Transcript MLH1
MLH1 & its role in Lynch Syndrome and sporadic colorectal cancers By Annie Jin Colorectal cancer (CRC) – cancer death in the US nd 2 leading cause of Approximately 50% of individuals with Lynch syndrome have mutations in MLH1 (mostly truncating mutations) Lynch syndrome is inherited in an autosomal dominant fashion Single base mismatches and insertion-deletion loops (IDLs) are recognized and repaired through Mammalian Mismatch Repair (MMR) Mammalian Mismatch Repair (MMR) MLH1 is an integral part of the heterodimer MutLα and allows the release of MMR proteins from DNA through its ATPase domain X-ray exposure at 10 weeks promoted tumorigenesis of gastrointestinal tumors (GIT) in MLH1-/- mice and accelerated the time to death Microsatellite instability (MSI) due to loss of MMR results in mutations in growth-regulatory genes The majority of MSI-high sporadic colon tumors are due to the inactivation MLH1 and most inactivations are due to MLH1 promoter hypermethylation Absence of MLH1 protein despite wild-type MLH1coding sequences suggest silencing of MLH1 alleles in 4 MSI-positive sporadic tumor cell lines Loss of MLH1 expression is associated with methylation of the MLH1 gene promoter Summary of molecular pathways leading to development of CRC Treatment – Fluorouracil treatment (in addition to surgery)not advised in MSI-high stage II CRC patients Treatment (cont.) References • Jang, E. and Chung, D. C. (2010). Hereditary Colon Cancer: Lynch Syndrome. Gut and Liver, 4(2):151-160. • Jovanovic J, Rønneberg JA, Tost J, Kristensen V. The epigenetics of breast cancer. Mol Oncol. 2010; 4(3):24254. • Kuismanen SA, Holmberg MT, Salovaara R, de la Chapelle A, Peltomäki P. Genetic and Epigenetic Modification of MLH1 Accounts for a Major Share of Microsatellite-Unstable Colorectal Cancers. The American Journal of Pathology. 2000;156(5):1773-1779. • Peltomaki P. Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Hum. Mol. Genet., 10: 735-740, 2001. • Ribic CM, Sargent DJ, Moore MJ, et al. Tumor Microsatellite-Instability Status as a Predictor of Benefit from Fluorouracil-Based Adjuvant Chemotherapy for Colon Cancer. The New England journal of medicine. 2003;349(3):247-257. doi:10.1056/NEJMoa022289. • Shokal U, Sharma PC. Implication of microsatellite instability in human gastric cancers. The Indian Journal of Medical Research. 2012;135(5):599-613. • Sinicrope, F. A. (2010). DNA mismatch repair and adjuvant chemotherapy in sporadic colon cancer. Nature Reviews. Clinical Oncology, 7(3), 174-7. doi:http://dx.doi.org/10.1038/nrclinonc.2009.235 • Tokairin Y, Kakinuma S, Arai M, et al. Accelerated growth of intestinal tumours after radiation exposure in Mlh1-knockout mice: evaluation of the late effect of radiation on a mouse model of HNPCC. International Journal of Experimental Pathology. 2006;87(2):89-99. doi:10.1111/j.0959-9673.2006.00464.x. • Veigl ML, Kasturi L, Olechnowicz J, et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(15):8698-8702. References (cont.) • http://www.cancer.gov/cancertopics/pdq/treatment/colon/Patient/page2 • Gastroenterology, Vol. 119, No. 3, Randall W. Burt, Colon Cancer Screening, Pages 837-853, Copyright (2000) • http://https://www.myriad.com/patients-families/disease-info/colon-cancer/ • http://www.cancer.gov/cancertopics/pdq/genetics/colorectal/HealthProfessional/page1 • http://www.niddk.nih.gov/about-niddk/staff-directory/intramural/peggyhsieh/ResearchImages/HsiehLabImage2_3389_Scheme-for-DNA[1].png