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Clinicopathological features of sporadic MSI colorectal cancer and Lynch syndrome: a single-center retrospective cohort study

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Abstract

Background

The clinical and pathological features of sporadic microsatellite instability-high (MSI) colorectal cancer (CRC) are still unclear. The present study aimed to clarify the clinicopathological features of sporadic MSI CRC in comparison with those of Lynch syndrome (LS) exploratorily.

Methods

The present study was a single-center, retrospective cohort study. Sporadic MSI CRC was defined as MSI CRC with aberrant promoter hypermethylation of the MLH1 gene, while hereditary MSI CRC was defined colorectal cancer in patients with LS.

Results

In total, 2653 patients were enrolled; of these, 120 (4.5%) had MSI CRC, 98 had sporadic MSI CRC, and 22 had LS. Patients with sporadic MSI CRC were significantly older (p < 0.001) than those with LS and had a right-sided colonic tumor (p < 0.001) which was pathologically poorly differentiated or mucinous (p = 0.025). The overall survival rate was significantly lower in patients with stage I, II or III MSI CRC than in those with LS (p = 0.024). However, the recurrence-free survival rate did not differ significantly (p = 0.85).

Conclusions

We concluded that patients with sporadic MSI are significantly older, tumors more likely to locate in the right-sided colon, pathologically poorly differentiated or mucinous, and worse overall survival than in those with LS.

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References

  1. Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68:7–30. https://doi.org/10.3322/caac.21442

    Article  PubMed  Google Scholar 

  2. Dienstmann R, Salazar R, Tabernero J (2014) The Evolution of Our Molecular Understanding of Colorectal Cancer: What We Are Doing Now, What the Future Holds, and How Tumor Profiling Is Just the Beginning. Am Soc Clin Oncol Educ Book 34:91–99. https://doi.org/10.14694/edbook_am.2014.34.91

  3. Devaud N, Gallinger S (2013) Chemotherapy of MMR-deficient colorectal cancer. FamCancer 12:301–306. https://doi.org/10.1007/s10689-013-9633-z

    Article  CAS  Google Scholar 

  4. Geiersbach KB, Samowitz WS (2011) Microsatellite instability and colorectal cancer. Arch Pathol Lab Med 135:1269–1277. https://doi.org/10.5858/arpa.2011-0035-RA

    Article  CAS  PubMed  Google Scholar 

  5. Canard G, Lefevre JH, Colas C et al (2012) Screening for lynch syndrome in colorectal cancer: are we doing enough? Ann Surg Oncol 19:809–816. https://doi.org/10.1245/s10434-011-2014-7

    Article  PubMed  Google Scholar 

  6. Ribic CM, Sargent DJ, Moore MJ et al (2003) Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349:247–257. https://doi.org/10.1056/nejmoa022289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ward R (2001) Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut 48:821–829. https://doi.org/10.1136/gut.48.6.821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shitoh K, Konishi F, Miyakura Y et al (2002) Microsatellite instability as a marker in predicting metachronous multiple colorectal carcinomas after surgery: a cohort-like study. Dis Colon Rectum 45:329–333. https://doi.org/10.1007/s10350-004-6177-1

    Article  PubMed  Google Scholar 

  9. Natsume S, Yamaguchi T, Takao M et al (2018) Clinicopathological and molecular differences between right-sided and left-sided colorectal cancer in Japanese patients. Jpn J Clin Oncol 48:609–618. https://doi.org/10.1093/jjco/hyy069

    Article  PubMed  Google Scholar 

  10. Perucho M, Boland CR, Thibodeau SN et al (1998) Correspondence re: C. R. Boland 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 color. Cancer Res 59:5248–5257

    Google Scholar 

  11. Ogino S, Kawasaki T, Brahmandam M et al (2006) Precision and performance characteristics of bisulfite conversion and real-time PCR ( MethyLight ) for quantitative DNA methylation analysis. J Mol Diagnostics 8:209–217. https://doi.org/10.2353/jmoldx.2006.050135

    Article  CAS  Google Scholar 

  12. Asaka SI, Arai Y, Nishimura Y 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. https://doi.org/10.1093/carcin/bgp017

    Article  CAS  PubMed  Google Scholar 

  13. Nosho K, Kure S, Irahara N et al (2009) A prospective cohort study shows unique epigenetic, genetic, and prognostic features of synchronous colorectal cancers. Gastroenterology 137:1–23. https://doi.org/10.1053/j.gastro.2009.08.002

    Article  CAS  Google Scholar 

  14. Vilar E, Gruber SB (2010) Microsatellite instability in colorectal cancer—the stable evidence. Nat Rev Clin Oncol 7:153–162

    Article  CAS  Google Scholar 

  15. Matloff J, Lucas A, Polydorides AD, Itzkowitz SH (2013) Molecular tumor testing for lynch syndrome in patients with colorectal cancer. JNCCN J Natl Compr Cancer Netw 11:1380–1385. https://doi.org/10.6004/jnccn.2013.0161

