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Low-Frequency Microsatellite Instability in Genomic Di-Nucleotide Sequences Correlates with Lymphatic Invasion and Poor Prognosis in Gastric Cancer

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Abstract

The clinical significance of low-frequency microsatellite instability (MSI-L) in gastric cancer (GC) has not been well established. The aim of this study was to evaluate the clinicopathological features of MSI-L in GC. We investigated microsatellite instability (MSI) in 5 di-nucleotide repeat sequences in 210 unselected GC patients. High-resolution fluorescent microsatellite analysis assay was utilized to detect MSI. Clinicopathological variables were compared among groups with different microsatellite statuses. The overall survival (OS) was analyzed by Kaplan–Meier method. Multivariable analysis was performed to identify prognostic factors and variables correlated with lymph node metastasis. High-frequency microsatellite instability (MSI-H), MSI-L, and microsatellite stable were identified, respectively, in 10.5, 10.0, and 79.5 % of unselected GC cases. Tumors with MSI-H were less invasive, and these patients showed a better OS. MSI-L was correlated with more advanced tumor Node Metastasis stage, and more frequent lymph node metastasis. The unfavorable prognosis predicted by MSI-L was ascribed to its correlation with lymphatic invasion. MSI-L characterized by di-nucleotide markers represents a distinct subcategory of GC with aggressive clinicopathological features, which are particularly affiliated to lymphatic system and correlated with a poor prognosis. MSI-L could be beneficial for predicting the clinical outcome of GC.

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References

  1. Jemal, A., Bray, F., Center, M. M., Ferlay, J., Ward, E., & Forman, D. (2011). Global cancer statistics. CA: A Cancer Journal for Clinicians, 61, 69–90.

    Google Scholar 

  2. Boland, C. R., Thibodeau, S. N., Hamilton, S. R., Sidransky, D., Eshleman, J. R., Burt, R. W., et al. (1998). 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 Research, 58, 5248–5257.

    CAS  PubMed  Google Scholar 

  3. Leach, F. S., Nicolaides, N. C., Papadopoulos, N., Liu, B., Jen, J., Parsons, R., et al. (1993). Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell, 75, 1215–1225.

    Article  CAS  PubMed  Google Scholar 

  4. Suzuki, H., Itoh, F., Toyota, M., Kikuchi, T., Kakiuchi, H., Hinoda, Y., et al. (1999). Distinct methylation pattern and microsatellite instability in sporadic gastric cancer. International Journal of Cancer, 83, 309–313.

    Article  CAS  Google Scholar 

  5. Laiho, P., Launonen, V., Lahermo, P., Esteller, M., Guo, M., Herman, J. G., et al. (2002). Low-level microsatellite instability in most colorectal carcinomas. Cancer Research, 62, 1166–1170.

    CAS  PubMed  Google Scholar 

  6. Tomlinson, I., Halford, S., Aaltonen, L., Hawkins, N., & Ward, R. (2002). Does MSI-low exist? Journal of Pathology, 197, 6–13.

    Article  CAS  PubMed  Google Scholar 

  7. Jass, J. R. (2007). Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology, 50, 113–130.

    Article  CAS  PubMed  Google Scholar 

  8. Kohonen-Corish, M. R., Daniel, J. J., Chan, C., Lin, B. P., Kwun, S. Y., Dent, O. F., et al. (2005). Low microsatellite instability is associated with poor prognosis in stage C colon cancer. Journal of Clinical Oncology, 23, 2318–2324.

    Article  CAS  PubMed  Google Scholar 

  9. Kim, H., An, J. Y., Noh, S. H., Shin, S. K., Lee, Y. C., & Kim, H. (2011). High microsatellite instability predicts good prognosis in intestinal-type gastric cancers. Journal of Gastroenterology and Hepatology, 26, 585–592.

    Article  CAS  PubMed  Google Scholar 

  10. Falchetti, M., Saieva, C., Lupi, R., Masala, G., Rizzolo, P., Zanna, I., et al. (2008). Gastric cancer with high-level microsatellite instability: Target gene mutations, clinicopathologic features, and long-term survival. Human Pathology, 39, 925–932.

    Article  CAS  PubMed  Google Scholar 

  11. Sakurai, M., Zhao, Y., Oki, E., Kakeji, Y., Oda, S., & Maehara, Y. (2007). High-resolution fluorescent analysis of microsatellite instability in gastric cancer. European Journal of Gastroenterology and Hepatology, 19, 701–709.

    Article  PubMed  Google Scholar 

  12. Kanemitsu, K., Kawasaki, K., Nakamura, M., Li, D., Yasuda, T., Kuroda, D., et al. (2007). MSI is frequently recognized among gastric cancer patients with a family history of cancer. Hepato-Gastroenterology, 54, 2410–2414.

