Concordance between microsatellite instability testing and immunohistochemistry for mismatch repair proteins and efficient screening of mismatch repair deficient gastric cancer

Yamamoto,Gou; Yamamoto,Gou; Ito,Tetsuya; Ito,Tetsuya; Suzuki,Okihide; Suzuki,Okihide; Kamae,Nao; Kamae,Nao; Kakuta,Miho; Kakuta,Miho; Takahashi,Akemi; Takahashi,Akemi; Iuchi,Katsuya; Iuchi,Katsuya; Arai,Tomio; Arai,Tomio; Ishida,Hideyuki; Ishida,Hideyuki; Akagi,Kiwamu; Akagi,Kiwamu

doi:10.3892/ol.2023.14081

Concordance between microsatellite instability testing and immunohistochemistry for mismatch repair proteins and efficient screening of mismatch repair deficient gastric cancer

Authors:
- Gou Yamamoto
- Tetsuya Ito
- Okihide Suzuki
- Nao Kamae
- Miho Kakuta
- Akemi Takahashi
- Katsuya Iuchi
- Tomio Arai
- Hideyuki Ishida
- Kiwamu Akagi
View Affiliations

Affiliations: Department of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama 362‑0806, Japan, Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama 350‑8550, Japan, Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University, Saitama 350‑8550, Japan, Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173‑0015, Japan
Published online on: September 29, 2023 https://doi.org/10.3892/ol.2023.14081
Article Number: 494
Copyright: © Yamamoto et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Microsatellite instability (MSI) testing, an established technique that has gained prominence in recent years for its predictive potential regarding the efficacy of immune checkpoint inhibitors, is used to evaluate DNA mismatch repair (MMR) deficiency (dMMR). As with other methods, the immunohistochemistry (IHC) of MMR proteins is also widely adopted. Although both techniques have been validated, their concordance rate remains unknown, particularly regarding non‑colorectal cancer. Therefore, the aim of the present study was to explore and elucidate their concordance in the context of gastric cancer (GC). A total of 489 surgically resected primary GC tissues were analyzed to compare the results yielded by the MSI test and those from IHC. Of 488 GC cases, 56 (11.5%) exhibited a loss of MMR proteins, whereas 52 (10.7%) were classified as high‑frequency MSI (MSI‑H). The concordance rate between these two categories was 99.2%. The microsatellite markers BAT26 and MONO27 demonstrated 100% sensitivity and 99.5% specificity in detecting dMMR GC. In addition, histopathological analysis revealed that MSI‑H was more prevalent in GCs exhibiting coexisting Tub2 and Por1 subtypes. However, four discordant cases were observed. All four cases were microsatellite‑stable cases but exhibited loss of MLH1 protein expression with hypermethylation of the MLH1 promoter. The results of the present study highlight that while there is a strong concordance between MSI and IHC testing results for determining dMMR status, IHC testing may offer superior efficacy in detecting dMMR.

