Analysis of the expression of proteins of the unpaired base repair system using immunohistochemical reaction
https://doi.org/10.17650/2618-7019-2024-7-3-17-25
Abstract
Mismatch repair system is one of the mechanisms underlying maintenance of the genome integrity. It is involved in mitotic and meiotic recombination, apoptosis, immune globulin gene rearrangement, somatic hypermutation and other processes. Deficiency of mismatch repair system (d-MMR) occurs in most types of tumors, it leads to hypermutability and microsatellite instability. Recognition of mismatch repair system deficiency or microsatellite instability is used for diagnostic, predictive, and prognostic purposes, in particular to screen for Lynch syndrome and identify patients who will respond to checkpoint inhibitor therapy, as well as for prognostic evaluation of clinical course. In the present article, we provide a brief overview of practical methods to recognize deficiency of mismatch repair system, focusing on clinical testing using immunohistochemical reaction and results’ interpretation.
About the Authors
A. G. KudaibergenovaRussian Federation
68 Leningradsky St., vil. Pesochny, Saint Petersburg 197758, Russia
A. I. Senderovich
Russian Federation
15 Marshala Timoshenko St., Moscow 121359, Russia
51/1 3rd Parkovaya St., Moscow 105425, Russia
N. A. Gorban
Russian Federation
Gorban Nina Andreevna
15 Marshala Timoshenko St., Moscow 121359, Russia
References
1. Popat S., Hubner R., Houlston R.S. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 2005;23(3):609–18. DOI: 10.1200/JCO.2005.01.086
2. Tejpar S., Saridaki Z., Delorenzi M. et al. Microsatellite instability, prognosis and drug sensitivity of stage II and III colorectal cancer: more complexity to the puzzle. J Natl Cancer Inst 2011;103(11):841–4. DOI: 10.1093/jnci/djr170
3. Hutchins G., Southward K., Handley K. et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol 2011;29(10):1261–70. DOI: 10.1200/JCO.2010.30.1366
4. Benatti P., Gafà R., Barana D. et al. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res 2005;11(23):8332–40. DOI: 10.1158/1078-0432.CCR-05-1030
5. Sargent D.J., Marsoni S., Monges G. et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracilbased adjuvant therapy in colon cancer. J Clin Oncol 2010;28(20):3219–26. DOI: 10.1200/JCO.2009.27.1825
6. Ribic C.M., Sargent D.J., Moore M.J. et al. Tumor microsatelliteinstability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003;349(3):247–57. DOI: 10.1056/NEJMoa022289
7. Carethers J.M., Smith E.J., Behling C.A. et al. Use of 5-fluorouracil and survival in patients with microsatelliteunstable colorectal cancer. Gastroenterology 2004;126(2):394–401. DOI: 10.1053/j.gastro.2003.12.023
8. Le D.T., Uram J.N., Wang H. et al. PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372(26):2509–20. DOI: 10.1056/NEJMoa1500596
9. Hampel H., Frankel W.L., Martin E. et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 2005;352(18):1851–60. DOI: 10.1056/NEJMoa043146
10. Lindor N.M., Burgart L.J., Leontovich O. et al. Thibodeau, Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 2002;20(4):1043–8. DOI: 10.1200/JCO.2002.20.4.1043
11. de Jong A.E., van Puijenbroek M., Hendriks Y. et al. Microsatellite instability, immunohistochemistry, and additional PMS2 staining in suspected hereditary nonpolyposis colorectal cancer. Clin Cancer Res 2004;10(3):972–80. DOI: 10.1158/1078-0432.ccr-0956-3
12. Southey M.C., Jenkins M.A., Mead L. et al. 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
13. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group, Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med 2009;11:35–41.
