sdü tıp fak derg Medical Journal of Süleyman Demirel University 2602-2109 Süleyman Demirel Üniversitesi 10.17343/sdutfd.866797 Clinical Sciences Klinik Tıp Bilimleri HATALI EŞLEŞME GENLERİNDEN MLH1, PMS2, MSH6, MSH2’İN MİDE KANSERLERİNDE İMMÜNHİSTOKİMYASAL EKSPRESYONU; BİR DOKU MİKROARRAY ÇALIŞMASI THE IMMUNOHISTOCHEMICAL EXPRESSIONS OF MISMATCH REPAIR GENES MLH1, PMS2, MSH6, MSH2 IN GASTRIC CANCER; A TISSUE MICROARRAY STUDY https://orcid.org/0000-0003-4704-7415 Erkılınç Gamze Süleyman Demirel Üniversitesi Tıp Fakültesi Tıbbı Patoloji Anabilim Dalı https://orcid.org/0000-0003-0883-4037 Karahan Nermin Süleyman Demirel Üniversitesi Tıp Fakültesi Tıbbı Patoloji Anabilim Dalı https://orcid.org/0000-0002-4947-7569 Başpınar Şirin Süleyman Demirel Üniversitesi Tıp Fakültesi Tıbbı Patoloji Anabilim Dalı https://orcid.org/0000-0002-7284-008X Kaymak Zümrüt Arda Süleyman Demirel Üniversitesi Tıp Fakültesi Radyasyon Onkolojisi Anabilim Dalı https://orcid.org/0000-0002-9907-0011 Evrimler Şehnaz Süleyman Demirel Üniversitesi Tıp Fakültesi Radyoloji Anabilim Dalı 09 13 2021 28 3 487 497 01 23 2021 09 07 2021 Copyright © 1994, Süleyman Demirel Üniversitesi Tıp Fakültesi Dergisi 1994 Süleyman Demirel Üniversitesi Tıp Fakültesi Dergisi

AmaçMide kanserinde MLH1, PMS2, MSH6, MSH2’in immünhistokimyasalekspresyonları ile klinikopatolojikparametrelerin arasındaki ilişkiyi değerlendirmeyiamaçladık.Gereç ve YöntemYüzüç primer mide adenokarsinom ve tümörsüz 27mide mukozasına ait doku mikroarray (DMA) kesitlerineimmünhistokimyasal uygulama yapıldı. Tümmarkerlar nükleer boyanma açısından değerlendirildi.Markerlardan herhangi birinde negatiflik eksiklikolarak kabul edildi. Daha sonra hatalı eşleşme genlerindeeksiklik var (dMMR) ve hatalı eşleşme genlerisağlam (pMMR) olmak üzere 2 alt grup arasındakarşılaştırma yapıldı.BulgularHistopatolojik olarak intestinal ve intestinal olmayanalt tiplerinden, MSH2’nin intestinal grupta intestinalolmayan gruba göre ekspresyonunda anlamlı kayıpgözlendi. PMS2 ekspresyonu taşlı yüzük hücreli karsinomdadiğer alt tiplere göre anlamlı olarak yüksekti.Ayrıca MLH1 ve PMS2 ekspresyonlarının kaybınınorta/kötü diferansiye tümörlerde, iyi diferansiyetümörlere göre daha yüksek olduğunu gözlemledik.MLH1, MSH6, PMS2 ekspresyon kaybı ve dMMRolan olgularda pMMR’li olgulara göre perinöral invazyonanlamlı şekilde daha yüksekti. Kemoterapi/radyoterapi alan ve almayan gruplar karşılaştırıldığındadMMR ve pMMR arasında anlamlı fark yoktu.MLH1, MSH2, MSH6, PMS2 ekspresyonları ile sağkalımarasında anlamlı ilişki bulunmadı.SonuçPerinöral invazyon ile MLH1, MSH6 ve PMS2 ekspresyonkaybı arasında anlamlı ilişki bulduk. PMS2ekspresyonu taşlı yüzük hücreli karsinomda diğer alttiplere göre anlamlı olarak yüksekti.

ObjectiveWe aimed to evaluate the correlation between theimmunohistochemical expressions of MLH1, PMS2,MSH6, MSH2 and clinicopathological parameters ingastric carcinoma.Matherials and MethodsImmunohistochemistry was performed on the tissuemicroarray (TMA) sections of 103 primary gastricadenocarcinoma and 27 gastric mucosal tissuesamples without tumor. All markers were evaluatedfor the presence of nuclear staining. Negative expressionin any of the markers was accepted as adeficiency. Then, the comparison was made betweenthe two subgroups as; deficient mismatch repair(dMMR) and proficient mismatch repair (pMMR).ResultsThe histopathological subtypes as intestinal andnon-intestinal, the intestinal group showed significantdeficient expression of MSH2 compared withthe non-intestinal group. PMS2 expression was significantlyhigher in the other subtypes than signet ringcell carcinoma. Also, we observed that the loss ofMLH1 and PMS2 expressions were higher in moderately/poor differantiated tumors than the well differantiatedones. Perineural invasion was significantlyhigher in patients with loss of MLH1, MSH6, PMS2expression and dMMR compared to patients withpMMR. There was no significant difference betweendMMR and pMMR when compared the groupswho received chemotherapy/ radiotherapy and whodid not. There was not found significant relationshipbetween MLH1, MSH2, MSH6, PMS2 expressionsand survival.ConclusionWe found a significant relationship between perineuralinvasion and the loss of expression of MLH1,MSH6 and PMS2. PMS2 expression was also significantlyhigher in the other subtypes of GC than signetring cell carcinomas.