    Article  Google Scholar 

  16. Das C, Lucia MSHK, TJ, (2017) Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiol Biomarkers Prev 26:404–412

    Article  Google Scholar 

  17. Li D, Hoodfar E, Jiang SF et al (2019) Comparison of universal versus age-restricted screening of colorectal tumors for lynch syndrome using mismatch repair immunohistochemistry: a cohort study. Ann Intern Med 171:19–26

    Article  Google Scholar 

  18. Adar T, Rodgers LH, Shannon KM et al (2018) Universal screening of both endometrial and colon cancers increases the detection of Lynch syndrome. Cancer 124:3145–3153. https://doi.org/10.1002/cncr.31534

    Article  CAS  PubMed  Google Scholar 

  19. Chika N, Eguchi H, Kumamoto K et al (2017) Prevalence of Lynch syndrome and Lynch-like syndrome among patients with colorectal cancer in a Japanese hospital-based population. Jpn J Clin Oncol 47:108–117. https://doi.org/10.1093/jjco/hyw178

    Article  PubMed  Google Scholar 

  20. Jiang W, Cai MY, Li SY et al (2019) Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features. Int J Cancer 144:2161–2168. https://doi.org/10.1002/ijc.32044

    Article  CAS  PubMed  Google Scholar 

  21. Moreira L, Balaguer F, Lindor N et al (2012) Identification of Lynch syndrome among patients with colorectal cancer. JAMA-J Am Med Assoc 308:1555–1565. https://doi.org/10.1001/jama.2012.13088

    Article  CAS  Google Scholar 

  22. Shia J (2008) Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome: Part I. The utility of immunohistochemistry. J Mol Diagnostics 10:293–300. https://doi.org/10.2353/jmoldx.2008.080031

    Article  Google Scholar 

  23. Yamada R, Yamaguchi T, Iijima T et al (2018) Differences in histological features and PD-L1 expression between sporadic microsatellite instability and Lynch-syndrome-associated disease in Japanese patients with colorectal cancer. Int J Clin Oncol 23:504–513

    Article  CAS  Google Scholar 

  24. Slattery ML, Curtin PDK, Wolff PDRK et al (2009) A comparison of colon and rectal somatic DNA 0terations. Dis colon rectum. 52:1304–1311. https://doi.org/10.1007/DCR.0b013e3181a0e5df

  25. Barault L, Funes M, Vega D et al (2008) Hypermethylator Phenotype in Sporadic Colon Cancer : Study on a Population-Based Series of 582 Cases. Cancer res 68:8541–8547. https://doi.org/10.1158/0008-5472.CAN-08-1171

  26. Nosho K, Irahara N, Shima K et al (2008) Comprehensive biostatistical analysis of CpG island methylator phenotype in colorectal cancer using a large population-based sample. PLoS ONE 3:e3698. https://doi.org/10.1371/journal.pone.0003698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Liu GC, Liu RY, Yan JP et al (2018) The heterogeneity between lynch-associated and sporadic mmr deficiency in colorectal cancers. J Natl Cancer Inst 110:975–984. https://doi.org/10.1093/jnci/djy004

    Article  CAS  PubMed  Google Scholar 

  28. Liu Y, Sethi NS, Hinoue T et al (2018) Comparative molecular analysis of gastrointestinal adenocarcinomas. Cancer Cell 33:721–735. https://doi.org/10.1016/j.ccell.2018.03.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Niwa T, Tsukamoto T, Toyoda T et al (2010) Inflammatory processes triggered by Helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells. Cancer Res 70:1430–1440. https://doi.org/10.1158/0008-5472.CAN-09-2755

    Article  CAS  PubMed  Google Scholar 

  30. Niwa T, Ushijima T (2010) Induction of epigenetic alterations by chronic inflammation and its significance on carcinogenesis. Elsevier Inc., Lyon

    Book  Google Scholar 

  31. Nosho K, Sukawa Y, Adachi Y et al (2016) Association of Fusobacterium nucleatum with immunity and molecular alterations in colorectal cancer. World J Gastroenterol 22:557–566. https://doi.org/10.3748/wjg.v22.i2.557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mima K, Nishihara R, Rong Qian Z et al (2016) Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis were responsible for collection of tumour tissue, and acquisition of epidemiologic, clinical and tumour tissue data, including histopathological and immunohistochemical character. Gut 65:1973–1980

    Article  CAS  Google Scholar 

  33. Tsai YJ, Huang SC, Lin HH et al (2018) Differences in gene mutations according to gender among patients with colorectal cancer. World J Surg Oncol 16:1–5. https://doi.org/10.1186/s12957-018-1431-5

