HATALI EŞLEŞME GENLERİNDEN MLH1, PMS2, MSH6, MSH2’İN MİDE KANSERLERİNDE İMMÜNHİSTOKİMYASAL EKSPRESYONU; BİR DOKU MİKROARRAY ÇALIŞMASI

Öz

Amaç Mide kanserinde MLH1, PMS2, MSH6, MSH2’in immünhistokimyasal ekspresyonları ile klinikopatolojik parametrelerin arasındaki ilişkiyi değerlendirmeyi amaçladık. Gereç ve Yöntem Yüzüç primer mide adenokarsinom ve tümörsüz 27 mide mukozasına ait doku mikroarray (DMA) kesitlerine immünhistokimyasal uygulama yapıldı. Tüm markerlar nükleer boyanma açısından değerlendirildi. Markerlardan herhangi birinde negatiflik eksiklik olarak kabul edildi. Daha sonra hatalı eşleşme genlerinde eksiklik var (dMMR) ve hatalı eşleşme genleri sağlam (pMMR) olmak üzere 2 alt grup arasında karşılaştırma yapıldı. Bulgular Histopatolojik olarak intestinal ve intestinal olmayan alt tiplerinden, MSH2’nin intestinal grupta intestinal olmayan gruba göre ekspresyonunda anlamlı kayıp gözlendi. PMS2 ekspresyonu taşlı yüzük hücreli karsinomda diğer alt tiplere göre anlamlı olarak yüksekti. Ayrıca MLH1 ve PMS2 ekspresyonlarının kaybının orta/kötü diferansiye tümörlerde, iyi diferansiye tümörlere göre daha yüksek olduğunu gözlemledik. MLH1, MSH6, PMS2 ekspresyon kaybı ve dMMR olan olgularda pMMR’li olgulara göre perinöral invazyon anlamlı şekilde daha yüksekti. Kemoterapi/ radyoterapi alan ve almayan gruplar karşılaştırıldığında dMMR ve pMMR arasında anlamlı fark yoktu. MLH1, MSH2, MSH6, PMS2 ekspresyonları ile sağkalım arasında anlamlı ilişki bulunmadı. Sonuç Perinöral invazyon ile MLH1, MSH6 ve PMS2 ekspresyon kaybı arasında anlamlı ilişki bulduk. PMS2 ekspresyonu taşlı yüzük hücreli karsinomda diğer alt tiplere göre anlamlı olarak yüksekti.

Anahtar Kelimeler

• Mide adenokarsinom
• MLH1
• MSH2
• PMS2
• MSH6

THE IMMUNOHISTOCHEMICAL EXPRESSIONS OF MISMATCH REPAIR GENES MLH1, PMS2, MSH6, MSH2 IN GASTRIC CANCER; A TISSUE MICROARRAY STUDY

Öz

Objective We aimed to evaluate the correlation between the immunohistochemical expressions of MLH1, PMS2, MSH6, MSH2 and clinicopathological parameters in gastric carcinoma. Matherials and Methods Immunohistochemistry was performed on the tissue microarray (TMA) sections of 103 primary gastric adenocarcinoma and 27 gastric mucosal tissue samples without tumor. All markers were evaluated for the presence of nuclear staining. Negative expression in any of the markers was accepted as a deficiency. Then, the comparison was made between the two subgroups as; deficient mismatch repair (dMMR) and proficient mismatch repair (pMMR). Results The histopathological subtypes as intestinal and non-intestinal, the intestinal group showed significant deficient expression of MSH2 compared with the non-intestinal group. PMS2 expression was significantly higher in the other subtypes than signet ring cell carcinoma. Also, we observed that the loss of MLH1 and PMS2 expressions were higher in moderately/ poor differantiated tumors than the well differantiated ones. Perineural invasion was significantly higher in patients with loss of MLH1, MSH6, PMS2 expression and dMMR compared to patients with pMMR. There was no significant difference between dMMR and pMMR when compared the groups who received chemotherapy/ radiotherapy and who did not. There was not found significant relationship between MLH1, MSH2, MSH6, PMS2 expressions and survival. Conclusion We found a significant relationship between perineural invasion and the loss of expression of MLH1, MSH6 and PMS2. PMS2 expression was also significantly higher in the other subtypes of GC than signet ring cell carcinomas.

Anahtar Kelimeler

• Gastric adenocarcinoma
• MLH1
• PMS2
• MSH2
• MSH6

Kaynakça

1. (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. (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. (3) Maleki SS, Röcken C. Chromosomal Instability in Gastric Cancer Biology. Neoplasia 2017;19:412-420.
4. (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. (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. (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. (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. (8) Peltomaki P. Update on Lynch syndrome genomics. Fam Cancer. 2016;15:385–393.

9. (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. (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. (11) Fukayama M., Rugge M, Washington MK, World Health Organisation (WHO) Classification of Tumours. Digestive System Tumours. Fifth Edition 2019;59-110.
12. (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. (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. (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. (15) Prolla TA, Abuin A, Bradley A. DNA mismatch repair deficient mice in cancer research. Cancer Biology 1996;7:241–247.
16. (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. (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. (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. (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. (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. (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. (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. (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. (24) Yamamoto H, Imai K. Microsatellite instability: an update. Arch Toxicol 2015.
25. (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. (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. (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. (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. (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. (30) Ross JS, McKenna BJ. The HER-2/neu oncogene in tumors of the gastrointestinal tract. Cancer Invest 2001;19:554-568.