The Effect of Microsatellite Instability on Clinicopathological Data and Survival in Colorectal Cancer

Year 2022, Volume: 75 Issue: 3, 348 - 355, 18.10.2022

Meriç Emre Bostancı , Murat Can Mollaoğlu , Hatice Özer , Kürşat Karadayı

Abstract

Objectives: Colorectal cancer is known as the third most common type of cancer worldwide. The microsatellite instability (MSI) pathway is effective
in the development of 15-20% of colorectal cancers. MSI is mainly caused by mutational inactivation of one of the four main MMR genes (MSH2,
MLH1, MSH6 or PMS2). This study was planned to investigate clinicopathological features of MSI in colorectal cancer and its effect on prognosis.
For this purpose, demographic and clinicopathological data of patient groups with MSI and microsatellite stability (MSS) were compared.

Materials and Methods: In this study, the pathology reports of 109 patients who were diagnosed with colorectal cancer and were operated on
between 01.01.2015 and 01.01.2019 in the Surgery Oncology Clinic of Cumhuriyet University Medical Faculty Hospital were analyzed retrospectively.
MLH-1, MSH-2, MSH-6, and PMS-2 antibodies were evaluated together with demographic and histopathological features and survival time of the
patients.

Results: The histological grade distribution difference between the MSS and MSI groups was not statistically significant (p=0.838). Mostly observed
T-stage was T3 in both groups, and the differences between the groups were not statistically significant (p=0.405). Regarding the N stage, N0 was
more common in MSS and N2 in MSI; however, no significant difference was observed between the two groups (p=0.844). Lymphovascular invasion
(LVI) was not observed in most cases in both groups, and the differences between the groups were not statistically significant (p=0.493). Perineural
invasion (PNI) was present in most cases in both groups, and the differences between the groups were not statistically significant (p=0.987). Survival rates according to the groups were evaluated using the Kaplan Meier test, and no statistically significant difference was found in the 2-year survival rates (p>0.05).

Conclusion: In this study, the relationship of MLH1, MSH2, MSH6, and PMS2’s immunohistochemical expression with clinicopathological parameters
and survival in patients with colorectal cancer was investigated. According to study results, the losses of expression in the cases were 13.7% for
MLH1, 9.1% for MSH2, 12.8% for MSH6, and 14.6% for PMS2. Although it was not statistically significant in the study, we think that the survival
rate is higher in cases with MSI. However, the

Keywords

Colorectal Cancer , Microsatellite Instability , Microsatellite Stability

Ethical Statement

Ethical approval was obtained from the ethics commission of the Sivas Cumhuriyet University where the study was conducted, (2022-04/24 number and 27.04.2022 date).

Supporting Institution

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Project Number

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Thanks

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Kolorektal Kanserde Mikrosatellit İnstabilitesinin Klinikopatolojik Veriler ve Sağkalım Üzerine Etkisi

Abstract

Amaç: Kolorektal kanserler tüm dünyada en yaygın görülen üçüncü kanser türü olarak bilinmektedir. Mikrosatellit instabilite (MSİ) yolağı kolorektal
kanserlerin %15-20’sinin gelişiminde etkilidir. MSİ, esas olarak dört ana MMR genlerinden birinin (MSH2, MLH1, MSH6 veya PMS2) mutasyonla
inaktivasyonundan kaynaklanır. Bu çalışma kolorektal kanserde MSİ’nin klinikopatolojik özellikler ve prognoz üzerine etkisini araştırmak için
planlandı. Bu amaçla; MSİ ve mikrosatellit stabilite (MSS) hasta gruplarına ait demografik ve klinikopatolojik veriler karşılaştırıldı.

Gereç ve Yöntem: Bu çalışmada, çalışma grubu olarak Cumhuriyet Üniversitesi Tıp Fakültesi Hastanesi Cerrahi Onkoloji Kliniği’nde 01.01.2015-
01.01.2019 tarihleri arasında kolorektal kanser tanısı almış ve opere edilmiş 109 hastaya ait patoloji raporları retrospektif olarak incelendi. MLH-1,
MSH-2, MSH-6, PMS-2 antikorları, hastaların demografik ve histopatolojik özellikleriyle ve sağkalım süreleriyle birlikte değerlendirildi.

