Demidova, I., Filipenko, M., Tsukanov, A., & Imyanitov, E. (2023). Microsatellite Instability: Laboratory Diagnostic Nuances (Position Statement of the Russian Interregional Organization of Molecular Geneticists in Oncology and Oncohematology). Voprosy Onkologii, 69(2), 174–179. https://doi.org/10.37469/0507-3758-2023-69-2-174-179

Abstract

Microsatellite instability (MSI) is the phenomenon of the accumulation of mutations (deletions and insertions) in short repeated sequences of DNA. The most common cause of MSI is a defect in the mismatch repair deficiency system (dMMR). MSI/dMMR analysis is utilized for the diagnosis of Lynch syndrome as well as for the selection of patients for therapy with immune checkpoint inhibitors. MSI testing involves analyzing the length of several informative microsatellite markers by PCR or NGS, while dMMR detection is based on immunohistochemical analysis of expression of 4 proteins (MLH1, MSH2, MSH6 and PMS2). These methods can be considered interchangeable in the case of colorectal cancer, so when analyzing colorectal carcinomas, the choice between MSI and dMMR testing may be determined by managerial and financial considerations. Carcinomas with low proliferative activity, including some types of tumors associated with Lynch syndrome, can demonstrate dMMR in the absence of MSI, being characterized by low mutational load and lack of sensitivity to immunotherapy. Procedures for detecting microsatellite instability in non-colorectal tumors remain insufficiently standardized and need further improvement.

https://doi.org/10.37469/0507-3758-2023-69-2-174-179

pdf (Русский)

References

Richman S. Deficient mismatch repair: Read all about it (Review). Int J Oncol. 2015;47(4):1189202. doi:10.3892/ijo.2015.3119.

Dumache R, Ciocan V, Muresan C, et al. Molecular DNA analysis in forensic identification. Clin Lab. 2016;62(12):2458. doi:10.7754/clin.lab.2015.150414.

Bzymek M, Lovett ST. Instability of repetitive DNA sequences: the role of replication in multiple mechanisms. Proc Natl Acad Sci U S A. 2001;98(15):831925. doi:10.1073/pnas.111008398.

Lin EI, Tseng LH, Gocke CD, et al. Mutational profiling of colorectal cancers with microsatellite instability, Oncotarget. 2015;6(39):4233444. doi:10.18632/oncotarget.5997.

Jiricny J. Postreplicative mismatch repair. Cold Spring Harb Perspect Biol. 2013;5(4):a012633. doi:10.1101/cshperspect.a012633.

Nebot-Bral L, Coutzac C, Kannouche PL, et al. Why is immunotherapy effective (or not) in patients with MSI/MMRD tumors? Bull Cancer. 2019;106(2):105113. doi:10.1016/j.bulcan.2018.08.007.

Цуканов А.С., Демидова И.А., Цаур Г.А. и др. Диагностика синдрома Линча у онкологических пациентов: позиция Межрегиональной организации молекулярных генетиков в онкологии и онкогематологии. Вопр. онкол. [В печати]. [Tsukanov AS, Demidova IA, Tsaur GA, et al. Diagnosis of Lynch syndrome in cancer patients: the position of the Interregional organization of molecular geneticists in Oncology and Oncohematology. Vopr Onkol. [in print] (In Russ)].

Veigl ML, Kasturi L, Olechnowicz J, et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci U S A. 1998;95(15):8698702. doi:10.1073/pnas.95.15.8698.

Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409413. doi:10.1126/science.aan6733.

Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18(9):11821191. doi:10.1016/S1470-2045(17)30422-9.

Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773779. doi:10.1200/JCO.2017.76.9901.

Lemery S, Keegan P, Pazdur R. First FDA approval agnostic of cancer site - when a biomarker defines the indication. N Engl J Med. 2017;377(15):14091412. doi:10.1056/NEJMp1709968.

Ministry of Health of the Russian Federation. Clinical Guidelines Rubricator. [Internet]. [cited 2022 Nov 6]. Available from: https://cr.minzdrav.gov.ru/clin_recomend.

Luchini C, Bibeau F, Ligtenberg MJL, 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 review-based approach. Ann Oncol. 2019;30(8):12321243. doi:10.1093/annonc/mdz116.

Wu X, Snir O, Rottmann D, et al. Minimal microsatellite shift in microsatellite instability high endometrial cancer: a significant pitfall in diagnostic interpretation. Mod Pathol. 2019;32(5):650658. doi:10.1038/s41379-018-0179-3.

Tachon G, Frouin E, Karayan-Tapon L, et al. Heterogeneity of mismatch repair defect in colorectal cancer and its implications in clinical practice. Eur J Cancer. 2018;95:112116. doi:10.1016/j.ejca.2018.01.087.