    Article  CAS  Google Scholar 

  34. Slattery ML, Potter JD, Curtin K et al (2001) Estrogens reduce and withdrawal of estrogens increase risk of microsatellite instability-positive colon cancer. Cancer Res 61:126–130

    CAS  PubMed  Google Scholar 

  35. Maccaroni E, Bracci R, Giampieri R, et al (2015) Prognostic impact of mismatch repair genes germline defects in colorectal cancer patients: Are all mutations equal? Oncotarget 6:38737–38748. https://doi.org/10.18632/oncotarget.5395

  36. Sinicrope FA, Foster NR, Thibodeau SN et al (2011) DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J Natl Cancer Inst 103:863–875. https://doi.org/10.1093/jnci/djr153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jover R, Nguyen TP, Pérez-Carbonell LZ et al (2011) 5-fluorouracil adjuvant chemotherapy does not increase survival in patients with CpG island methylator phenotype colorectal cancer. Gastroenterology 140:1174–1181

    Article  CAS  Google Scholar 

  38. Dkk T, Burgermeister E, Ph D et al (2012) TFAP2E–DKK4 and chemoresistance in colorectal cancer. N Engl J Med 366:44–53

    Article  Google Scholar 

  39. Perez-Carbonell L, Balaguer F, Toiyama Y et al (2014) IGFBP3 methylation is a novel diagnostic and predictive biomarker in colorectal cancer. PLoS ONE 9:1–11. https://doi.org/10.1371/journal.pone.0104285

    Article  CAS  Google Scholar 

  40. André T, Shiu K-K, Kim TW et al (2020) Pembrolizumab in microsatellite-instability–high advanced colorectal cancer. N Engl J Med 383:2207–2218. https://doi.org/10.1056/nejmoa2017699

    Article  CAS  PubMed  Google Scholar 

  41. Marabelle A, Le DT, Ascierto PA et al (2020) Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/ mismatch repair–deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol 38:1–10. https://doi.org/10.1200/JCO.19.02105

    Article  CAS  PubMed  Google Scholar 

  42. Overman MJ, Lonardi S, Wong KYM et al (2018) Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 36:773–779. https://doi.org/10.1200/JCO.2017.76.9901

    Article  CAS  PubMed  Google Scholar 

  43. Kang SY, Park CK, Chang DK et al (2015) Lynch-like syndrome: characterization and comparison with EPCAM deletion carriers. Int J Cancer 136:1568–1578. https://doi.org/10.1002/ijc.29133

    Article  CAS  PubMed  Google Scholar 

  44. Mensenkamp AR, Vogelaar IP, Van Zelst-Stams WAG et al (2014) Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in lynch syndrome-like tumors. Gastroenterology 146:643-646.e8. https://doi.org/10.1053/j.gastro.2013.12.002

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We wish to express our gratitude to the Office of Metropolitan Hospital Management, Tokyo Metropolitan Government for their support. We are grateful to all the patients and their families for their participation in our study and would like to thank Mr. James R. Valera for his assistance in editing this manuscript.

Funding

The Office of Metropolitan Hospital Management, Tokyo Metropolitan Government provided funding for this study.

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Authors and Affiliations

  1. Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-0021, Japan

    Yujiro Nakayama, Misato Takao & Tatsuro Yamaguchi

  2. Department of Clinical Genetics, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-0021, Japan

    Takeru Iijima, Takuhiko Inokuchi, Ekumi Kojika & Tatsuro Yamaguchi

  3. Department of Gastroenterology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-0021, Japan

    Akinari Takao & Koichi Koizumi

  4. Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-0021, Japan

    Shin-ichiro Horiguchi & Tsunekazu Hishima

  5. Department of Minimally Invasive Surgical and Medical Oncology, Fukushima Medical University, Hikarigaoka, Fukushima, 960-1247, Japan

    Yujiro Nakayama

  6. Department of Surgery, Southern Tohoku General Hospital, Fukushima, 963-8052, Japan

    Yujiro Nakayama

Authors
  1. Yujiro Nakayama
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  2. Takeru Iijima
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  9. Tsunekazu Hishima
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  10. Tatsuro Yamaguchi
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Contributions

YN, TI, TI, EK, MT, AT, SH, and TH: substantial contributions to the conception and design of the study and acquisition, analysis or interpretation of data. YN and TY: drafting or critical revision of the manuscript for important intellectual content. TY: final approval of the version to be published.

Corresponding author

Correspondence to Tatsuro Yamaguchi.

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Nakayama, Y., Iijima, T., Inokuchi, T. et al. Clinicopathological features of sporadic MSI colorectal cancer and Lynch syndrome: a single-center retrospective cohort study. Int J Clin Oncol 26, 1881–1889 (2021). https://doi.org/10.1007/s10147-021-01968-y

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  • DOI: https://doi.org/10.1007/s10147-021-01968-y

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