Mismatch Repair Protein Expression in Colorectal Cancer

Overview

Journal J Gastrointest Oncol

Date 2013 Dec 3

PMID 24294512

Citations 32

Authors

Elrasheid A H Kheirelseid

Nicola Miller

Kah Hoong Chang

Catherine Curran

Emer Hennessey

Margaret Sheehan

Michael J Kerin

Affiliations

Soon will be listed here.

Abstract

Introduction: Alterations in at least six of the genes that encode proteins involved in the mismatch repair (MMR) system have been identified in either HNPCC or sporadic colon cancer. We aimed to analyse the proportion of patients with colorectal cancer with loss of immunostaining for MMR proteins in order to determine the feasibility of molecular screening for the loss of MMR proteins through the study of unselected patients with colorectal cancer.

Methods: A group of 33 patients with colorectal cancer was randomly selected from the department of surgery bio-bank to determine the expression of MMR proteins in their FFPE tumour tissues using immunohistochemistry techniques. Changes in protein expression following transfection of colorectal tissues were observed in stained cells using Olympus BX60 microscope and image analySIS software.

Results: Of the tissue specimens in which acceptable immunostaining was achieved, three samples showed loss of one or more of the MMR proteins. Both hMLH1 and hPMS2 proteins were not expressed in a 36 years old woman with cancer of the caecum. The expression of hMSH6 protein was undetermined in tumour tissues retrieved from a 61 years old man with cancer of the proximal colon. The third case was a 77 years old man with no documented family history of cancer, who had carcinoma of the rectum. He showed loss of hMLH1 expression in the tumour tissues.

Conclusions: Our findings and the previous reports pointed out the importance of molecular screening of patients with colorectal cancer for MSI using immunohistochemistry. This strategy managed to identify mutations in patients otherwise would not have been detected.

Citing Articles

Genomic Medicine in the Developing World: Cancer Spectrum, Cumulative Risk and Survival Outcomes for Lynch Syndrome Variant Heterozygotes with Germline Pathogenic Variants in the and Genes.

Ndou L, Chambuso R, Algar U, Boutall A, Goldberg P, Ramesar R Biomedicines. 2025; 12(12.

PMID: 39767815 PMC: 11672899. DOI: 10.3390/biomedicines12122906.

Deep learning for automated scoring of immunohistochemically stained tumour tissue sections - Validation across tumour types based on patient outcomes.

Kildal W, Cyll K, Kalsnes J, Islam R, Julbo F, Pradhan M Heliyon. 2024; 10(13):e32529.

PMID: 39040241 PMC: 11261074. DOI: 10.1016/j.heliyon.2024.e32529.

Unraveling the Interplay of KRAS, NRAS, BRAF, and Micro-Satellite Instability in Non-Metastatic Colon Cancer: A Systematic Review.

Orlandi E, Giuffrida M, Trubini S, Luzietti E, Ambroggi M, Anselmi E Diagnostics (Basel). 2024; 14(10).

PMID: 38786299 PMC: 11120454. DOI: 10.3390/diagnostics14101001.

Synchronous Gastric and Colonic Adenocarcinoma: A Case Report With its Molecular Implications.

V L, Grace Priyadarshini S, Agarwal N, B S P Cureus. 2024; 16(3):e56607.

PMID: 38646233 PMC: 11031629. DOI: 10.7759/cureus.56607.

Colon cancer in primary care.

Lackman M, Wilkinson A Can Fam Physician. 2024; 70(1):33-37.

PMID: 38262748 PMC: 11126293. DOI: 10.46747/cfp.700133.

