MMR/MSI

  • DNA mismatch repair/microsatellite instability.

MMR and MSI Biology

  • DNA mismatch repair (MMR) is involved in preserving genomic fidelity by repairing DNA after mismatching errors after replication or recombination.1,2
  • MMR is also involved in cell cycle regulation and apoptosis in response to DNA damage.3,4
  • Four genes regulate MMR mechanisms, and the protein dimers they form are responsible for mismatch recognition, insertion-deletion loops, base excision, and other functions.
  • Biallelic inactivation of 1 (or more) MMR genes can result from either somatic or germline mutations, as well as from epigenetic silencing.1,5
  • Germline mutations in MMR genes are frequently associated with Lynch syndrome, which is known to increase the risk of gastric and various other types of cancers.6
  • Microsatellites are short tandem nucleotide repeats (1-6 nucleotides) that are scattered throughout the genome and prone to high rates of mutation. Microsatellite instability (MSI) refers to a hypermutable phenotype that results when MMR genes are inactive or faulty.7
  • High microsatellite instability (MSI-H) refers to more than 1 satellite site undergoing mutation.7

Etiology and Epidemiology

  • Gastric cancer (GC) is a heterogeneous disease with multiple subtypes identified. One subtype is GC with MSI-H, and this subtype features high mutational load and hypermethylation.8
  • MSI GCs account for approximately 22% of all GCs and contain a variety of altered genes that are involved in cell cycle progression, DNA integrity maintenance, mitosis, signal transduction, major histocompatibility complex class I, and other functions.8,9
  • MSI GCs have been associated with an older age (≥65 years), female sex, tumor location in the middle/lower gastric body, less likely lymph node involvement, and reduced propensity to invade serosal layers.9,10
  • In addition, patients with MSI GCs are more often diagnosed earlier in terms of disease stage.10,11

Testing for MMR/MSI Status

  • When to Test: All patients with gastric cancer should receive MSI or MMR testing at the time of diagnosis.12
  • Available Testing Methods: Two techniques are used to test for the presence of MMR deficiency in cancer, including GC. There are commercially available antibodies against the MMR proteins, thereby enabling immunohistochemical (IHC) methods to detect these proteins in the nucleus. Polymerase chain reaction (PCR)-based assays can be used on DNA extracted from fresh or frozen tumor tissue to detect MSI.12,13
  • Guideline Recommendations for Testing: All newly diagnosed patients with gastric cancer should receive universal testing for MSI via PCR or MMR via IHC.12

Treatment

  • Approved Agents: Pembrolizumab, a programmed death receptor 1 blocking antibody, was approved by the FDA in 2017 for patients with dMMR/MSI-H solid tumors that are considered unresectable or metastatic.13,14 The agency’s approval was the first driven solely by biomarker, regardless of the primary tumor’s site or histological type.13 More recently, in 2021, dostarlimab was granted accelerated approval for adult patients with dMMR recurrent or advanced solid tumors.15
  • Mechanism of Action: Pembrolizumab and dostarlimab are monoclonal antibodies that target the programmed death receptor-1 (PD-1), blocking its interaction with the ligands PD-L1 and PD-L2, thereby promoting anti-tumor activity.14,15

Learn more about Dostarlimab >

Learn more about Pembrolizumab >

References

  1. Modrich P, Lahue R. Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Annu Rev Biochem. 1996;65:101-133. doi:10.1146/annurev.bi.65.070196.000533
  2. Marti TM, Kunz C, Fleck O. DNA mismatch repair and mutation avoidance pathways. J Cell Physiol. 2002;191(1):28-41. doi:10.1002/jcp.10077
  3. Bellacosa A. Functional interactions and signaling properties of mammalian DNA mismatch repair proteins. Cell Death Differ. 2001;8(11):1076-1092. doi:10.1038/sj.cdd.4400948
  4. Peters AC, Young LC, Maeda T, Tron VA, Andrew SE. Mammalian DNA mismatch repair protects cells from UVB-induced DNA damage by facilitating apoptosis and p53 activation. DNA Repair (Amst). 2003;2(4):427-435. doi:10.1016/s1568-7864(03)00003-x
  5. Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA. 1998;95(12):6870-6875. doi:10.1073/pnas.95.12.6870
  6. Kumar S, Farha N, Burke CA, Katona BW. Upper gastrointestinal cancer surveillance in Lynch syndrome. Cancers (Basel). 2022;14(4):1000. doi:10.3390/cancers14041000
  7. Puliga E, Corso S, Pietrantonio F, Giordano S. Microsatellite instability in gastric cancer: between lights and shadows. Cancer Treat Rev. 2021;95:102175. doi:10.1016/j.ctrv.2021.102175
  8. Bass AJ, Thorsson V, Shmulevich I, et al; The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202-209. doi:10.1038/nature13480
  9. Polom K, Marano L, Marrelli D, et al. Meta-analysis of microsatellite instability in relation to clinicopathological characteristics and overall survival in gastric cancer. British J Surg. 2018;105(3):159-167. doi:10.1002/bjs.10663
  10. Zubarayev M, Min E-K, Son T. Clinical and molecular prognostic markers of survival after surgery for gastric cancer: tumor-node-metastasis staging system and beyond. Transl Gastroenterol Hepatol. 2019;4:59. doi:10.21037/tgh.2019.08.05
  11. Martinez-Ciarpaglini C, Fleitas-Kanonnikoff T, Gambardella V, et al. Assessing molecular subtypes of gastric cancer: microsatellite unstable and Epstein-Barr virus subtypes. Methods for detection and clinical and pathological implications. ESMO Open. 2019;4(3):e000470. doi:10.1136/esmoopen-2018-000470
  12. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Gastric Cancer, v4.2024. Accessed September 30, 2024. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf
  13. Dhakras P, Uboha N, Horner V, Reinig E, Matkowskyj KA. Gastrointestinal cancers: current biomarkers in esophageal and gastric adenocarcinoma. Transl Gastroenterol Hepatol. 2020;5:55. doi:10.21037/tgh.2020.01.08
  14. KEYTRUDA (pembrolizumab). Prescribing information. Merck & Co, Inc; 2018. Accessed June 12, 2024. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
  15. JEMPERLI (dostarlimab). Prescribing information. GlaxoSmithKline LLC; 2024. Accessed September 9, 2024. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Jemperli/pdf/JEMPERLI-PI-MG.PDF

Additional Reading

Maio M, Amonkar MM, Norquist JM, et al. Health-related quality of life in patients treated with pembrolizumab for microsatellite instability-high/mismatch repair-deficient advanced solid tumours: results from the KEYNOTE-158 study. Eur J Cancer. 2022;169:188-197. doi:10.1016/j.ejca.2022.03.040

Maio M, Ascierto PA, Manzyuk L, et al. Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study. Ann Oncol. 2022;33(9):929-938. doi:10.1016/j.annonc.2022.05.519