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 dimer proteins they form are responsible for mismatch recognition, insertion-deletion loops, base excision, and other functions.3,4
  • Biallelic inactivation of one (or more) MMR genes can result from either somatic or germline mutations, as well as from epigenetic silencing.5,6
  • Lynch syndrome arises from inherited (germline) mutations in four MMR genes (MLH1, MSH2, MSH6, and PMS2) and stands as the predominant genetically linked predisposition to colorectal cancer (CRC), accounting for approximately 2% to 4% of all CRC cases.7-10
  • Microsatellites are short tandem nucleotide repeats (1-6 nucleotides) which are scattered throughout the genome and prone to high rates of mutation.11,12
  • Microsatellite instability (MSI) refers to a hyper-mutable phenotype that results when MMR genes are inactive or faulty.MSI status is generally categorized into three types: high microsatellite instability (MSI-H), low microsatellite instability (MSI-L) and microsatellite stability (MSS). 

Testing for MMR/MSI Status

When to Test:

  • All newly diagnosed patients with CRC should undergo MMR or MSI testing.13,14

Available Testing Methods:

  • Several techniques are used to test for the presence of MMR deficiency (dMMR) in CRC, including immunohistochemical (IHC) or polymerase chain reaction- (PCR-) based assays as well as NGS based testing.13,14

Guideline Recommendations for Testing:

  • Universal testing is recommended for all newly diagnosed patients with CRC. IHC assays test for the protein expression of 4 MMR genes known to be mutated in Lynch Syndrome.
  • Under normal physiological conditions all 4 MMR proteins are expressed.
  • However, the loss of expression of one or more of these suggests the presence of a MMR gene mutation and warrants further testing, including screening for the presence of BRAF V600E mutations.13,14  

Targeted Therapy

Approved Agents:

  • The FDA has approved several immunotherapy agents for the treatment of patients with dMMR/MSI-H metastatic CRC.15-18
  • Based findings from the CheckMate-142 trial, nivolumab received accelerated approval as a single agent in this setting; approval was later extended to nivolumab in combination with ipilimumab in 2018.19,20
  • Pembrolizumab received approval as a first-line agent for the treatment of dMMR/MSI-H metastatic CRC in 2020 based on safety and efficacy demonstrated in the KEYNOTE-177 trial.21
  • Subsequently, in 2021, dostarlimab received accelerated approval for dMMR recurrent or advanced solid tumors with no satisfactory alternative treatment options based on findings from GARNET.22 

Mechanism of Action:

  • Approved immunotherapy agents act by inhibiting the programmed death ligand 1 (PD-L1) receptor found on T cells, thereby restoring the anti-tumor immune response.15-18

Learn more about Dostarlimab >

Learn more about Nivolumab and Ipilimumab >

Learn more about Pembrolizumab >

References

  1. Modrich P, Lahue R. Mismatch repair in replication fidelity, genetic recombination, and cancer biology. AnnuRev Biochem. 1996;65:101-33.
  2. Marti TM, Kunz C, Fleck O. DNA mismatch repairand mutation avoidance pathways. J Cell Physiol. 2002;191:28-41. 
  3. Bellacosa A. Functional interactions and signaling properties of mammalian DNA mismatch repair proteins. Cell Death Differ. 2001;8:1076-92.
  4. Peters AC, Young LC, Maeda T, et al. Mammalian DNAmismatch repair protects cells from UVB-induced DNA damage by facilitating apoptosis and p53 activation. DNARepair (Amst). 2003;2:427-35.
  5. Modrich P, Lahue R. Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Annu Rev Biochem. 1996; 65:101-33.
  6. Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci. 1998;95:6870-5.
  7. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol. 2008;26:5783-5788.
  8. Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med. 2003;348:919-932.
  9. Aaltonen LA, Salovaara R, Kristo P, et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screeningfor the disease. N Engl J Med. 1998;338:1481-1487.
  10. Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005;352:1851-1860
  11. Bonneville R, Krook MA, Chen HZ, et al. Detection of microsatellite instability biomarkers via next-generation sequencing. Methods Mol Biol. 2020;2055:119–32.
  12. Li K, Luo H, Huang L, Luo H, Zhu X. Microsatellite instability: a review of what the oncologist should know. Cancer Cell Int. 2020;20:16. doi: 10.1186/s12935-019-1091-8.
  13. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Colon Cancer, v1.2024. Accessed April 10, 2024. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf 
  14. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Rectal Cancer, v1.2024. Accessed April 10, 2024.https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf 
  15. 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
  16. OPDIVO (nivolumab). Prescribing information. Princeton, NJ, USA: Bristol-Myers Squibb Company; 2024. https://packageinserts.bms.com/pi/pi_opdivo.pdf
  17. YERVOY (ipilimumab). Prescribing information. Princeton, NJ, USA: Bristol-Myers Squibb Company; 2023. https://packageinserts.bms.com/pi/pi_yervoy.pdf
  18. 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
  19. FDA.gov. FDA grants nivolumab accelerated approval for MSI-H or dMMR colorectal cancer. Updated August 1, 2017. Accessed April 10, 2024.
  20. FDA.gov. FDA grants accelerated approval to ipilimumab for MSI-H or dMMR metastatic colorectal cancer. Updated July 11, 2018. Accessed April 10, 2024.
  21. FDA.gov. FDA approves pembrolizumab for first-line treatment of MSI-H/dMMR colorectal cancer. Updated June 30, 2020. Accessed April 10, 2024.
  22. FDA.gov. FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors. Updated July 18, 2023. Accessed April 10, 2024.