Chen W, Hampel H, Pearlman R, et al. Unexpected expression of mismatch repair protein is more commonly seen with pathogenic missense than with other mutations in Lynch syndrome. Hum Pathol. 2020;103:3441. doi:10.1016/j.humpath.2020.07.001.

Cortes-Ciriano I, Lee S, Park WY, et al. A molecular portrait of microsatellite instability across multiple cancers. Nat Commun. 2017;8:15180. doi:10.1038/ncomms15180.

Long DR, Waalkes A, Panicker VP, et al. Identifying Optimal Loci for the Molecular Diagnosis of Microsatellite Instability. Clin Chem. 2020;66(10):13101318. doi:10.1093/clinchem/hvaa177.

Karamurzin Y, Zeng Z, Stadler ZK, et al. Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: a report of new cases and review of the literature. Hum Pathol. 2012;43(10):167787. doi:10.1016/j.humpath.2011.12.012.

Latham A, Srinivasan P, Kemel Y, et al. Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer. J Clin Oncol. 2019;37(4):286295. doi:10.1200/JCO.18.00283. Erratum in: J Clin Oncol. 2019;37(11):942.

Shia J. The diversity of tumours with microsatellite instability: molecular mechanisms and impact upon microsatellite instability testing and mismatch repair protein immunohistochemistry. Histopathology. 2021;78(4):485497. doi:10.1111/his.14271.

Jaffrelot M, Fares N, Brunac AC, et al. An unusual phenotype occurs in 15% of mismatch repair-deficient tumors and is associated with non-colorectal cancers and genetic syndromes. Mod Pathol. 2022;35(3):427437. doi:10.1038/s41379-021-00918-3.

Wang C, Zhang L, Vakiani E, et al. Detecting mismatch repair deficiency in solid neoplasms: immunohistochemistry, microsatellite instability, or both? Mod Pathol. 2022; 35(11):15151528. doi:10.1038/s41379-022-01109-4.

Mandal R, Samstein RM, Lee KW, et al. Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response. Science. 2019;364(6439):485491. doi:10.1126/science.aau0447.

Smithgall MC, Remotti H, Hsiao SJ, et al. Investigation of discrepant mismatch repair immunohistochemistry and microsatellite instability polymerase chain reaction test results for gynecologic cancers using next-generation sequencing. Hum Pathol. 2022;119:4150. doi:10.1016/j.humpath.2021.10.004.

Kim TM, Laird PW, Park PJ, The landscape of microsatellite instability in colorectal and endometrial cancer genomes. Cell. 2013;155(4):85868. doi:10.1016/j.cell.2013.10.015.

Evrard C, Tachon G, Randrian V, et al. Microsatellite Instability: Diagnosis, Heterogeneity, Discordance, and Clinical Impact in Colorectal Cancer. Cancers (Basel). 2019;11(10):1567. doi:10.3390/cancers11101567.

Niu B, Ye K, Zhang Q, et al. MSIsensor: microsatellite instability detection using paired tumor-normal sequence data. Bioinformatics. 2014;30(7):10156. doi:10.1093/bioinformatics/btt755.

Salipante SJ, Scroggins SM, Hampel HL, et al. Microsatellite instability detection by next generation sequencing. Clin Chem. 2014;60(9):11929. doi:10.1373/clinchem.2014.223677.

Huang MN, McPherson JR, Cutcutache I, et al. MSIseq: Software for Assessing Microsatellite Instability from Catalogs of Somatic Mutations. Sci Rep. 2015;5:13321. doi:10.1038/srep13321.

Hause RJ, Pritchard CC, Shendure J, et al. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med. 2016;22(11):13421350. doi:10.1038/nm.4191. Erratum in: Nat Med. 2017;23(10):1241. Erratum in: Nat Med. 2018;24(4):525.

Kautto EA, Bonneville R, Miya J, et al. Performance evaluation for rapid detection of pan-cancer microsatellite instability with MANTIS. Oncotarget. 2017;8(5):74527463. doi:10.18632/oncotarget.13918.

Middha S, Zhang L, Nafa K, et al. Reliable Pan-Cancer Microsatellite Instability Assessment by Using Targeted Next-Generation Sequencing Data. JCO Precis Oncol. 2017;(1):1–17. doi:10.1200/PO.17.00084.

Vanderwalde A, Spetzler D, Xiao N, et al. Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients. Cancer Med. 2018;7(3):74656. doi:10.1002/cam4.1372.

Wang C, Liang C. MSIpred: a python package for tumor microsatellite instability classification from tumor mutation annotation data using a support vector machine. Sci Rep. 2018;8(1):17546. doi:10.1038/s41598-018-35682-z.

