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Clinical Implications of Microsatellite Instability in Early Gastric Cancer

  • Kim, Dong Gyu (Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine) ;
  • An, Ji Yeong (Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Kim, Hyunki (Department of Pathology, Yonsei University Health System, Yonsei University College of Medicine) ;
  • Shin, Su-Jin (Department of Pathology, Yonsei University Health System, Yonsei University College of Medicine) ;
  • Choi, Seohee (Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine) ;
  • Seo, Won Jun (Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine) ;
  • Roh, Chul Kyu (Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine) ;
  • Cho, Minah (Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine) ;
  • Son, Taeil (Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine) ;
  • Kim, Hyoung-Il (Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine) ;
  • Cheong, Jae-Ho (Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine) ;
  • Hyung, Woo Jin (Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine) ;
  • Noh, Sung Hoon (Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine) ;
  • Choi, Yoon Young (Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine)
  • Received : 2019.04.22
  • Accepted : 2019.10.07
  • Published : 2019.12.31

Abstract

Purpose: We aimed to evaluate the clinical characteristics of microsatellite instability in early gastric cancer. Materials and Methods: The microsatellite instability status of resected early gastric tumors was evaluated using two mononucleotide repeat markers (BAT25 and BAT26) and three dinucleotide repeat markers (D5S346, D2S123, and D17S250). Tumors with instability in two or more markers were defined as microsatellite instability-high (MSI-H) and others were classified as microsatellite stable (MSS). Results: Overall, 1,156 tumors were included in the analysis, with 85 (7.4%) classified as MSI-H compared with MSS tumors. For MSI-H tumors, there was a significant correlation with the female sex, older age, tumor location in the lower gastric body, intestinal histology, lymphovascular invasion (LVI), and submucosal invasion (P<0.05). There was also a trend toward an association with lymph node (LN) metastasis (P=0.056). In mucosal gastric cancer, there was no significant difference in MSI status in tumors with LN metastasis or tumors with LVI. In submucosal gastric cancer, LVI was more frequently observed in MSI-H than in MSS tumors (38.9% vs. 25.0%, P=0.027), but there was no difference in the presence of LN metastases. The prognosis of MSI-H tumors was similar to that of MSS tumors (log-rank test, P=0.797, the hazard ratio for MSI-H was adjusted by age, sex, pT stage, and the number of metastatic LNs, 0.932; 95% confidence interval, 0.423-2.054; P=0.861). Conclusions: MSI status was not useful in predicting prognosis in early gastric cancer. However, the frequent presence of LVI in early MSI-H gastric cancer may help guide the appropriate treatment for patients, such as endoscopic treatment or limited LN surgical dissection.

