Download 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