    PubMed  Google Scholar 

  13. Leite, M., Corso, G., Sousa, S., Milanezi, F., Afonso, L. P., Henrique, R., et al. (2011). MSI phenotype and MMR alterations in familial and sporadic gastric cancer. International Journal of Cancer, 128, 1606–1613.

    Article  CAS  Google Scholar 

  14. Beghelli, S., de Manzoni, G., Barbi, S., Tomezzoli, A., Roviello, F., Di Gregorio, C., et al. (2006). Microsatellite instability in gastric cancer is associated with better prognosis in only stage II cancers. Surgery, 139, 347–356.

    Article  PubMed  Google Scholar 

  15. Sepulveda, A. R., Santos, A. C., Yamaoka, Y., Wu, L., Gutierrez, O., Kim, J. G., et al. (1999). Marked differences in the frequency of microsatellite instability in gastric cancer from different countries. American Journal of Gastroenterology, 94, 3034–3038.

    Article  CAS  PubMed  Google Scholar 

  16. Kang, J. U., & Koo, S. H. (2011). Assessment of the beneficial loci and prognostic implications of microsatellite instability in gastric carcinoma. Molecular Medicine Report, 4, 1175–1181.

    CAS  Google Scholar 

  17. Yamamoto, H., Itoh, F., Fukushima, H., Adachi, Y., Itoh, H., Hinoda, Y., et al. (1999). Frequent Bax frameshift mutations in gastric cancer with high but not low microsatellite instability. Journal of Experimental and Clinical Cancer Research, 18, 103–106.

    PubMed  Google Scholar 

  18. Corso, G., Pedrazzani, C., Marrelli, D., Pascale, V., Pinto, E., & Roviello, F. (2009). Correlation of microsatellite instability at multiple loci with long-term survival in advanced gastric carcinoma. Archives of Surgery, 144, 722–727.

    Article  CAS  PubMed  Google Scholar 

  19. Fang, D. C., Jass, J. R., Wang, D. X., Zhou, X. D., Luo, Y. H., & Young, J. (1999). Infrequent loss of heterozygosity of APC/MCC and DCC genes in gastric cancer showing DNA microsatellite instability. Journal of Clinical Pathology, 52, 504–508.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Vauhkonen, M., Vauhkonen, H., Sajantila, A., & Sipponen, P. (2005). Differences in genomic instability between intestinal- and diffuse-type gastric cancer. Gastric Cancer, 8, 238–244.

    Article  CAS  PubMed  Google Scholar 

  21. Pinto, M., Oliveira, C., Machado, J. C., Cirnes, L., Tavares, J., Carneiro, F., et al. (2000). MSI-L gastric carcinomas share the hMLH1 methylation status of MSI-H carcinomas but not their clinicopathological profile. Laboratory Investigation, 80, 1915–1923.

    Article  CAS  PubMed  Google Scholar 

  22. Gazvoda, B., Juvan, R., Zupanic-Pajnic, I., Repse, S., Ferlan-Marolt, K., Balazic, J., et al. (2007). Genetic changes in Slovenian patients with gastric adenocarcinoma evaluated in terms of microsatellite DNA. European Journal of Gastroenterology and Hepatology, 19, 1082–1089.

    Article  CAS  PubMed  Google Scholar 

  23. Sano, T. (2010). Evaluation of the gastric cancer treatment guidelines of the Japanese Gastric Cancer Association. Gan to Kagaku Ryoho, 37, 582–586.

    PubMed  Google Scholar 

  24. Oda, S., Oki, E., Maehara, Y., & Sugimachi, K. (1997). Precise assessment of microsatellite instability using high resolution fluorescent microsatellite analysis. Nucleic Acids Research, 25, 3415–3420.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Umar, A., Boland, C. R., Terdiman, J. P., Syngal, S., de la Chapelle, A., Rüschoff, J., et al. (2004). Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (lynch syndrome) and microsatellite instability. Journal of the National Cancer Institute, 96, 261–268.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Xicola, R. M., Llor, X., Pons, E., Castells, A., Alenda, C., Piñol, V., et al. (2007). Performance of different microsatellite marker panels for detection of mismatch repair-deficient colorectal tumors. Journal of the National Cancer Institute, 99, 244–252.

    Article  CAS  PubMed  Google Scholar 

  27. Asaka, S., Arai, Y., Nishimura, Y., Yamaguchi, K., Ishikubo, T., Yatsuoka, T., et al. (2009). Microsatellite instability-low colorectal cancer acquires a KRAS mutation during the progression from Dukes’ A to Dukes’ B. Carcinogenesis, 30, 494–499.

    Article  CAS  PubMed  Google Scholar 

  28. Kets, C. M., Hoogerbrugge, N., Bodmer, D., Willems, R., Brunner, H. G., van Krieken, J. H., et al. (2006). Unfavorable pathological characteristics in familial colorectal cancer with low-level microsatellite instability. Modern Pathology, 19, 1624–1630.

