Immunohistochemical Expression of MMR Proteins with Clinicopathological Correlation in Colorectal Cancer in Egypt

Nahed A. Soliman; Deaa Fekri Morsi; Noha A. H. Helmy

doi:10.3889/oamjms.2019.357

Authors

Nahed A. Soliman Department of Pathology, Faculty of Medicine, Helwan University, Helwan 11795, Egypt; Department of Pathology, Faculty of Medicine, University of Mansoura, Mansoura 35516, Egypt
Deaa Fekri Morsi Department of Pathology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
Noha A. H. Helmy National Center for Research, Giza 12622, Egypt

DOI:

https://doi.org/10.3889/oamjms.2019.357

Keywords:

Microsatellite instability, Colorectal carcinoma, Immunohistochemistry, Mismatch repair, Tumour-infiltrating lymphocyte

Abstract

BACKGROUND: Microsatellite instability (MSI) is the genetic pathway underlying 15% of sporadic colorectal carcinoma (CRC) and hereditary non-polyposis CRC. MSI-H CRC has a distinct clinicopathological characteristic including excess mucin and signet ring component, proximal colon, Crohnâ€™s like reaction, lymphocytic infiltration, and better survival.

AIM: This research aims to screen Egyptian CRC patients for MSI status by IHC testing of expression of the MMR proteins in correlation to its clinicopathological features.

MATERIAL AND METHODS: Immunohistochemistry study for mismatch repair proteins (MMR) was done on 115 cases of CRC. Their expressions were assessed and correlated to clinicopathological parameters in an attempt to obtain the most significant predictors of MSI.

RESULTS: MSI (low and high) represents 67% of the study cases. The most frequent expression pattern was combined loss of MLH, and PMS2 (38% of MSI) followed by a combined loss of MSH2, and MSH6 (29% of MSI). There was significant correlation of expression pattern of MMR proteins with the laterality, lymphovascular emboli, perineural invasion, grade, T stage, N stage, signet ring component, tumor infiltrating lymphocyte, and peritumoral lesion (0.014, 0.035, 0.012, 0.033, 0.013, 0.000, 0.041, 0.012, and 0.009 respectively). Proximal location (right sided) and lower grade, higher nodal stage, and marked TIL were selected as predictors of MS-H CRC (0.005, 0.031, 0.025, and 0.000 respectively).

CONCLUSION: All clinicopathological and histological parameters should be assessed in CRC for the sake of predicting MSI. The optimal approach to MSI evaluation is (IHC) assessment of MMR proteins.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Gkekas I, Novotny JAN, Pecen L, StrigÃ¥rd K, Palmqvist R, Gunnarsson ULF. Microsatellite Instability as a Prognostic Factor in Stage II Colon Cancer Patients, a Meta-Analysis of Published Literature. Anticancer Res. 2017; 37(12):6563-74.

Fujiyoshi K, Yamaguchi T, Kakuta M, Takahashi A, Arai Y, Yamada M, et al. Predictive model for high-frequency microsatellite instability in colorectal cancer patients over 50 years of age. Cancer Med. 2017; 6(6):1255-63. https://doi.org/10.1002/cam4.1088 PMid:28544821 PMCid:PMC5463087

Sayar I, Akbas EM, Isik A, Gokce A, Peker K, Demirtas L, et al. Relationship among mismatch repair deficiency, CDX2 loss, p53 and E-cadherin in colon carcinoma and suitability of using a double panel of mismatch repair proteins by immunohistochemistry. Polish J Pathol. 2015; 3(3):246-53. https://doi.org/10.5114/pjp.2015.54958

Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon cancer. Gastroenterology. 2010; 138(6):2044-58. https://doi.org/10.1053/j.gastro.2010.01.054 PMid:20420945 PMCid:PMC3057468

PDQ Cancer Genetics Editorial Board PCGE. Genetics of Colorectal Cancer (PDQÂ®): Health Professional Version [Internet]. PDQ Cancer Information Summaries. National Cancer Institute (US); 2002.

