Impact of Mutations in DNA Repair Genes in Lynch Syndrome: A Systematic Literature Review
DOI:
https://doi.org/10.56226/93Keywords:
Lynch Syndrome, Colorectal Cancer, Repair Gene, DNAAbstract
Introduction: Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer, is a genetic condition that significantly increases the risk of developing colorectal cancer and other types of cancer. This syndrome is caused by mutations in DNA repair (MMR) genes, which are responsible for correcting errors that occur during DNA replication. Methodology: Scientific databases such as PubMed, Scopus, and Web of Science were consulted for this systematic review. Studies that addressed mutations in MMR genes (MLH1, MSH2, MSH6, PMS2 and EPCAM) and their association with Lynch syndrome were included. Studies that did not present relevant clinical data or that were not systematic reviews were excluded. Results: The results showed that mutations in MMR genes are responsible for approximately 1-7% of all cases of colorectal cancer. The most common mutations are found in the MLH1 (50%) and MSH2 (40%) genes, while MSH6, PMS2 and EPCAM represent a smaller proportion1. These mutations lead to genomic instability, resulting in a high rate of mutations in tumour cells, which contributes to the development of cancer. Conclusion: The systematic review demonstrated that mutations in DNA repair genes have a significant impact on Lynch Syndrome, increasing the risk of colorectal cancer and other types of cancer. Identifying these mutations is crucial for early diagnosis and implementation of screening and prevention programs. Furthermore, understanding the molecular basis of the syndrome may lead to the development of new targeted therapies.
References
Aarnio, M., Mustonen, H., Mecklin, J. P., & Järvinen, H. J. (1998). Prognosis of colorectal cancer varies in different high-risk conditions. Annals of medicine, 30(1), 75–80. https://doi.org/10.3109/07853899808999387
Aarnio, M., Mecklin, J. P., Aaltonen, L. A., Nyström-Lahti, M., & Järvinen, H. J. (1995). Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. International journal of cancer, 64(6), 430–433. https://doi.org/10.1002/ijc.2910640613
Alarcon, F., Lasset, C., Carayol, J., Bonadona, V., Perdry, H., Desseigne, F., Wang, Q., & Bonaïti-Pellié, C. (2007). Estimating cancer risk in HNPCC by the GRL method. European journal of human genetics : EJHG, 15(8), 831–836. https://doi.org/10.1038/sj.ejhg.5201843
Bonis, P. A., Trikalinos, T. A., Chung, M., Chew, P., Ip, S., DeVine, D. A., & Lau, J. (2007). Hereditary nonpolyposis colorectal cancer: diagnostic strategies and their implications. Evidence report/technology assessment, (150), 1–180.
Burn, J., Gerdes, A. M., Macrae, F., Mecklin, J. P., Moeslein, G., Olschwang, S., Eccles, D., Evans, D. G., Maher, E. R., Bertario, L., Bisgaard, M. L., Dunlop, M. G., Ho, J. W., Hodgson, S. V., Lindblom, A., Lubinski, J., Morrison, P. J., Murday, V., Ramesar, R., Side, L., … CAPP2 Investigators (2011). Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet (London, England), 378(9809), 2081–2087. https://doi.org/10.1016/S0140-6736(11)61049-0
Cairns, S. R., Scholefield, J. H., Steele, R. J., Dunlop, M. G., Thomas, H. J., Evans, G. D., Eaden, J. A., Rutter, M. D., Atkin, W. P., Saunders, B. P., Lucassen, A., Jenkins, P., Fairclough, P. D., Woodhouse, C. R., British Society of Gastroenterology, & Association of Coloproctology for Great Britain and Ireland (2010). Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut, 59(5), 666–689. https://doi.org/10.1136/gut.2009.179804
Clendenning, M., Senter, L., Hampel, H., Robinson, K. L., Sun, S., Buchanan, D., Walsh, M. D., Nilbert, M., Green, J., Potter, J., Lindblom, A., & de la Chapelle, A. (2008). A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome. Journal of medical genetics, 45(6), 340–345. https://doi.org/10.1136/jmg.2007.056150
Costa, L. F., Caixeta, L. V. V., de Carvalho, L. O. R., Barbosa, C. O., Ferreira, I. B., Reis, V. H. S., de Toledo, L. F. e S., Moura Neto, L. A. dos R., Olavarria, R. de C., Oliveira, A. G. L., & Gomes, K. H. (2023). Síndrome de Lynch: uma abordagem diagnóstica, evolução clínica e revisão. Brazilian Journal of Health Review, 6(5), 21402–21409. https://doi.org/10.34119/bjhrv6n5-168
Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (2009). Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genetics in medicine : official journal of the American College of Medical Genetics, 11(1), 35–41. https://doi.org/10.1097/GIM.0b013e31818fa2ff
Felix, R., Bodmer, W., Fearnhead, N. S., van der Merwe, L., Goldberg, P., & Ramesar, R. S. (2006). GSTM1 and GSTT1 polymorphisms as modifiers of age at diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) in a homogeneous cohort of individuals carrying a single predisposing mutation. Mutation research, 602(1-2), 175–181. https://doi.org/10.1016/j.mrfmmm.2006.09.004
Grigorie, T. R., Potlog, G., & Alexandrescu, S. T. (2025). Lynch Syndrome-Impact of the Type of Deficient Mismatch Repair Gene Mutation on Diagnosis, Clinical Presentation, Surveillance and Therapeutic Approaches. Medicina (Kaunas, Lithuania), 61(1), 120. https://doi.org/10.3390/medicina61010120
Gómez, L., Adi, J., Ibarra, J., & Roqué, M. (2010). Mutación fundadora en una familia argentina con cáncer colorrectal hereditario [Detection of a founder mutation in an Argentine family with hereditary non polyposis colorectal cancer]. Medicina, 70(1), 31–36.
