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

Year 2021, Volume: 28 Issue: 3, 487 - 497, 13.09.2021
https://doi.org/10.17343/sdutfd.866797

Abstract

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.

Supporting Institution

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Project Number

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Thanks

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References

  • (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.

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

Year 2021, Volume: 28 Issue: 3, 487 - 497, 13.09.2021
https://doi.org/10.17343/sdutfd.866797

Abstract

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.

Project Number

-

References

  • (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.
There are 30 citations in total.

Details

Primary Language English
Subjects Clinical Sciences
Journal Section Research Articles
Authors

Gamze Erkılınç 0000-0003-4704-7415

Nermin Karahan 0000-0003-0883-4037

Şirin Başpınar 0000-0002-4947-7569

Zümrüt Arda Kaymak 0000-0002-7284-008X

Şehnaz Evrimler 0000-0002-9907-0011

Project Number -
Publication Date September 13, 2021
Submission Date January 23, 2021
Acceptance Date September 7, 2021
Published in Issue Year 2021 Volume: 28 Issue: 3

Cite

Vancouver Erkılınç G, Karahan N, Başpınar Ş, Kaymak ZA, Evrimler Ş. THE IMMUNOHISTOCHEMICAL EXPRESSIONS OF MISMATCH REPAIR GENES MLH1, PMS2, MSH6, MSH2 IN GASTRIC CANCER; A TISSUE MICROARRAY STUDY. Med J SDU. 2021;28(3):487-9.

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