Kumar V, Abbas AK, Aster JC, Perkins JA. Robbins basic pathology [Internet]. 10th ed. Vinay Kumar, Abul K Abbas, Jon C Aster, Jon C PJ, editor. 2018:935. [cited 2018 Dec 19] Available from: https://smtebooks.eu/book/7756/robbins-basic-pathology-10th-edition-pdf

Fearon ER. Molecular genetics of colorectal cancer. Ann N Y Acad Sci. 1995; 768:101-10. https://doi.org/10.1111/j.1749-6632.1995.tb12114.x PMid:8526339

Pawlik TM, Raut CP, Rodriguez-Bigas MA. Colorectal carcinogenesis: MSI-H versus MSI-L. Disease markers. 2004; 20(4, 5):199-206. https://doi.org/10.1155/2004/368680 PMid:15528785 PMCid:PMC3839332

Hashmi AA, Ali R, Hussain ZF, Faridi N, Khan EY, Bakar SMA, et al. Mismatch repair deficiency screening in colorectal carcinoma by a four-antibody immunohistochemical panel in Pakistani population and its correlation with histopathological parameters. World J Surg Oncol. 2017; 15(1):4-11. https://doi.org/10.1186/s12957-017-1158-8 PMid:28651545 PMCid:PMC5485685

Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993; 260(5109):816-9. https://doi.org/10.1126/science.8484122 PMid:8484122

Yuan L, Chi Y, Chen W, Chen X, Wei P, Sheng 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):20988-1000.

PeltomÃ¤ki P. DNA mismatch repair and cancer. Mutat Res. 2001; 488(1):77-85. https://doi.org/10.1016/S1383-5742(00)00058-2

Matsubara N. Diagnostic application of hMLH1 methylation in hereditary non-polyposis colorectal cancer. Disease markers. 2004; 20(4-5):277-82. https://doi.org/10.1155/2004/371941 PMid:15528793 PMCid:PMC3839271

Poulogiannis G, Frayling IM, Arends MJ. DNA mismatch repair deficiency in sporadic colorectal cancer and Lynch syndrome. Histopathology. 2010; 56(2):167-79. https://doi.org/10.1111/j.1365-2559.2009.03392.x PMid:20102395

Smyrk TC, Watson P, Kaul K, Lynch HT. Tumor-Infiltrating Lymphocytes Are a Marker for Microsatellite Instability in Colorectal Carcinoma BACKGROUND. Cells with deficient DNA mismatch repair develop microsatellite. 2001; 2417-22. https://doi.org/10.1002/1097-0142(20010615)91:12<2417::AID-CNCR1276>3.3.CO;2-L

Sengupta SB, Yiu C-Y, Boulos PB, De Silva M, Sams VR, Delhanty JDA. Genetic instability in patients with metachronous colorectal cancers. Br J Surg. 1997; 84(7):996-1000. https://doi.org/10.1002/bjs.1800840725 PMid:9240146

De Angelis P, Kravik KL, De Angelis PM. DNA damage signaling in response to 5-fluorouracil in three colorectal cancer cell lines with different mismatch repair and TP53 status. Int J Oncol. 2011; 39(3):673-82. https://doi.org/10.3892/ijo.2011.1080 PMid:21674128

Stupart DA, Goldberg PA, Baigrie RJ, Algar U, Ramesar R. Surgery for colonic cancer in HNPCC: total vs segmental colectomy. Color Dis. 2011; 13(12):1395-9. https://doi.org/10.1111/j.1463-1318.2010.02467.x PMid:20969713

Jass JR, Do KA, Simms LA, Iino H, Wynter C, Pillay SP, et al. Morphology of sporadic colorectal cancer with DNA replication errors. Gut. 1998; 42(5):673-9. https://doi.org/10.1136/gut.42.5.673 PMid:9659163 PMCid:PMC1727100

Theise ND, Nakashima O, Park YN, Nakanuma Y. WHO Classification of Tumours of the Digestive System. Lyon: IARC Press; International Agency for Research on Cancer, 2010:225-227.

APMG Mismatch Repair Genes Resource. J Natl Compr Canc Netw, 2011:1311-20.

Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, 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 Colorectal Cancer. 1998.

