; 15:821–4.

60. Lei Z, Tan IB, Das K, et al. Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil. Gastroenterology. 2013; 145:554–65.

61. Grabsch HI, Tan P. Gastric cancer pathology and underlying molecular mechanisms. Dig Surg. 2013; 30:150–8.

62. Jimeno A, Hidalgo M. Blockade of epidermal growth factor receptor (EGFR) activity. Crit Rev Oncol Hematol. 2005; 53:179–92.

63. Terashima M, Kitada K, Ochiai A, et al. Impact of expression of human epidermal growth factor receptors EGFR and ERBB2 on survival in stage II/III gastric cancer. Clin Cancer Res. 2012; 18:5992–6000.

64. U.S. Food and Drug Administration. Trastuzumab [Internet]. Office of Medical Products and Tobacco [Internet]. Silver Spring: U.S. Food and Drug Administration;2010. [cited 2015 Oct 1]. Available from: http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm230418.htm.

65. Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011; 29:2866–74.

66. Lee J, Ou SH. Towards the goal of personalized medicine in gastric cancer: time to move beyond HER2 inhibition. Part II: Targeting gene mutations and gene amplifications and the angiogenesis pathway. Discov Med. 2013; 16:7–14.

67. van Grieken NC, Aoyama T, Chambers PA, et al. KRAS and BRAF mutations are rare and related to DNA mismatch repair deficiency in gastric cancer from the East and the West: results from a large international multicentre study. Br J Cancer. 2013; 108:1495–501.

68. Cepero V, Sierra JR, Corso S, et al. MET and KRAS gene amplification mediates acquired resistance to MET tyrosine kinase inhibitors. Cancer Res. 2010; 70:7580–90.

69. Janne PA, Shaw AT, Pereira JR, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2013; 14:38–47.

70. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002; 417:949–54.

71. Puzanov I, Amaravadi RK, McArthur GA, et al. Long-term outcome in BRAF(V600E) melanoma patients treated with vemurafenib: patterns of disease progression and clinical management of limited progression. Eur J Cancer. 2015; 51:1435–43.

72. Lee SH, Lee JW, Soung YH, et al. BRAF and KRAS mutations in stomach cancer. Oncogene. 2003; 22:6942–5.

73. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350:2335–42.

74. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006; 355:2542–50.

75. Shah MA, Jhawer M, Ilson DH, et al. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol. 2011; 29:868–74.

76. Shah MA. Gastrointestinal cancer: targeted therapies in gastric cancer-the dawn of a new era. Nat Rev Clin Oncol. 2014; 11:10–1.

77. Subramaniam D, Ramalingam S, Houchen CW, Anant S. Cancer stem cells: a novel paradigm for cancer prevention and treatment. Mini Rev Med Chem. 2010; 10:359–71.

78. Tan DS, Gerlinger M, Teh BT, Swanton C. Anti-cancer drug resistance: understanding the mechanisms through the use of integrative genomics and functional RNA interference. Eur J Cancer. 2010; 46:2166–77.

79. Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007; 7:415–28.

80. Voutsadakis IA. The ubiquitin-proteasome system and signal transduction pathways regulating epithelial mesenchymal transition of cancer. J Biomed Sci. 2012; 19:67.

81. Bierie B, Moses HL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer. 2006; 6:506–20.

82. Watabe T, Miyazono K. Roles of TGF-beta family signaling in stem cell renewal and differentiation. Cell Res. 2009; 19:103–15.

83. Zhou J, Wulfkuhle J, Zhang H, et al. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci U S A. 2007; 104:16158–63.

84. Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 2009; 69:7507–11.

85. Lee CK, Jung M, Jung I, et al. Cumulative metformin use and its impact on survival in gastric cancer patients after gastrectomy. Ann Surg. 2015; Oct. 22. [Epub]. http://dx.doi.org/10.1097/SLA.0000000000001086.

86. Takaishi S, Okumura T, Tu S, et al. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells. 2009; 27:1006–20.

87. Wadhwa R, Song S, Lee JS, Yao Y, Wei Q, Ajani JA. Gastric cancer-molecular and clinical dimensions. Nat Rev Clin Oncol. 2013; 10:643–55.