Jia P, Yang X, Guo L, et al. MSIsensor-pro: fast, accurate, and matched-normal-sample-free detection of microsatellite instability. Genomics Proteomics Bioinformatics. 2020;18(1):6571. doi:10.1016/j.gpb.2020.02.001.

Pang J, Gindin T, Mansukhani M, et al. Microsatellite instability detection using a large next-generation sequencing cancer panel across diverse tumour types. J Clin Pathol. 2020;73(2):8389. doi:10.1136/jclinpath-2019-206136.

Ratovomanana T, Cohen R, Svrcek M, et al. Performance of Next-Generation Sequencing for the Detection of Microsatellite Instability in Colorectal Cancer With Deficient DNA Mismatch Repair. Gastroenterology. 2021;161(3):814826.e7. doi:10.1053/j.gastro.2021.05.007.

Yu F, Makrigiorgos A, Leong KW, et al. Sensitive detection of microsatellite instability in tissues and liquid biopsies: Recent developments and updates. Comput Struct Biotechnol J. 2021;19:493140. doi:10.1016/j.csbj.2021.08.037.

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Most read articles by the same author(s)

Alexey Tsukanov, Irina Demidova, Grigory Tsaur, Alexander Druy, Yulia Olshanskaya, Tatyana Kekeyeva, Maxim Filipenko, Evgeny Imyanitov, Diagnosis of Lynch syndrome in cancer patients: the position of the Interregional organization of molecular geneticists in Oncology and Oncohematology , Voprosy onkologii : Vol. 69 No. 1 (2023)
Ekaterina Degtiareva, Svetlana Protsenko, Aglaya Iyevleva, Evgeny Imyanitov, Real-world data on the incidence of immune-related adverse events associated with anti-PD-1/PD-L1 treatment in Russia , Voprosy onkologii : Vol. 68 No. 2 (2022)
Ilya Stepanov, Elena Vasilyeva, Anna Sokolenko, Evgeny Imyanitov, Features of heritable TP53-related cancer syndrome , Voprosy onkologii : Vol. 68 No. 2 (2022)
Natalia Mitiushkina , Evgeny Imyanitov, Molecular diagnostics of aberrations in the FGFR family genes , Voprosy onkologii : Vol. 69 No. 3 (2023)
Tatiana Gorodnova, Anna Sokolenko, Kh.B Kotiv , Alexandr Ivantsov, Maria Yakovleva , Olga Lavrinovich, Nikolay Mikaya, Zaur Ibragimov, Yurii Trifanov, Nikolay Bondarev , Olga Smirnova, Konstantin Guseinov, Elena Bakhidze, Irina Meshkova, Elena Konstantinova, Adel Urmancheeva, Igor Berlev, Alexei Belyaev, Evgeny Imyanitov, The prospective randomized trial evaluating the efficacy of the mitomycin C and cisplatin regimen (MP) versus standard first-line chemotherapy in patients with advanced BRCA1/2-associated ovarian cancer (NCT04747717) , Voprosy onkologii : Vol. 68 No. 5 (2022)
Alexandr Romanko , Elena Preobrazhenskaya , Natalia Mitiushkina , Vladislav Tiurin , Rimma Mulkidzhan, Elena Krivosheeva , Evgeny Imyanitov , Polymerase chain reaction (PCR) as an effective screening method for detecting translocations involving NTRK genes in non-small cell lung cancer , Voprosy onkologii : Vol. 68 No. 2 (2022)
Grigoriy Yanus, Tatiana Laidus, Aleksandr S Martianov, Svetlana Aleksakhina, Ekaterina Kuligina, Evgeny Imyanitov, Liquid biopsy as the universal DNA-based method for early cancer detection: problems, approaches, solutions , Voprosy onkologii : Vol. 67 No. 5 (2021)
Grigorii Ianus, A.G. Iyevleva, Svetlana Aleksakhina, Evgeny Imyanitov, Predictive molecular genetic tests in clinical oncology , Voprosy onkologii : Vol. 68 No. 1 (2022)
Aglaya Iyevleva, Mikhail Kramchaninov, Svetlana Aleksakhina, Tatiana Sokolova, Tatiana Solovieva, Artem Kosmin, Vadim Dmitriev, Vladislav Petkau, Vladimir Moiseenko, Evgeny Imyanitov, Predictive role of CCND1, FGFR1 gene amplifications and PIK3CA mutations for endocrine therapy of primary metastatic breast cancer , Voprosy onkologii : Vol. 67 No. 5 (2021)
Evgeny Imyanitov, Maxim Filipenko, Tatyana Kekeyeva , Irina Demidova, Practical aspects of BRCA1/2 testing: position of the Russian society of molecular geneticists in oncology and oncohematology , Voprosy onkologii : Vol. 68 No. 3 (2022)

1 2 > >>