References

Popat S, Hubner R, Houlston R . Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005; 23(3):609-18. DOI: 10.1200/JCO.2005.01.086. View

Marra G, Boland C . Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J Natl Cancer Inst. 1995; 87(15):1114-25. DOI: 10.1093/jnci/87.15.1114. View

Elsaleh H, Powell B, Soontrapornchai P, Joseph D, GORIA F, Spry N . p53 gene mutation, microsatellite instability and adjuvant chemotherapy: impact on survival of 388 patients with Dukes' C colon carcinoma. Oncology. 2000; 58(1):52-9. DOI: 10.1159/000012079. View

Syngal S, Fox E, Eng C, Kolodner R, Garber J . Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1. J Med Genet. 2000; 37(9):641-5. PMC: 1734690. DOI: 10.1136/jmg.37.9.641. View

Chung D, Rustgi A . The hereditary nonpolyposis colorectal cancer syndrome: genetics and clinical implications. Ann Intern Med. 2003; 138(7):560-70. DOI: 10.7326/0003-4819-138-7-200304010-00012. View

Kane M, Loda M, Gaida G, Lipman J, Mishra R, Goldman H . Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 1997; 57(5):808-11. View

Hampel H, Frankel W, Martin E, Arnold M, Khanduja K, Kuebler P . Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005; 352(18):1851-60. DOI: 10.1056/NEJMoa043146. View

Wullenweber H, Sutter C, Autschbach F, Willeke F, Kienle P, Benner A . Evaluation of Bethesda guidelines in relation to microsatellite instability. Dis Colon Rectum. 2001; 44(9):1281-9. DOI: 10.1007/BF02234785. View

Pinol V, Castells A, Andreu M, Castellvi-Bel S, Alenda C, Llor X . Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA. 2005; 293(16):1986-94. DOI: 10.1001/jama.293.16.1986. View

10.

Hawkins N, Ward R . Sporadic colorectal cancers with microsatellite instability and their possible origin in hyperplastic polyps and serrated adenomas. J Natl Cancer Inst. 2001; 93(17):1307-13. DOI: 10.1093/jnci/93.17.1307. View

11.

Wahlberg S, Schmeits J, Thomas G, Loda M, Garber J, Syngal S . Evaluation of microsatellite instability and immunohistochemistry for the prediction of germ-line MSH2 and MLH1 mutations in hereditary nonpolyposis colon cancer families. Cancer Res. 2002; 62(12):3485-92. View

12.

Kinzler K, Vogelstein B . Lessons from hereditary colorectal cancer. Cell. 1996; 87(2):159-70. DOI: 10.1016/s0092-8674(00)81333-1. View

13.

Prolla T, Pang Q, Alani E, Kolodner R, Liskay R . MLH1, PMS1, and MSH2 interactions during the initiation of DNA mismatch repair in yeast. Science. 1994; 265(5175):1091-3. DOI: 10.1126/science.8066446. View

14.

Boland C, Thibodeau S, Hamilton S, Sidransky D, Eshleman J, Burt R . 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. Cancer Res. 1998; 58(22):5248-57. View

15.

Aaltonen L, Salovaara R, Kristo P, Canzian F, Hemminki A, Peltomaki P . Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med. 1998; 338(21):1481-7. DOI: 10.1056/NEJM199805213382101. View

16.

Southey M, Jenkins M, Mead L, Whitty J, Trivett M, Tesoriero A . Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer. J Clin Oncol. 2005; 23(27):6524-32. DOI: 10.1200/JCO.2005.04.671. View

17.

Lynch H, de la Chapelle A . Hereditary colorectal cancer. N Engl J Med. 2003; 348(10):919-32. DOI: 10.1056/NEJMra012242. View

18.

Herman J, Umar A, Polyak K, Graff J, Ahuja N, Issa J . Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A. 1998; 95(12):6870-5. PMC: 22665. DOI: 10.1073/pnas.95.12.6870. View

19.

Drummond J, Li G, Longley M, Modrich P . Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells. Science. 1995; 268(5219):1909-12. DOI: 10.1126/science.7604264. View

20.

Salovaara R, Loukola A, Kristo P, Kaariainen H, Ahtola H, Eskelinen M . Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol. 2000; 18(11):2193-200. DOI: 10.1200/JCO.2000.18.11.2193. View