14. Hampel H. NCCN increases the emphasis on genetic/familial high-risk assessment in colorectal cancer. J Natl Compr Canc Netw 2014;12(5 Suppl):829–31. DOI: 10.6004/jnccn.2014.0200
15. Syngal S., Brand R.E., Church J.M. et al. American College of Gastroenterology, ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 2015;110(2):223–62, quiz 263. DOI: 10.1038/ajg.2014.435
16. Luchini C., Bibeau F., Ligtenberg M.J.L. et al. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic reviewbased approach. Ann Oncol 2019;30(8):1232–43. DOI: 10.1093/annonc/mdz116
17. Lynch H.T., Snyder C.L., Shaw T.G. et al. Milestones of Lynch syndrome: 1895–2015. Nat Rev Cancer 2015;15(3):181–94. DOI: 10.1038/nrc3878
18. Hampel H., Frankel W.L., Martin E. et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol 2008;26(35):5783–8. DOI: 10.1200/JCO.2008.17.5950
19. Gruber S.B. New developments in Lynch syndrome (hereditary nonpolyposis colorectal cancer) and mismatch repair gene testing. Gastroenterology 2006;130(2):577–87. DOI: 10.1053/j.gastro.2006.01.031
20. Li G.-M. Mechanisms and functions of DNA mismatch repair. Cell Res 2008;18(1):85–98. DOI: 10.1038/cr.2007.115
21. Pearlman R., Markow M., Knight D. et al. Twostain immunohistochemical screening for Lynch syndrome in colorectal cancer may fail to detect mismatch repair deficiency. Mod Pathol 2018;31(12):1891–900. DOI: 10.1038/s41379-018-0058-y
22. Boland C.R., Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 2010;138(6):2073–87.e3. DOI: 10.1053/j.gastro.2009.12.064
23. Rahner N., Friedrichs N., Steinke V. et al. Coexisting somatic promoter hypermethylation and pathogenic MLH1 germline mutation in Lynch syndrome. J Pathol 2008;14(1):10–6. DOI: 10.1002/path.2263
24. Niessen R.C., Hofstra R.M.W., Westers H. et al. Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes Chromosomes Cancer 2009;48(8):737–44. DOI: 10.1002/gcc.20678
25. Weisenberger D.J., Siegmund K.D., Campan M. et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 2006;38(7):787–93. DOI: 10.1038/ng1834
26. Parsons M.T., Buchanan D.D., Thompson B. et al. Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification. J Med Genet 2012;49(3):151–7. DOI: 10.1136/jmedgenet-2011-100714
27. Adar T., Rodgers L.H., Shannon K.M. et al. A tailored approach to BRAF and MLH1 methylation testing in a universal screening program for Lynch syndrome. Mod Pathol 2017;30(3):440–7. DOI: 10.1038/modpathol.2016.211
28. Yuan Z.-X., Wang X.-Y., Qin Q.-Y. et al. The prognostic role of BRAF mutation in metastatic colorectal cancer receiving antiEGFR monoclonal antibodies: a meta-analysis. PLoS One 2013;8(6):e65995. DOI: 10.1371/journal.pone.0065995
29. Roth A.D., Tejpar S., Delorenzi M. et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol 2010;28(3):466–74. DOI: 10.1200/JCO.2009.23.3452
30. Bellizzi A.M. Screening for Lynch syndrome: a no-brainer: BRAF V600E mutation-specific immunohistochemistry: caveat emptor. Am J Clin Pathol 2015;143:320–4. DOI: 10.1309/AJCP3ZDD3LTHWCZK
31. Haraldsdottir S., Hampel H., Tomsic J. et al. Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. Gastroenterology 2014;147(6):1308–16.e1. DOI: 10.1053/j.gastro.2014.08.041
32. Hemminger J.A., Pearlman R., Haraldsdottir S. et al. Histology of colorectal adenocarcinoma with double somatic mismatch-repair mutations is indistinguishable from those caused by Lynch syndrome. Hum Pathol 2018;78:125–30. DOI: 10.1016/j.humpath.2018.04.017
33. Chen W., Swanson B.J., Frankel W.L. Molecular genetics of microsatellite-unstable colorectal cancer for pathologists. Diagn Pathol 2017;12(1):24. DOI: 10.1186/s13000-017-0613-8
34. Kumarasinghe A.P., de Boer B., Bateman A.C., Kumarasinghe M.P. DNA mismatch repair enzyme immunohistochemistry in colorectal cancer: a comparison of biopsy and resection material. Pathology 2010;42(5):414–20. DOI: 10.3109/00313025.2010.493862
35. Shia J., Stadler Z., Weiser M.R. et al. Immunohistochemical staining for DNA mismatch repair proteins in intestinal tract carcinoma: how reliable are biopsy samples? Am J Surg Pathol 2011;35(3):447–54. DOI: 10.1097/PAS.0b013e31820a091d
36. Vilkin A., Leibovici-Weissman Y., Halpern M. Immunohistochemistry staining for mismatch repair proteins: the endoscopic biopsy material provides useful and coherent results. Hum Pathol 2015;46(11):1705–11. DOI: 10.1016/j.humpath.2015.07.009
37. Bao F., Panarelli N.C., Rennert H. et al. Neoadjuvant therapy induces loss of MSH6 expression in colorectal carcinoma. Am J Surg Pathol 2010;34(12):1798–804. DOI: 10.1097/PAS.0b013e3181f906cc
38. Radu O.M., Nikiforova M.N., Farkas L.M., Krasinskas A.M. Challenging cases encountered in colorectal cancer screening for Lynch syndrome reveal novel findings: nucleolar MSH6 staining and impact of prior chemoradiation therapy. Hum Pathol 2011;42(9):1247–58. DOI: 10.1016/j.humpath.2010.11.016