    Article  CAS  PubMed  Google Scholar 

  29. Halford, S. E., Sawyer, E. J., Lambros, M. B., Gorman, P., Macdonald, N. D., Talbot, I. C., et al. (2003). MSI-low, a real phenomenon which varies in frequency among cancer types. Journal of Pathology, 201, 389–394.

    Article  CAS  PubMed  Google Scholar 

  30. Jass J. R., Whitehall V. L., Young J., Leggett B., Meltzer S. J., Matsubara N., et al. (2002). Correspondence re: P. Laiho et al. Low-level microsatellite instability in most colorectal carcinomas. Cancer Research, 62, 5988–5989.

    CAS  PubMed  Google Scholar 

  31. Plaschke, J., Preußler, M., Ziegler, A., & Schackert, H. K. (2012). Aberrant protein expression and frequent allelic loss of MSH3 in colorectal cancer with low-level microsatellite instability. International Journal of Colorectal Disease, 27, 911–999.

    Article  PubMed  Google Scholar 

  32. Vladimirova, V., Denkhaus, D., Soerensen, N., Wagner, S., Wolff, J. E., & Pietsch, T. (2008). Low level of microsatellite instability in pediatric malignant astrocytomas. Neuropathology and Applied Neurobiology, 34, 547–554.

    Article  CAS  PubMed  Google Scholar 

  33. Imai, K., & Yamamoto, H. (2008). Carcinogenesis and microsatellite instability: The interrelationship between genetics and epigenetics. Carcinogenesis, 29, 673–680.

    Article  CAS  PubMed  Google Scholar 

  34. Campregher, C., Scharl, T., Nemeth, M., Honeder, C., Jascur, T., Boland, C. R., et al. (2010). The nucleotide composition of microsatellites impacts both replication fidelity and mismatch repair in human colorectal cells. Human Molecular Genetics, 19, 2648–2657.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Oda, S., Maehara, Y., Ikeda, Y., Oki, E., Egashira, A., Okamura, Y., et al. (2005). Two modes of microsatellite instability in human cancer: differential connection of defective DNA mismatch repair to dinucleotide repeat instability. Nucleic Acids Research, 33, 1628–1636.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Thibodeau, S. N., Bren, G., & Schaid, D. (1993). Microsatellite instability in cancer of the proximal colon. Science, 260, 816–819.

    Article  CAS  PubMed  Google Scholar 

  37. Zhao, Y., Miyashita, K., Ando, T., Kakeji, Y., Yamanaka, T., Taguchi, K., et al. (2008). Exclusive KRAS mutation in microsatellite-unstable human colorectal carcinomas with sequence alterations in the DNA mismatch repair gene, MLH1. Gene, 423, 188–193.

    Article  CAS  PubMed  Google Scholar 

  38. Karran, P., & Bignami, M. (1996). Drug-related killings: A case of mistaken identity. Chemistry & Biology, 3, 875–879.

    Article  CAS  Google Scholar 

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Acknowledgments

We sincerely thank Dr. Shinya Oda, Dr. Eiji Oki, Prof. Yoshihiro Kakeji, Prof. Zhiwei Zhou, Prof. Huimian Xu, and Prof. Qiang Wang for providing critical comments on our manuscript. We offer our sincere gratitude to Prof. Yoshihiko Maehara for his generous support. The current study was supported by “Liaoning BaiQianWan Talents Program” #2010921037, a grant from the National Ministry of Human Resources and Social Security of China #2011LX005, and the National Science Foundation of Liaoning Province, China #201102110.

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Authors and Affiliations

  1. Department of Stomach Surgery, Liaoning Cancer Hospital & Institute, 44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning, 110042, People’s Republic of China

    Yan Zhao, Zhi-Chao Zheng, Guo-Liang Zheng, Tao Zhang & Jian-Jun Zhang

  2. Department of Radiology, Liaoning Cancer Hospital & Institute, 44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning, 110042, People’s Republic of China

    Ya-Hong Luo

  3. Department of Neurosurgery, Liaoning Cancer Hospital & Institute, 44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning, 110042, People’s Republic of China

    Hao-Zhe Piao

  4. Postgraduate School of Dalian Medical University, 9 North Lvshun Road, Lvshunkou District, Dalian, 116044, People’s Republic of China

    Jing-Yi Shi

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  1. Yan Zhao
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Correspondence to Zhi-Chao Zheng.

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Zhao, Y., Zheng, ZC., Luo, YH. et al. Low-Frequency Microsatellite Instability in Genomic Di-Nucleotide Sequences Correlates with Lymphatic Invasion and Poor Prognosis in Gastric Cancer. Cell Biochem Biophys 71, 235–241 (2015). https://doi.org/10.1007/s12013-014-0189-9

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