Keywords

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108. https://doi.org/10.3322/caac.21262
  2. Jung KW, Won YJ, Kong HJ, Lee ES; Community of Population-Based Regional Cancer Registries. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2015. Cancer Res Treat 2018;50:303-316. https://doi.org/10.4143/crt.2018.143
  3. Sugano K. Screening of gastric cancer in Asia. Best Pract Res Clin Gastroenterol 2015;29:895-905. https://doi.org/10.1016/j.bpg.2015.09.013
  4. Nakagawa M, Choi YY, An JY, Chung H, Seo SH, Shin HB, et al. Difficulty of predicting the presence of lymph node metastases in patients with clinical early stage gastric cancer: a case control study. BMC Cancer 2015;15:943. https://doi.org/10.1186/s12885-015-1948-8
  5. Lai JF, Kim S, Kim K, Li C, Oh SJ, Hyung WJ, et al. Prediction of recurrence of early gastric cancer after curative resection. Ann Surg Oncol 2009;16:1896-1902. https://doi.org/10.1245/s10434-009-0473-x
  6. Choi YY, An JY, Katai H, Seto Y, Fukagawa T, Okumura Y, et al. A lymph node staging system for gastric cancer: a hybrid type based on topographic and numeric systems. PLoS One 2016;11:e0149555. https://doi.org/10.1371/journal.pone.0149555
  7. Cheong JH, Yang HK, Kim H, Kim WH, Kim YW, Kook MC, et al. Predictive test for chemotherapy response in resectable gastric cancer: a multi-cohort, retrospective analysis. Lancet Oncol 2018;19:629-638. https://doi.org/10.1016/S1470-2045(18)30108-6
  8. Roh CK, Choi YY, Choi S, Seo WJ, Cho M, Jang E, et al. Single patient classifier assay, microsatellite instability, and epstein-barr virus status predict clinical outcomes in stage II/III gastric cancer: results from CLASSIC trial. Yonsei Med J 2019;60:132-139. https://doi.org/10.3349/ymj.2019.60.2.132
  9. Choi YY, Jang E, Seo WJ, Son T, Kim HI, Kim H, et al. Modification of the TNM staging system for stage II/III gastric cancer based on a prognostic single patient classifier algorithm. J Gastric Cancer 2018;18:142-151. https://doi.org/10.5230/jgc.2018.18.e14
  10. Choi YY, Cho M, Kwon IG, Son T, Kim HI, Choi SH, et al. Ten thousand consecutive gastrectomies for gastric cancer: perspectives of a master surgeon. Yonsei Med J 2019;60:235-242. https://doi.org/10.3349/ymj.2019.60.3.235
  11. Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science 1993;260:816-819. https://doi.org/10.1126/science.8484122
  12. Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 1993;363:558-561. https://doi.org/10.1038/363558a0
  13. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014;513:202-209. https://doi.org/10.1038/nature13480
  14. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998;58:5248-5257.
  15. Veigl ML, Kasturi L, Olechnowicz J, Ma AH, Lutterbaugh JD, Periyasamy S, et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci U S A 1998;95:8698-8702. https://doi.org/10.1073/pnas.95.15.8698
  16. Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med 2015;21:449-456. https://doi.org/10.1038/nm.3850
  17. 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;131:505-511. https://doi.org/10.1002/ijc.26399
  18. Choi YY, Bae JM, An JY, Kwon IG, Cho I, Shin HB, et al. Is microsatellite instability a prognostic marker in gastric cancer? A systematic review with meta-analysis. J Surg Oncol 2014;110:129-135. https://doi.org/10.1002/jso.23618
  19. Kim SY, Choi YY, An JY, Shin HB, Jo A, Choi H, 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;137:819-825. https://doi.org/10.1002/ijc.29449
  20. Polom K, Marrelli D, Pascale V, Ferrara F, Voglino C, Marini M, et al. The pattern of lymph node metastases in microsatellite unstable gastric cancer. Eur J Surg Oncol 2017;43:2341-2348. https://doi.org/10.1016/j.ejso.2017.09.007
  21. Polom K, Marano L, Marrelli D, De Luca R, Roviello G, Savelli V, et al. Meta-analysis of microsatellite instability in relation to clinicopathological characteristics and overall survival in gastric cancer. Br J Surg 2018;105:159-167. https://doi.org/10.1002/bjs.10663
  22. Choi YY, Kim H, Shin SJ, Kim HY, Lee J, Yang HK, et al. Microsatellite instability and programmed cell death-ligand 1 expression in stage II/III gastric cancer: post hoc analysis of the CLASSIC randomized controlled study. Ann Surg 2019;270:309-316. https://doi.org/10.1097/SLA.0000000000002803
  23. Smyth EC, Wotherspoon A, Peckitt C, Gonzalez D, Hulkki-Wilson S, Eltahir Z, et al. Mismatch repair deficiency, microsatellite instability, and survival: an exploratory analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. JAMA Oncol 2017;3:1197-1203. https://doi.org/10.1001/jamaoncol.2016.6762