39. Vilkin A., Halpern M., Morgenstern S. How reliable is immunohistochemical staining for DNA mismatch repair proteins performed after neoadjuvant chemoradiation? Hum Pathol 2014;45(10):2029–36. DOI: 10.1016/j.humpath.2014.07.005
40. Kuan S.-F., Ren B., Brand R. et al. Neoadjuvant therapy in microsatellite-stable colorectal carcinoma induces concomitant loss of MSH6 and Ki-67 expression. Hum Pathol 2017;63:33–9. DOI: 10.1016/j.humpath.2017.02.003
41. Haraldsdottir S., Roth R., Pearlman R. et al. Mismatch repair deficiency concordance between primary colorectal cancer and corresponding metastasis. Fam Cancer 2016;15(2):253–60. DOI: 10.1007/s10689-015-9856-2
42. Sepulveda A.R., Hamilton S.R., Allegra C.J. et al. Molecular biomarkers for the evaluation of colorectal cancer: Guideline from the American Society for clinical pathology, College of american pathologists, Association for molecular pathology, and American Society of clinical oncology. J Clin Oncol 2017;35(13):1453–86. DOI: 10.1200/JCO.2016.71.9807
43. Roth R.M., Haraldsdottir S., Hampel H. et al. Discordant mismatch repair protein immunoreactivity in Lynch syndromeassociated neoplasms: A recommendation for screening synchronous/metachronous neoplasms. Am J Clin Pathol 2016;146(1):50–6. DOI: 10.1093/ajcp/aqw067
44. Bellizzi A.M., Frankel W.L. Colorectal cancer due to deficiency in DNA mismatch repair function: a review. Adv Anat Pathol 2009;16(6):405–17. DOI: 10.1097/PAP.0b013e3181bb6bdc
45. Kalady M.F., Kravochuck S.E., Heald B. et al. Defining the adenoma burden in lynch syndrome Dis Colon Rectum 2015;58(4):388–92. DOI: 10.1097/DCR.0000000000000333
46. Walsh M.D., Buchanan D.D., Pearson S.-A. et al. Immunohistochemical testing of conventional adenomas for loss of expression of mismatch repair proteins in Lynch syndrome mutation carriers: a case series from the Australasian site of the colon cancer family registry. Mod Pathol 2012;25(5):722–30. DOI: 10.1038/modpathol.2011.209
47. Yurgelun M.B., Goel A., Hornick J.L. et al. Microsatellite instability and DNA mismatch repair protein deficiency in Lynch syndrome colorectal polyps. Cancer Prev Res 2012;5(4):574–82. DOI: 10.1158/1940-6207.CAPR-11-0519
48. Bartley A.N., Hamilton S.R., Alsabeh R. et al. Members of the cancer biomarker reporting Workgroup, College of american pathologists, template for reporting results of biomarker testing of specimens from patients with carcinoma of the colon and rectum. Arch Pathol Lab Med 2014;138(2):166–70. DOI: 10.5858/arpa.2013-0231-CP
49. Pai R.K., Pai Re.K. A practical approach to the evaluation of gastrointestinal tract carcinomas for Lynch syndrome. Am J Surg Pathol 2016;40(4):e17–34. DOI: 10.1097/PAS.0000000000000620
50. Chang C.L., Marra G., Chauhan D.P. et al. Oxidative stress inactivates the human DNA mismatch repair system. Am J Physiol Cell Physiol 2002;283(1):C148–54. DOI: 10.1152/ajpcell.00422.2001
51. Mihaylova V.T., Bindra R.S., Yuan J. et al. Decreased expression of the DNA mismatch repair gene Mlh1 under hypoxic stress in mammalian cells. Mol Cell Biol 2003;23(9):3265–73. DOI: 10.1128/MCB.23.9.3265-3273.2003
52. Dhar S.S., Ruiz-Garcia E., Barresi V., Brunetti O. Molecular mechanisms and targeted therapies for colorectal cancer. Frontiers Media SA, 2022.
53. Graham R.P., Kerr S.E., Butz M.L. et al. Heterogenous MSH6 loss is a result of microsatellite instability within MSH6 and occurs in sporadic and hereditary colorectal and endometrial carcinomas. Am J Surg Pathol 2015;39(10):1370–6. DOI: 10.1097/PAS.0000000000000459
54. Shia J., Zhang L., Shike M. et al. Secondary mutation in a coding mononucleotide tract in MSH6 causes loss of immunoexpression of MSH6 in colorectal carcinomas with MLH1/PMS2 deficiency. Mod Pathol 2013;26(1):131–8. DOI: 10.1038/modpathol.2012.138
55. Dudley B., Brand R.E., Thull D. et al. Germline MLH1 mutations are frequently identified in Lynch syndrome patients with colorectal and endometrial carcinoma demonstrating isolated loss of PMS2 immunohistochemical expression. Am J Surg Pathol 2015;39(8):1114–20. DOI: 10.1097/PAS.0000000000000425
56. Rosty C., Clendenning M., Walsh M.D. et al. Germline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the Colon Cancer Family Registry Cohort. BMJ Open 2016;6(2):e010293. DOI: 10.1136/bmjopen-2015-010293
Review
For citations:
Kudaibergenova A.G., Senderovich A.I., Gorban N.A. Analysis of the expression of proteins of the unpaired base repair system using immunohistochemical reaction. ONCOPATHOLOGY. 2024;7(3):17-25. (In Russ.) https://doi.org/10.17650/2618-7019-2024-7-3-17-25
JATS XML
