Abstract
Recent studies suggest that colorectal cancer with microsatellite instability (MSI) might be resistant to fluorouracil-based chemotherapy; however, little is known about the clinical significance of MSI analysis for gastric cancer. We therefore conducted a prospective single center study analyzing MSI in gastric cancer. Of 123 consecutive gastric cancers analyzed, 12 (9.8 %) were MSI-positive and two patients with MSI-positive gastric cancer underwent systemic chemotherapy because of unresectable disease. Neither cases had concurrent nor past history of other malignancies but one had cancer family history meeting the revised Bethesda criteria. These two MSI-positive gastric cancers shared multiple clinical features, such as direct invasion to adjacent organs, extensive nodal metastasis but no distant metastasis, resistance to fluorouracil and death of tumor bleeding. The two cases had unmethylated MLH1 promoter, suggestive of Lynch syndrome. Germline mutation analysis demonstrated MSH6 alterations of unknown significance in both cases.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Yamamoto H, Perez-Piteira J, Yoshida T, Terada M, Itoh F, Imai K, et al. Gastric cancers of the microsatellite mutator phenotype display characteristic genetic and clinical features. Gastroenterology. 1999;116:1348–57.
Beghelli S, de Manzoni G, Barbi S, Tomezzoli A, Roviello F, Di Gregorio C, et al. Microsatellite instability in gastric cancer is associated with better prognosis in only stage II cancers. Surgery. 2006;139:347–56.
Ribic CM, Sargent DJ, Moor MJ, Thibodeau SN, French AJ, Goldberg RM, 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.
Carethers JM, Smith EJ, Behling CA, Nguyen L, Tajima A, Doctolero RT, et al. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology. 2004;126:394–401.
Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, 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.
Elsaleh H, Joseph D, Grieu F, Zeps N, Spry N, Iacopetta B. Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet. 2000;355:1745–50.
Hemminki A, Mecklin JP, Jarvinen H, Aaltonen LA, Joensuu H. Microsatellite instability is a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy. Gastroenterology. 2000;119:921–8.
Gryfe R, Kim H, Hsieh ET, Aronson MD, Holowaty EJ, Bull SB, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342:69–77.
Sinicrope FA, Rego RL, Foster N, Sargent DJ, Windschitl HE, Burgart LJ, et al. Microsatellite instability accounts for tumor site-related differences in clinicopathologic variables and prognosis in human colon cancers. Am J Gastroenterol. 2006;101:2818–25.
Kim GP, Colangelo LH, Wieand HS, Paik S, Kirsch IR, Wolmark N, et al. Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a national cancer institute-national surgical adjuvant breast and bowel project collaborative study. J Clin Oncol. 2007;25:767–72.
An JY, Kim H, Cheong JH, Hyung WJ, Kim H, Noh SH. Microsatellite instability in sporadic gastric cancer: its prognostic role and guidance for 5FU based chemotherapy after R0 resection. Int J Cancer 2012; 131 (2): 505−11.
Maul JS, Warner NR, Kuwada SK, Burt RW, Cannon-Albright LA. Extracolonic cancers associated with hereditary nonpolyposis colorectal cancer in the Utah population database. Am J Gastroenterol. 2006;101:1591–6.
Capelle LG, van Grieken NC, Lingsma HF, Steyerberg EW, Klokman WJ, Bruno MJ, et al. Risk and epidemiological time trends of gastric cancer in Lynch syndrome carriers in the Netherlands. Gastroenteology. 2010;138:487–92.
Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005;352:1851–60.
Barnetson RA, Tenesa A, Farrington SM, Nicholl ID, Cetnarskyj R, Porteous ME, et al. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med. 2006;354:2751–63.
Berends MJ, Wu Y, Sijmons RH, Mensink RG, van der Sluis T, Hordijk-Hos JM, et al. Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant. Am J Hum Genet. 2002;70:26–37.
Baglietto L, Lindor NM, Dowty JG, White DM, Wagner A, Gomez Garcia EB, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010;102:193–201.
Acknowledgments
We are grateful to FALCO biosystems and Mr. Hiroshi Fujimori for the germline mutation analysis. Part of this study is funded by Yuasa Memorial Foundation.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yamashita, K., Arimura, Y., Saito, M. et al. Gastric cancers with microsatellite instability sharing clinical features, chemoresistance and germline MSH6 variants. Clin J Gastroenterol 6, 122–126 (2013). https://doi.org/10.1007/s12328-013-0376-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12328-013-0376-z