Järvinen, H. J., Mecklin, J. P., & Sistonen, P. (1995). Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer. Gastroenterology, 108(5), 1405–1411. https://doi.org/10.1016/0016-5085(95)90688-6
Kwok, C. T., Vogelaar, I. P., van Zelst-Stams, W. A., Mensenkamp, A. R., Ligtenberg, M. J., Rapkins, R. W., Ward, R. L., Chun, N., Ford, J. M., Ladabaum, U., McKinnon, W. C., Greenblatt, M. S., & Hitchins, M. P. (2014). The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype. European journal of human genetics : EJHG, 22(5), 617–624. https://doi.org/10.1038/ejhg.2013.200
Lynch, H. T., Lynch, P. M., Lanspa, S. J., Snyder, C. L., Lynch, J. F., & Boland, C. R. (2009). Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clinical genetics, 76(1), 1–18. https://doi.org/10.1111/j.1399-0004.2009.01230.x
Müller, A., Giuffre, G., Edmonston, T. B., Mathiak, M., Roggendorf, B., Heinmöller, E., Brodegger, T., Tuccari, G., Mangold, E., Buettner, R., Rüschoff, J., & German HNPCC Consortium German Cancer Aid (Deutsche Krebshilfe) (2004). Challenges and pitfalls in HNPCC screening by microsatellite analysis and immunohistochemistry. The Journal of molecular diagnostics : JMD, 6(4), 308–315. https://doi.org/10.1016/S1525-1578(10)60526-0
Oliveira, C., Westra, J. L., Arango, D., Ollikainen, M., Domingo, E., Ferreira, A., Velho, S., Niessen, R., Lagerstedt, K., Alhopuro, P., Laiho, P., Veiga, I., Teixeira, M. R., Ligtenberg, M., Kleibeuker, J. H., Sijmons, R. H., Plukker, J. T., Imai, K., Lage, P., Hamelin, R., … Hofstra, R. M. (2004). Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status. Human molecular genetics, 13(19), 2303–2311. https://doi.org/10.1093/hmg/ddh238
Pande, M., Amos, C. I., Osterwisch, D. R., Chen, J., Lynch, P. M., Broaddus, R., & Frazier, M. L. (2008). Genetic variation in genes for the xenobiotic-metabolizing enzymes CYP1A1, EPHX1, GSTM1, GSTT1, and GSTP1 and susceptibility to colorectal cancer in Lynch syndrome. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 17(9), 2393–2401. https://doi.org/10.1158/1055-9965.EPI-08-0326
Peltomäki, P., Nyström, M., Mecklin, J. P., & Seppälä, T. T. (2023). Lynch syndrome genetics and clinical implications. Gastroenterology, 164(5), 783-799. https://doi.org/10.1053/j.gastro.2022.08.058
Ponti, G., Castellsagué, E., Ruini, C., Percesepe, A., & Tomasi, A. (2015). Mismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome. Clinical genetics, 87(6), 507–516. https://doi.org/10.1111/cge.12529
Ramsoekh, D., Wagner, A., van Leerdam, M. E., Dooijes, D., Tops, C. M., Steyerberg, E. W., & Kuipers, E. J. (2009). Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different risk profiles may influence clinical management. Hereditary cancer in clinical practice, 7(1), 17. https://doi.org/10.1186/1897-4287-7-17
Reeves, S. G., Rich, D., Meldrum, C. J., Colyvas, K., Kurzawski, G., Suchy, J., Lubinski, J., & Scott, R. J. (2008). IGF1 is a modifier of disease risk in hereditary non-polyposis colorectal cancer. International journal of cancer, 123(6), 1339–1343. https://doi.org/10.1002/ijc.23668
