Microsatellite Instability: A Review of Molecular Epidemiology and Implications for Immune Checkpoint Inhibitor Therapy

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2023 May 16

PMID 37190216

Authors

Alexandra Kavun

Egor Veselovsky

Alexandra Lebedeva

Ekaterina Belova

Olesya Kuznetsova

Valentina Yakushina

Tatiana Grigoreva

Vladislav Mileyko

Mikhail Fedyanin

Maxim Ivanov

Affiliations

Soon will be listed here.

Abstract

Microsatellite instability (MSI) is one of the most important molecular characteristics of a tumor, which occurs among various tumor types. In this review article, we examine the molecular characteristics of MSI tumors, both sporadic and Lynch-associated. We also overview the risks of developing hereditary forms of cancer and potential mechanisms of tumor development in patients with Lynch syndrome. Additionally, we summarize the results of major clinical studies on the efficacy of immune checkpoint inhibitors for MSI tumors and discuss the predictive role of MSI in the context of chemotherapy and checkpoint inhibitors. Finally, we briefly discuss some of the underlying mechanisms causing therapy resistance in patients treated with immune checkpoint inhibitors.

Citing Articles

Deep visual proteomics reveals DNA replication stress as a hallmark of signet ring cell carcinoma.

Kabatnik S, Zheng X, Pappas G, Steigerwald S, Padula M, Mann M NPJ Precis Oncol. 2025; 9(1):37.

PMID: 39910169 PMC: 11799539. DOI: 10.1038/s41698-025-00819-7.

Blood-based prognostic scores and early dynamics under immunotherapy to select patients with metastatic solid tumors for continuing immune check-point inhibition: a prospective longitudinal study.

Garcia-Corbacho J, Indacochea A, Victoria I, Moreno D, Angelats L, Gonzalez Navarro A Cancer Immunol Immunother. 2025; 74(3):85.

PMID: 39891724 PMC: 11787139. DOI: 10.1007/s00262-024-03933-w.

Endometrial Atypical Hyperplasia and Risk of Endometrial Cancer.

Chou A, Bing R, Ding D Diagnostics (Basel). 2024; 14(22).

PMID: 39594136 PMC: 11593242. DOI: 10.3390/diagnostics14222471.

Myeloid subsets impede the efficacy of anti-PD1 therapy in patients with advanced gastric cancer (WJOG10417GTR study).

Shoji H, Kudo-Saito C, Nagashima K, Imazeki H, Tsugaru K, Takahashi N J Immunother Cancer. 2024; 12(11).

PMID: 39489543 PMC: 11535716. DOI: 10.1136/jitc-2024-010174.

MSI-H Detection by ddPCR in Endoscopic Ultrasound Fine Needle Biopsy (EUS-FNB) from Pancreatic Ductal Adenocarcinoma.

Piano M, Boldrin E, Moserle L, Salerno N, Fanelli D, Peserico G Int J Mol Sci. 2024; 25(20).

PMID: 39456871 PMC: 11507452. DOI: 10.3390/ijms252011090.

References

Chang D, Ricciardiello L, Goel A, Chang C, Boland C . Steady-state regulation of the human DNA mismatch repair system. J Biol Chem. 2000; 275(24):18424-31. DOI: 10.1074/jbc.M001140200. View

Kambara T, Simms L, Whitehall V, Spring K, Wynter C, Walsh M . BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut. 2004; 53(8):1137-44. PMC: 1774130. DOI: 10.1136/gut.2003.037671. View

Yurgelun M, Goel A, Hornick J, Sen A, Turgeon D, Ruffin 4th M . Microsatellite instability and DNA mismatch repair protein deficiency in Lynch syndrome colorectal polyps. Cancer Prev Res (Phila). 2012; 5(4):574-82. PMC: 3461594. DOI: 10.1158/1940-6207.CAPR-11-0519. View