Bulgular: MSS ve MSI grupları arasındaki histolojik derece dağılım farkı istatistiksel olarak anlamsızdı (p=0,838). Her iki grupta da T-evresi çoğunlukla
T3 olup, gruplar arasındaki farklılıklar istatistiksel olarak anlamlı değildi (p=0,405). N evresi de MSS’de N0, MSİ’de ise N2 çoğunluktaydı ve her iki grup
arasında anlamlı bir fark görülmedi (p=0,844). Lenfovasküler invazyon (LVI) her iki grupta da olguların çoğunluğunda olmayıp, gruplar arasındaki
farklılıklar da istatistiksel olarak anlamlı değildi (p=0,493). Perinöral invazyon (PNI) her iki grupta da olguların çoğunluğunda var iken, gruplar
arasındaki farklılıklar istatistiksel olarak anlamlı değildi (p=0,987). Gruplara göre sağkalım oranları Kaplan-Meier testi ile değerlendirildiğinde 2 yıllık
sağkalım oranları arasında istatistiksel olarak anlamlı farklılık saptanmamıştır (p>0,05).

Sonuç: Olgularımız arasında ekspresyon kaybı MLH1 için %13,7, MSH2 için %9,1, MSH6 için %12,8 ve PMS2 için %14,6 olarak bulunmuştur.
Çalışmamızda MSİ gösteren olgularda, istatistiksel olarak anlamlı olmamakla birlikte sağ kalım oranının yüksek olduğunu düşünüyoruz. Ancak MSI
için cinsiyet, yaş, grade, lokalizasyon, LVI, PNI açısından istatistiksel olarak anlamlı bir farklılık yoktu. MSI tespit etmek için daha çok parametrenin
çalışılması gerektiği kanaatindeyiz