View Figures

View References

1	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI
2	Honda M, Wong SL, Healy MA, Nakajima T, Watanabe M, Fukuma S, Fukuhara S and Ayanian JZ: Long-term trends in primary sites of gastric adenocarcinoma in Japan and the United States. J Cancer. 8:1935–1942. 2017. View Article : Google Scholar : PubMed/NCBI
3	Katanoda K, Hori M, Saito E, Shibata A, Ito Y, Minami T, Ikeda S, Suzuki T and Matsuda T: Updated trends in cancer in Japan: Incidence in 1985–2015 and mortality in 1958–2018-A sign of decrease in cancer incidence. J Epidemiol. 31:426–450. 2021. View Article : Google Scholar : PubMed/NCBI
4	Cortes-Ciriano I, Lee S, Park WY, Kim TM and Park PJ: A molecular portrait of microsatellite instability across multiple cancers. Nat Commun. 8:151802017. View Article : Google Scholar : PubMed/NCBI
5	Germano G, Amirouchene-Angelozzi N, Rospo G and Bardelli A: The clinical impact of the genomic landscape of mismatch repair-deficient cancers. Cancer Discov. 8:1518–1528. 2018. View Article : Google Scholar : PubMed/NCBI
6	Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, Nakagawa H, Sotamaa K, Prior TW, Westman J, et al: Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 352:1851–1860. 2005. View Article : Google Scholar : PubMed/NCBI
7	Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, et al: PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 372:2509–2520. 2015. View Article : Google Scholar : PubMed/NCBI
8	Guyot D'Asnières De Salins A, Tachon G, Cohen R, Karayan-Tapon L, Junca A, Frouin E, Godet J, Evrard C, Randrian V, Duval A, et al: Discordance between immunochemistry of mismatch repair proteins and molecular testing of microsatellite instability in colorectal cancer. ESMO Open. 6:1001202021. View Article : Google Scholar : PubMed/NCBI
9	Wang Y, Shi C, Eisenberg R and Vnencak-Jones CL: Differences in microsatellite instability profiles between endometrioid and colorectal cancers: A potential cause for false-negative results? J Mol Diagn. 19:57–64. 2017. View Article : Google Scholar : PubMed/NCBI
10	Mangold E, Pagenstecher C, Friedl W, Fischer HP, Merkelbach-Bruse S, Ohlendorf M, Friedrichs N, Aretz S, Buettner R, Propping P and Mathiak M: Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining. J Pathol. 207:385–395. 2005. View Article : Google Scholar : PubMed/NCBI
11	Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Rüschoff J, Fishel R, Lindor NM, Burgart LJ, Hamelin R, et al: Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 96:261–268. 2004. View Article : Google Scholar : PubMed/NCBI
12	Akagi K, Oki E, Taniguchi H, Nakatani K, Aoki D, Kuwata T and Yoshino T: Real-world data on microsatellite instability status in various unresectable or metastatic solid tumors. Cancer Sci. 112:1105–1113. 2021. View Article : Google Scholar : PubMed/NCBI
13	Beghelli S, de Manzoni G, Barbi S, Tomezzoli A, Roviello F, Di Gregorio C, Vindigni C, Bortesi L, Parisi A, Saragoni L, et al: Microsatellite instability in gastric cancer is associated with better prognosis in only stage II cancers. Surgery. 139:347–356. 2006. View Article : Google Scholar : PubMed/NCBI
14	Seo HM, Chang YS, Joo SH, Kim YW, Park YK, Hong SW and Lee SH: Clinicopathologic characteristics and outcomes of gastric cancers with the MSI-H phenotype. J Surg Oncol. 99:143–147. 2009. View Article : Google Scholar : PubMed/NCBI
15	Ito T, Suzuki O, Kamae N, Tamaru JI, Arai T, Yamaguchi T, Akagi K, Eguchi H, Okazaki Y, Mochiki E and Ishida H: Comprehensive analysis of DNA mismatch repair-deficient gastric cancer in a Japanese hospital-based population. Jpn J Clin Oncol. 51:886–894. 2021. View Article : Google Scholar : PubMed/NCBI
16	Japanese Gastric Cancer Association, . Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 14:101–112. 2011. View Article : Google Scholar : PubMed/NCBI
17	Nakamura K, Sugano H and Takagi K: Carcinoma of the stomach in incipient phase: Its histogenesis and histological appearances. Gan. 59:251–258. 1968.PubMed/NCBI