Jemal A, Siegel R, Xu J, Ward E. Cancer Statistics, 2010. CA Cancer J Clin. 2010; 60(5):277-300. https://doi.org/10.3322/caac.20073 PMid:20610543

Hampel H. Population Screening for Hereditary Colorectal Cancer. Surg Oncol Clin N Am. 2018; 27(2):319-25. https://doi.org/10.1016/j.soc.2017.11.006 PMid:29496092

Smyrk TC, Watson P, Kaul K, Lynch HT. Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma. Cancer. 2001; 91(12):2417-22. https://doi.org/10.1002/1097-0142(20010615)91:12<2417::AID-CNCR1276>3.0.CO;2-U

Chew M-H, Koh P-K, Tan M, Lim K-H, Carol L, Tang C-L. Mismatch Repair Deficiency Screening via Immunohistochemical Staining in Young Asians with Colorectal Cancers. World J Surg. 2013; 37(10):2468-75. https://doi.org/10.1007/s00268-013-2134-2 PMid:23887594

Zhi W, Ying J, Zhang Y, Li W, Zhao H, Lu N, et al. DNA Mismatch Repair Deficiency in Colorectal Adenocarcinoma and its Association with Clinicopathological Features. 2015.

Guastadisegni C, Colafranceschi M, Ottini L, Dogliotti E. Microsatellite instability as a marker of prognosis and response to therapy: A meta-analysis of colorectal cancer survival data. Eur J Cancer. 2010; 46(15):2788-98. https://doi.org/10.1016/j.ejca.2010.05.009 PMid:20627535

Hall G, Clarkson A, Shi A, Langford E, Leung H, Eckstein RP, et al. Immunohistochemistry for PMS2 and MSH6 alone can replace a four antibody panel for mismatch repair deficiency screening in colorectal adenocarcinoma. Pathology. 2010; 42(5):409-13. https://doi.org/10.3109/00313025.2010.493871 PMid:20632815

Kumar A, Jain M, Yadav A, Kumari N, Krishnani N. Pattern of mismatch repair protein loss and its clinicopathological correlation in colorectal cancer in North India. S Afr J Surg. 2018; 56(1):25-9. https://doi.org/10.17159/2078-5151/2018/v56n1a2285 PMid:29638089

Kato A, Sato N, Sugawara T, Takahashi K, Kito M, Makino K, et al. Isolated Loss of PMS2 Immunohistochemical Expression is Frequently Caused by Heterogenous MLH1 Promoter Hypermethylation in Lynch Syndrome Screening for Endometrial Cancer Patients. Am J Surg Pathol. 2016; 40(6):770-6. https://doi.org/10.1097/PAS.0000000000000606 PMid:26848797 PMCid:PMC4885527

Salahshor S, Koelble K, Rubio C, Lindblom A. Microsatellite Instability and hMLH1 and hMSH2 Expression Analysis in Familial and Sporadic Colorectal Cancer. Lab Investig. 2001; 81(4):535-41. https://doi.org/10.1038/labinvest.3780262 PMid:11304573

Jenkins MA, Hayashi S, O'Shea A-M, Burgart LJ, Smyrk TC, Shimizu D, et al. Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Gastroenterology. 2007; 133(1):48-56. https://doi.org/10.1053/j.gastro.2007.04.044 PMid:17631130 PMCid:PMC2933045

Yoon YS, Yu CS, Kim TW, Kim JH, Jang SJ, Cho DH, et al. Mismatch repair status in sporadic colorectal cancer: Immunohistochemistry and microsatellite instability analyses. J Gastroenterol Hepatol. 2011; 26(12):1733-9. https://doi.org/10.1111/j.1440-1746.2011.06784.x PMid:21615788

Kim H, Jen J, Vogelstein B, Hamilton SR. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol. 1994; 145(1):148-56.

Alexander J, Watanabe T, Wu TT, Rashid A, Li S, Hamilton SR. Histopathological identification of colon cancer with microsatellite instability. Am J Pathol. 2001; 158(2):527-35. https://doi.org/10.1016/S0002-9440(10)63994-6

Greenson JK, Huang S-C, Herron C, Moreno V, Bonner JD, Tomsho LP, et al. Pathologic predictors of microsatellite instability in colorectal cancer. Am J Surg Pathol. 2009; 33(1):126-33. https://doi.org/10.1097/PAS.0b013e31817ec2b1 PMid:18830122 PMCid:PMC3500028

Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, RÃ¼schoff J, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004; 96(4):261-8. https://doi.org/10.1093/jnci/djh034 PMid:14970275 PMCid:PMC2933058