 Gastric adenocarcinoma MLH1 PMS2 MSH2 MSH6 Mide adenokarsinom MLH1 MSH2 PMS2 MSH6 none (1) Bösch F, Todorova R, Link H, et.al. Molecular subtyping of gastric cancer with respect to the growth pattern of lymph node metastases Journal of Cancer Research and Clinical Oncology 2019; 145(11), 2689-2697. (2) Seo HM, Chang YS, Joo SH, et.al. Clinicopathologic Characteristics and Outcomes of Gastric Cancers With the MSI-H Phenotype. Journal of Surgical Oncology 2009;99:143–147. (3) Maleki SS, Röcken C. Chromosomal Instability in Gastric Cancer Biology. Neoplasia 2017;19:412-420. (4) Thibodeau SN, French AJ, Roche PC, et al. Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. Cancer Res 1996; 56:4836–4840. (5) Yamamoto H, Adachi Y, Taniguchi H, et.al. Interrelationship between microsatellite instability and microRNA in gastrointestinal cancer. World J Gastroenterol 2012 June 14; 18(22): 2745-2755. (6) Ikenoue T, Arai M, Ishioka C, et al. Importance of gastric cancer for the diagnosis and surveillance of Japanese Lynch syndrome patients. Journal of Human Genetics 2019;64.12:1187-1194. (7) Ligtenberg MJ, Kuiper RP, Chan TL, et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nat Genet. 2009;41:112–117. (8) Peltomaki P. Update on Lynch syndrome genomics. Fam Cancer. 2016;15:385–393. (9) Cunningham JM, Kim CY, Christensen ER, et al. The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am J Hum Genet. 2001;69:780–790. (10) Beghelli S, de Manzoni G, Barbi S, et al. Microsatellite instability in gastric cancer is associated with better prognosis in only stage II cancers. Surgery 2006;139:347–356. (11) Fukayama M., Rugge M, Washington MK, World Health Organisation (WHO) Classification of Tumours. Digestive System Tumours. Fifth Edition 2019;59-110. (12) Protocol for the Examination of Specimens From Patients With Carcinoma of the Stomach Collage of American Pathologists. Includes pTNM requirements from the 8th Edition, AJCC Staging Manual June 2017. (13) 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(11):20988–21000. (14) Kitajima Y, Miyazaki K, Matsukura S, et. al. Loss of expression of DNA repair enzymes MGMT, hMLH1, and hMSH2 during tumor progression in gastric cancer. Gastric Cancer. 2003;6:86–95. (15) Prolla TA, Abuin A, Bradley A. DNA mismatch repair deficient mice in cancer research. Cancer Biology 1996;7:241–247. (16) Chen X, Li X, Liang H, Wei L, et.al. A new mutL homolog 1 c.1896+5G>A germline mutation detected in a Lynch syndrome associated lung and gastric double primary cancer patient. Mol Genet Genomic Med. 2019;00:787. (17) Karimi M, Salomé JV, Aravidis C, et al. A retrospective study of extracolonic, non-endometrial cancer in Swedish Lynch syndrome families. Karimi et al. Hereditary Cancer in Clinical Practice 2018;16:16. (18) Vasen HF, Blanco I, Aktan-Collan K, et al. Revised guidelines for the clinical management of lynch syndrome (HNPCC): recommendations by a group of European experts. Gut. 2013;62(6):812–823. (19) Barrow E, Robinson L, Alduaij W, et al. Cumulative lifetime incidence of extracolonic cancers in lynch syndrome: a report of 121 families with proven mutations. Clin Genet. 2009;75(2):141–149. (20) Chong J-M, Fukayama M, Hayashi Y, et al.: Microsatellite instability in the progression of gastric carcinoma. Cancer Res 1994;54:4595–4597. (21) Beghelli S, de Manzoni G, Barbi S, et al.: Microsatellite instability in gastric cancer is associated with better prognosis in only stage II cancers. Surgery 2006;139:347–356. (22) Neri S, Gardini A, Facchini A, et al.: Mismatch repair system and aging: Microsatellite instability in peripheral blood cells from differently aged participants. J Gerontol A Biol Sci Med Sci 2005;60:285–292. (23) Yamamoto H, Perez-Piteira J, Yoshida T, et.al. Gastric cancers of the microsatellite mutator phenotype display characteristic genetic and clinical features. Gastroenterology 1999;116:1348–1357. (24) Yamamoto H, Imai K. Microsatellite instability: an update. Arch Toxicol 2015. (25) Arai T, Sakurai U, Sawabe M, et.al. Frequent microsatellite instability in papillary and solid-type, poorly differentiated adenocarcinomas of the stomach. Gastric Cancer 2013;16:505–512. (26) Hirotsu Y, Mochizuki H, Amemiya K, et al. Deficiency of mismatch repair genes is less frequently observed in signet ring cell compared with non-signet ring cell gastric cancer. Medical Oncology 2019;36:23. (27) Shenying J, et al. The PD-1, PD-L1 expression and CD3 + T cell infiltration in relation to outcome in advanced gastric signet-ring cell carcinoma, representing a potential biomarker for immunotherapy. Oncotarget. 2017;8:38850–38862. (28) Kim KJ, Lee TH, Cho NY, et.al. Differential clinicopathologic features in microsatellite-unstable gastric cancers with and without MLH1 methylation. Human Pathology 2013;44.6:1055-1064 (29) Kim HS, Shin SJ, Beom SH, et. al.Comprehensive expression profiles of gastric cancer molecular subtypes by immunohistochemistry: implications for individualized therapy. Oncotarget 2016(7):28. (30) Ross JS, McKenna BJ. The HER-2/neu oncogene in tumors of the gastrointestinal tract. Cancer Invest 2001;19:554-568.