  24. Guideline Committee of the Korean Gastric Cancer Association (KGCA), Development Working Group & Review Panel. Korean Practice Guideline for Gastric Cancer 2018: an evidence-based, multi-disciplinary approach. J Gastric Cancer 2019;19:1-48. https://doi.org/10.5230/jgc.2019.19.e8
  25. Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Rüschoff J, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004;96:261-268. https://doi.org/10.1093/jnci/djh034
  26. Sobin LH, Compton CC. TNM seventh edition: what's new, what's changed: communication from the International Union Against Cancer and the American Joint Committee on Cancer. Cancer 2010;116:5336-5339. https://doi.org/10.1002/cncr.25537
  27. Lauren 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. https://doi.org/10.1111/apm.1965.64.1.31
  28. Gotoda T, Iwasaki M, Kusano C, Seewald S, Oda I. Endoscopic resection of early gastric cancer treated by guideline and expanded National Cancer Centre criteria. Br J Surg 2010;97:868-871. https://doi.org/10.1002/bjs.7033
  29. Gambardella V, Cervantes A. Precision medicine in the adjuvant treatment of gastric cancer. Lancet Oncol 2018;19:583-584. https://doi.org/10.1016/S1470-2045(18)30131-1
  30. Choi YY, Cheong JH. Comment on "To Treat, or Not to Treat, That is the Question Biomarker-guided Adjuvant Chemotherapy for Stage II and III Gastric Cancer". Ann Surg 2019;270:e40-e41. https://doi.org/10.1097/SLA.0000000000003102
  31. Kim ST, Cristescu R, Bass AJ, Kim KM, Odegaard JI, Kim K, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med 2018;24:1449-1458. https://doi.org/10.1038/s41591-018-0101-z
  32. Kim HH, Han SU, Kim MC, Kim W, Lee HJ, Ryu SW, et al. Effect of laparoscopic distal gastrectomy vs open distal gastrectomy on long-term survival among patients with stage I gastric cancer: the KLASS-01 randomized clinical trial. JAMA Oncol 2019;5:506-513. https://doi.org/10.1001/jamaoncol.2018.6727
  33. An JY, Min JS, Lee YJ, Jeong SH, Hur H, Han SU, et al. Safety of laparoscopic sentinel basin dissection in patients with gastric cancer: an analysis from the SENORITA Prospective Multicenter Quality Control Trial. J Gastric Cancer 2018;18:30-36. https://doi.org/10.5230/jgc.2018.18.e6
  34. Ryu KW, Kim YW, Min JS, Yoon HM, An JY, Eom BW, et al. Results of interim analysis of the multicenter randomized phase III SENORITA trial of laparoscopic sentinel node oriented, stomach-preserving surgery versus laparoscopic standard gastrectomy with lymph node dissection in early gastric cancer. J Clin Oncol 2017;35:4028. https://doi.org/10.1200/JCO.2017.35.15_suppl.4028
  35. Kim TM, Laird PW, Park PJ. The landscape of microsatellite instability in colorectal and endometrial cancer genomes. Cell 2013;155:858-868. https://doi.org/10.1016/j.cell.2013.10.015
  36. Park JH, Kim EK, Kim YH, Kim JH, Bae YS, Lee YC, et al. Epstein-Barr virus positivity, not mismatch repair-deficiency, is a favorable risk factor for lymph node metastasis in submucosa-invasive early gastric cancer. Gastric Cancer 2016;19:1041-1051. https://doi.org/10.1007/s10120-015-0565-1
  37. Sugimoto R, Sugai T, Habano W, Endoh M, Eizuka M, Yamamoto E, et al. Clinicopathological and molecular alterations in early gastric cancers with the microsatellite instability-high phenotype. Int J Cancer 2016;138:1689-1697. https://doi.org/10.1002/ijc.29916
  38. Jahng J, Youn YH, Kim KH, Yu J, Lee YC, Hyung WJ, et al. Endoscopic and clinicopathologic characteristics of early gastric cancer with high microsatellite instability. World J Gastroenterol 2012;18:3571-3577. https://doi.org/10.3748/wjg.v18.i27.3571
  39. Mathiak M, Warneke VS, Behrens HM, Haag J, Boger C, Kruger S, et al. Clinicopathologic characteristics of microsatellite instable gastric carcinomas revisited: urgent need for standardization. Appl Immunohistochem Mol Morphol 2017;25:12-24. https://doi.org/10.1097/PAI.0000000000000264
  40. Cho J, Lee J, Bang H, Kim ST, Park SH, An JY, et al. Programmed cell death-ligand 1 expression predicts survival in patients with gastric carcinoma with microsatellite instability. Oncotarget 2017;8:13320-13328. https://doi.org/10.18632/oncotarget.14519
  41. 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;7:24269-24283. https://doi.org/10.18632/oncotarget.8169
  42. Kim KJ, Yang HK, Kim WH, Kang GH. Combined prognostic effect of PD-L1 expression and immunoscore in microsatellite-unstable advanced gastric cancers. Oncotarget 2017;8:58887-58902. https://doi.org/10.18632/oncotarget.19439

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