18	Ishikubo T, Nishimura Y, Yamaguchi K, Khansuwan U, Arai Y, Kobayashi T, Ohkura Y, Hashiguchi Y, Tanaka Y and Akagi K: The clinical features of rectal cancers with high-frequency microsatellite instability (MSI-H) in Japanese males. Cancer Lett. 216:55–62. 2004. View Article : Google Scholar : PubMed/NCBI
19	Yamamoto A, Yamaguchi T, Suzuki O, Ito T, Chika N, Kamae N, Tamaru JI, Nagai T, Seki H, Arai T, et al: Prevalence and molecular characteristics of DNA mismatch repair deficient endometrial cancer in a Japanese hospital-based population. Jpn J Clin Oncol. 51:60–69. 2021. View Article : Google Scholar : PubMed/NCBI
20	Murphy KM, Zhang S, Geiger T, Hafez MJ, Bacher J, Berg KD and Eshleman JR: Comparison of the microsatellite instability analysis system and the Bethesda panel for the determination of microsatellite instability in colorectal cancers. J Mol Diagn. 8:305–311. 2006. View Article : Google Scholar : PubMed/NCBI
21	Deschoolmeester V, Baay M, Wuyts W, Van Marck E, Van Damme N, Vermeulen P, Lukaszuk K, Lardon F and Vermorken JB: Detection of microsatellite instability in colorectal cancer using an alternative multiplex assay of quasi-monomorphic mononucleotide markers. J Mol Diagn. 10:154–159. 2008. View Article : Google Scholar : PubMed/NCBI
22	Mathiak M, Warneke VS, Behrens HM, Haag J, Böger C, Krüger S and Röcken C: Clinicopathologic characteristics of microsatellite in gastric carcinomas revisited: Urgent need for standardization. Appl Immunohistochem Mol Morphol. 25:12–24. 2017. View Article : Google Scholar : PubMed/NCBI
23	Hong SP, Min BS, Kim TI, Cheon JH, Kim NK, Kim H and Kim WH: The differential impact of microsatellite instability as a marker of prognosis and tumour response between colon cancer and rectal cancer. Eur J Cancer. 48:1235–1243. 2012. View Article : Google Scholar : PubMed/NCBI
24	Kim JY, Shin NR, Kim A, Lee HJ, Park WY, Kim JY, Lee CH, Huh GY and Park DY: Microsatellite instability status in gastric cancer: A reappraisal of its clinical significance and relationship with mucin phenotypes. Korean J Pathol. 47:28–35. 2013. View Article : Google Scholar : PubMed/NCBI
25	Arai T, Sakurai U, Sawabe M, Honma N, Aida J, Ushio Y, Kanazawa N, Kuroiwa K and Takubo K: Frequent microsatellite instability in papillary and solid-type, poorly differentiated adenocarcinomas of the stomach. Gastric Cancer. 16:505–512. 2013. View Article : Google Scholar : PubMed/NCBI
26	Shigeyasu K, Nagasaka T, Mori Y, Yokomichi N, Kawai T, Fuji T, Kimura K, Umeda Y, Kagawa S, Goel A and Fujiwara T: Clinical significance of MLH1 methylation and CpG island methylator phenotype as prognostic markers in patients with gastric cancer. PLoS One. 10:e01304092015. View Article : Google Scholar : PubMed/NCBI
27	Kazama Y, Watanabe T, Kanazawa T, Tanaka J, Tanaka T and Nagawa H: Poorly differentiated colorectal adenocarcinomas show higher rates of microsatellite instability and promoter methylation of p16 and hMLH1: A study matched for T classification and tumor location. J Surg Oncol. 97:278–283. 2008. View Article : Google Scholar : PubMed/NCBI
28	Arai T, Matsuda Y, Aida J, Takubo K and Ishiwata T: Solid-type poorly differentiated adenocarcinoma of the stomach: Clinicopathological and molecular characteristics and histogenesis. Gastric Cancer. 22:314–322. 2019. View Article : Google Scholar : PubMed/NCBI
29	Shin SY, Kim JH, Kook MC, Park DY, Ryu KW, Choi IJ, Noh SH, Kim H and Lee YC: Clinicopathologic features of submucosal papillary gastric cancer differ from those of other differentiated-type histologies. Gut Liver. 15:44–52. 2021. View Article : Google Scholar : PubMed/NCBI
30	Alam MR, Abdul-Ghafar J, Yim K, Thakur N, Lee SH, Jang HJ, Jung CK and Chong Y: Recent applications of artificial intelligence from histopathologic image-based prediction of microsatellite instability in solid cancers: A systematic review. Cancers (Basel). 14:25902022. View Article : Google Scholar : PubMed/NCBI