Seppälä, T. T., Latchford, A., Negoi, I., Sampaio Soares, A., Jimenez-Rodriguez, R., Sánchez-Guillén, L., Evans, D. G., Ryan, N., Crosbie, E. J., Dominguez-Valentin, M., Burn, J., Kloor, M., Knebel Doeberitz, M. V., Duijnhoven, F. J. B. V., Quirke, P., Sampson, J. R., Møller, P., Möslein, G., & European Hereditary Tumour Group (EHTG) and European Society of Coloproctology (ESCP) (2021). European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender. The British journal of surgery, 108(5), 484–498. https://doi.org/10.1002/bjs.11902
Tomsic, J., Senter, L., Liyanarachchi, S., Clendenning, M., Vaughn, C. P., Jenkins, M. A., Hopper, J. L., Young, J., Samowitz, W., & de la Chapelle, A. (2013). Recurrent and founder mutations in the PMS2 gene. Clinical genetics, 83(3), 238–243. https://doi.org/10.1111/j.1399-0004.2012.01898.x
Umar, A., Boland, C. R., Terdiman, J. P., Syngal, S., de la Chapelle, A., Rüschoff, J., Fishel, R., Lindor, N. M., Burgart, L. J., Hamelin, R., Hamilton, S. R., Hiatt, R. A., Jass, J., Lindblom, A., Lynch, H. T., Peltomaki, P., Ramsey, S. D., Rodriguez-Bigas, M. A., Vasen, H. F., Hawk, E. T., … Srivastava, S. (2004). Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. Journal of the National Cancer Institute, 96(4), 261–268. https://doi.org/10.1093/jnci/djh034
Vasen HFA, Moslein G, Alonso A, Bernstein I, Bertario L, Blanco I, et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 2007;44:353–62. http://dx.doi.org/10.1136/jmg.2007.048991
Vasen, H. F., Möslein, G., Alonso, A., Aretz, S., Bernstein, I., Bertario, L., Blanco, I., Bulow, S., Burn, J., Capella, G., Colas, C., Engel, C., Frayling, I., Rahner, N., Hes, F. J., Hodgson, S., Mecklin, J. P., Møller, P., Myrhøj, T., Nagengast, F. M., … Müller, H. (2010). Recommendations to improve identification of hereditary and familial colorectal cancer in Europe. Familial cancer, 9(2), 109–115. https://doi.org/10.1007/s10689-009-9291-3
Vasen, H. F., Blanco, I., Aktan-Collan, K., Gopie, J. P., Alonso, A., Aretz, S., Bernstein, I., Bertario, L., Burn, J., Capella, G., Colas, C., Engel, C., Frayling, I. M., Genuardi, M., Heinimann, K., Hes, F. J., Hodgson, S. V., Karagiannis, J. A., Lalloo, F., Lindblom, A., … Mallorca group (2013). Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut, 62(6), 812–823. https://doi.org/10.1136/gutjnl-2012-304356
Wijnen, J. T., Brohet, R. M., van Eijk, R., Jagmohan-Changur, S., Middeldorp, A., Tops, C. M., van Puijenbroek, M., Ausems, M. G., Gómez García, E., Hes, F. J., Hoogerbrugge, N., Menko, F. H., van Os, T. A., Sijmons, R. H., Verhoef, S., Wagner, A., Nagengast, F. M., Kleibeuker, J. H., Devilee, P., Morreau, H., … Vasen, H. F. (2009). Chromosome 8q23.3 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome. Gastroenterology, 136(1), 131–137. https://doi.org/10.1053/j.gastro.2008.09.033
Zecevic, M., Amos, C. I., Gu, X., Campos, I. M., Jones, J. S., Lynch, P. M., Rodriguez-Bigas, M. A., & Frazier, M. L. (2006). IGF1 gene polymorphism and risk for hereditary nonpolyposis colorectal cancer. Journal of the National Cancer Institute, 98(2), 139–143. https://doi.org/10.1093/jnci/djj016
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 The Publisher
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution (CC-BY) 4.0 License that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
Start-up >