Keywords

Kolorektal Kanser , Mikrosatellit İnstabilitesi , Mikrosatellit Stabilitesi

Ethical Statement

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Supporting Institution

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Project Number

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Thanks

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References

• 1. Granados-Romero JJ, Valderrama-Treviῆo AI, Contreras- Flores EH, et al. Colorectalcancer: A review. Int J Res Med Sci. 2017;5:4667-4676.
• 2. World HealthOrganization. Cancer. September 12, 2018.Available at: https://www.who.int/news-room/fact-sheets/detail/cancerAccessedDecember28, 2019.
• 3. Wang JY, Wang YH, Jao SW, et al. Molecular mechanisms underlying the tumorigenesis of colorectal adenomas: correlation to activated K-ras oncogene. Oncol Rep. 2006;16:1245-1252.
• 4. Carethers JM, Smith EJ, Behling CA, et al. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology. 2004;126:394-401.
• 5. De’ Angelis GL, Bottarelli L, Azzoni C, et al. Microsatellite instability in colorectal cancer. Acta Biomed. 2018;89:97-101.
• 6. Al-Sohaily S, Biankin A, Leong R, et al. Molecular pathways in colorectal cancer. J Gastroenterol Hepatol. 2012;27:1423-1431.
• 7. Yamamoto H, Imai K. Microsatellite instability: an update. Arch Toxicol. 2015;89:899-921.
• 8. Jass JR. HNPCC and sporadic MSI-H colorectal cancer: a review of the morphological similarities and differences. Fam Cancer. 2004;3:93-100.
• 9. Jess P, Hansen IO, Gamborg M, et al. A nationwide Danish cohort study challenging the categorisation into right-sided and left-sided colon cancer. BMJ Open. 2013;3:1-7.
• 10. Parc Y, Gueroult S, Mourra N, et al. Prognostic significance of microsatellite instability determined by immunohistochemical staining of MSH2 and MLH1 in sporadic T3N0M0 colon cancer. Gut. 2004;53:371-375.
• 11. Meyers M, Hwang A, Wagner MW, et al. Role of DNA mismatch repair in apoptotic responses to therapeutic agents. Environ Mol Mutagen. 2004;44:249-264.
• 12. Ilyas M, Straub J, Tomlinson IP, et al. Genetic pathways in colorectal and other cancers. Eur J Cancer. 1999;35:1986-2002.
• 13. Jenkins MA, Hayashi S, O’Shea AM, et al. Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a populationbased study. Gastroenterology. 2007;133:48-56.
• 14. Ismael NE, El Sheikh SA, Talaat SM, et al. Mismatch Repair Proteins and Microsatellite Instability in Colorectal Carcinoma (MLH1, MSH2, MSH6 and PMS2): Histopathological and Immunohistochemical Study. Open Access Maced J Med Sci. 2017;5:9-13.
• 15. Rosai J. Gastrointestinal Tract. In: Rosai J, editor. Rosaiand Ackerman’s Surgical Pathologyurgical Pathology. China: Elsevier Saunders; 2011. p. 731-803.
• 16. Gupta S, Ashfaq R, Kapur P, et al. Microsatellite instability among individuals of Hispanic origin with colorectal cancer. Cancer. 2010;116:4965-4972.
• 17. Haydon AM, Jass JR. Emerging pathways in colorectal-cancer development. Lancet Oncol. 2002;3:83-88.
• 18. Hampel H, Frankel W, Panescu J, et al. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res. 2006;66:7810-7817.
• 19. Lawes DA, SenGupta S, Boulos PB. The clinical importance and prognostic implications of microsatellite instability in sporadic cancer. Eur J Surg Oncol. 2003;29:201-212.
• 20. Scartozzi M, Bianchi F, Rosati S, et al. Mutations of hMLH1 and hMSH2 in patients with suspected hereditary nonpolyposis colorectal cancer: correlation with microsatellite instability and abnormalities of mismatch repair protein expression. J Clin Oncol. 2002;20:1203-1208.
• 21. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96:261-268.
• 22. Yuan L, Chi Y, Chen W, et al. Immunohistochemistry and microsatellite instability analysis in molecular subtyping of colorectal carcinoma based on mismatch repair competency. Int J Clin Exp Med. 2015;8:20988-21000.
• 23. Shia J, Zhang L, Shike M, et al. Secondary mutation in a coding mononucleotide tract in MSH6 causes loss of immunoexpression of MSH6 in colorectal carcinomas with MLH1/PMS2 deficiency. Mod Pathol. 2013;26:131-138.
• 24. Kim JH, Kang GH. Molecular and prognostic heterogeneity of microsatelliteunstable colorectal cancer. World J Gastroenterol. 2014;20:4230-4243.
• 25. Rosty C, Clendenning M, Walsh MD, et al. Germline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the Colon Cancer Family Registry Cohort. BMJ Open. 2016;6:e010293.
• 26. Karahan B, Argon A, Yıldırım M, et al. Relationship between MLH-1, MSH2, PMS-2,MSH-6 expression and clinicopathological features in colorectal cancer. Int J Clin Exp Pathol. 2015;8:4044-4053.
• 27. Alexander J, Watanabe T, Wu TT, et al. Histopathological identification of colon cancer with microsatellite instability. Am J Pathol. 2001;158:527-535.
• 28. Xiao H, Yoon YS, Hong SM, et al. Poorly differentiated colorectal cancers: correlation of microsatellite instability with clinicopathologic features and survival. Am J Clin Pathol. 2013;140:341-347.
• 29. Thibodeau SN, French AJ, Cunningham JM, et al. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res. 1998;58:1713-1718.
• 30. Des Guetz G, Schischmanoff O, Nicolas P, et al. Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur J Cancer. 2009;45:1890-1896. 31. Halling KC, French AJ, McDonnell SK, et al. Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. J Natl Cancer Inst. 1999;91:1295-1303.
• 32. Kurzawski G, Suchy J, Debniak T, Kładny J, Lubiński J.,Importance of microsatelliteinstability (MSI) in colorectalcancer: MSI as a diagnostictool. Ann Oncol. 2004;5:283-284.
• 33. Kahlenberg MS, Sullivan JM, Witmer DD, et al. Molecular prognostics in colorectal cancer. Surg Oncol. 2003;12:173-186.
• 34. Salahshor S, Kressner U, Fischer H, et al. Microsatellite instability in sporadic colorectal cancer is not an independent prognostic factor. Br J Cancer. 1999;81:190-193.
• 35. Yu Y, Carey M, Pollett W, Green J, Dicks E, Parfrey P, Yilmaz YE, Savas S, Thelong-termsurv ivalcharact eristics of a cohort of colorectalcan cerpatientsandbase linevariables associatedwithsurvi valoutcomeswit horwithout time-varyingef fects. BMC Med. 2019;17:150.
• 36. Goldstein J, Tran B, Ensor J, et al. Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H). Ann Oncol. 2014;25:1032-1038.
• 37. Seppälä TT, Böhm JP, Friman M, et al. Combination of microsatellite instability and BRAF mutation status for subtyping colorectal cancer. Br J Cancer. 2015;112:1966-1975.
• 38. Karahan B, Argon A, Yıldırım M, et al. Relationship between MLH-1, MSH2, PMS-2,MSH-6 expression and clinicopathological features in colorectal cancer. Int J Clin Exp Pathol. 2015;8:4044-4053.
• 39. Lin CC, Lai YL, Lin TC, et al. Clinicopathologic features and prognostic analysis of MSI-high colon cancer. Int J Colorectal Dis. 2012;27:277-286.
• 40. Parc Y, Gueroult S, Mourra N, et al. Prognostic significance of microsatellite instability determined by immunohistochemical staining of MSH2 and MLH1 in sporadic T3N0M0 colon cancer. Gut. 2004;53:371-375.
• 41. Batur S, Vuralli Bakkaloglu D, Kepil N, et al. Microsatellite instability and B-type Raf proto-oncogene mutation in colorectal cancer: Clinicopathological characteristics and effects on survival. Bosn J Basic Med Sci. 2016;16:254-260