31	Sugimoto R, Endo M, Osakabe M, Toya Y, Yanagawa N, Matsumoto T and Sugai T: Immunohistochemical analysis of mismatch repair gene proteins in early gastric cancer based on microsatellite status. Digestion. 102:691–700. 2021. View Article : Google Scholar : PubMed/NCBI
32	de la Chapelle A and Hampel H: Clinical relevance of microsatellite instability in colorectal cancer. J Clin Oncol. 28:3380–3387. 2010. View Article : Google Scholar : PubMed/NCBI
33	Sepulveda AR, Santos AC, Yamaoka Y, Wu L, Gutierrez O, Kim JG and Graham DY: Marked differences in the frequency of microsatellite instability in gastric cancer from different countries. Am J Gastroenterol. 94:3034–3038. 1999. View Article : Google Scholar : PubMed/NCBI
34	Huo X, Xiao X, Zhang S, Du X, Li C, Bai Z and Chen Z: Characterization and clinical evaluation of microsatellite instability and loss of heterozygosity in tumor-related genes in gastric cancer. Oncol Lett. 21:4302021. View Article : Google Scholar : PubMed/NCBI
35	Hu G, Qin L, Zhang X, Ye G and Huang T: Epigenetic silencing of the MLH1 promoter in relation to the development of gastric cancer and its use as a biomarker for patients with microsatellite instability: A systematic analysis. Cell Physiol Biochem. 45:148–162. 2018. View Article : Google Scholar : PubMed/NCBI
36	Ho SWT and Tan P: Dissection of gastric cancer heterogeneity for precision oncology. Cancer Sci. 110:3405–3414. 2019. View Article : Google Scholar : PubMed/NCBI
37	Varley KE, Mutch DG, Edmonston TB, Goodfellow PJ and Mitra RD: Intra-tumor heterogeneity of MLH1 promoter methylation revealed by deep single molecule bisulfite sequencing. Nucleic Acids Res. 37:4603–4612. 2009. View Article : Google Scholar : PubMed/NCBI
38	Pai RK, Plesec TP, Abdul-Karim FW, Yang B, Marquard J, Shadrach B and Roma AR: Abrupt loss of MLH1 and PMS2 expression in endometrial carcinoma: Molecular and morphologic analysis of 6 cases: Molecular and morphologic analysis of 6 cases. Am J Surg Pathol. 39:993–999. 2015. View Article : Google Scholar : PubMed/NCBI
39	Ta RM, Hecht JL and Lin DI: Discordant loss of mismatch repair proteins in advanced endometrial endometrioid carcinoma compared to paired primary uterine tumors. Gynecol Oncol. 151:401–406. 2018. View Article : Google Scholar : PubMed/NCBI
40	Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Bragagnoli AC, et al: First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial. Lancet. 398:27–40. 2021. View Article : Google Scholar : PubMed/NCBI
41	Pietrantonio F, Randon G, Di Bartolomeo M, Luciani A, Chao J, Smyth EC and Petrelli F: Predictive role of microsatellite instability for PD-1 blockade in patients with advanced gastric cancer: A meta-analysis of randomized clinical trials. ESMO Open. 6:1000362021. View Article : Google Scholar : PubMed/NCBI
42	Chao J, Fuchs CS, Shitara K, Tabernero J, Muro K, Van Cutsem E, Bang YJ, De Vita F, Landers G, Yen CJ, et al: Assessment of pembrolizumab therapy for the treatment of microsatellite instability-high gastric or gastroesophageal junction cancer among patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 clinical trials. JAMA Oncol. 7:895–902. 2021. View Article : Google Scholar : PubMed/NCBI
43	Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, Morse MA, Van Cutsem E, McDermott R, Hill A, et al: Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 36:773–779. 2018. View Article : Google Scholar : PubMed/NCBI
44	Kawakami H, Hironaka S, Esaki T, Chayama K, Tsuda M, Sugimoto N, Kadowaki S, Makiyama A, Machida N, Hirano H, et al: An investigator-initiated phase 2 study of nivolumab plus low-dose ipilimumab as first-line therapy for microsatellite instability-high advanced gastric or esophagogastric junction cancer (NO LIMIT, WJOG13320G/CA209-7W7). Cancers (Basel). 13:8052021. View Article : Google Scholar : PubMed/NCBI