Venderbosch S, Nagtegaal I, Maughan T, Smith C, Cheadle J, Fisher D . Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res. 2014; 20(20):5322-30. PMC: 4201568. DOI: 10.1158/1078-0432.CCR-14-0332. View

Smyrk T, Watson P, Kaul K, Lynch H . Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma. Cancer. 2001; 91(12):2417-22. View

Liu J, Blake S, Yong M, Harjunpaa H, Ngiow S, Takeda K . Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease. Cancer Discov. 2016; 6(12):1382-1399. DOI: 10.1158/2159-8290.CD-16-0577. View

Luchini C, Bibeau F, Ligtenberg M, Singh N, Nottegar A, Bosse T . 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. View

Dominguez-Valentin M, Joost P, Therkildsen C, Jonsson M, Rambech E, Nilbert M . Frequent mismatch-repair defects link prostate cancer to Lynch syndrome. BMC Urol. 2016; 16:15. PMC: 4806412. DOI: 10.1186/s12894-016-0130-1. View

Fallik D, Borrini F, Boige V, Viguier J, Jacob S, Miquel C . Microsatellite instability is a predictive factor of the tumor response to irinotecan in patients with advanced colorectal cancer. Cancer Res. 2003; 63(18):5738-44. View

10.

Simpkins S, Bocker T, Swisher E, Mutch D, Gersell D, Kovatich A . MLH1 promoter methylation and gene silencing is the primary cause of microsatellite instability in sporadic endometrial cancers. Hum Mol Genet. 1999; 8(4):661-6. DOI: 10.1093/hmg/8.4.661. View

11.

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

12.

South C, Hampel H, Comeras I, Westman J, Frankel W, de la Chapelle A . The frequency of Muir-Torre syndrome among Lynch syndrome families. J Natl Cancer Inst. 2008; 100(4):277-81. DOI: 10.1093/jnci/djm291. View

13.

Hecht J, Mutter G . Molecular and pathologic aspects of endometrial carcinogenesis. J Clin Oncol. 2006; 24(29):4783-91. DOI: 10.1200/JCO.2006.06.7173. View

14.

Engel C, Ahadova A, Seppala T, Aretz S, Bigirwamungu-Bargeman M, Blaker H . Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome. Gastroenterology. 2020; 158(5):1326-1333. DOI: 10.1053/j.gastro.2019.12.032. View

15.

Diaz-Padilla I, Romero N, Amir E, Matias-Guiu X, Vilar E, Muggia F . Mismatch repair status and clinical outcome in endometrial cancer: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2013; 88(1):154-67. DOI: 10.1016/j.critrevonc.2013.03.002. View

16.

Goodfellow P, Billingsley C, Lankes H, Ali S, Cohn D, Broaddus R . Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study. J Clin Oncol. 2015; 33(36):4301-8. PMC: 4678181. DOI: 10.1200/JCO.2015.63.9518. View

17.

Rossi L, Le Frere-Belda M, Laurent-Puig P, Buecher B, de Pauw A, Stoppa-Lyonnet D . Clinicopathologic Characteristics of Endometrial Cancer in Lynch Syndrome: A French Multicenter Study. Int J Gynecol Cancer. 2017; 27(5):953-960. DOI: 10.1097/IGC.0000000000000985. View

18.

Abushukair H, Ababneh O, Zaitoun S, Saeed A . Primary and secondary immune checkpoint inhibitors resistance in colorectal cancer: Key mechanisms and ways to overcome resistance. Cancer Treat Res Commun. 2022; 33:100643. DOI: 10.1016/j.ctarc.2022.100643. View

19.

Tiwari A, Roy H, Lynch H . Lynch syndrome in the 21st century: clinical perspectives. QJM. 2015; 109(3):151-8. DOI: 10.1093/qjmed/hcv137. View

20.

Diaz Jr L, Shiu K, Kim T, Jensen B, Jensen L, Punt C . Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022; 23(5):659-670. PMC: 9533375. DOI: 10.1016/S1470-2045(22)00197-8. View