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MLH1 & its role in Lynch Syndrome and sporadic colorectal cancers
By Annie JinSlide2
Colorectal cancer (CRC) â 2nd leading cause of cancer death in the USSlide3
Approximately 50% of individuals with Lynch syndrome have mutations in MLH1 (mostly truncating mutations)Slide4
Lynch syndrome is inherited in an autosomal dominant fashionSlide5
Single base mismatches and insertion-deletion loops (IDLs) are recognized and repaired through Mammalian Mismatch Repair (MMR)Slide6
Mammalian Mismatch Repair (MMR)Slide7
MLH1 is an integral part of the heterodimer MutLÎ± and allows the release of MMR proteins from DNA through its ATPase domainSlide8
X-ray exposure at 10 weeks promoted tumorigenesis of gastrointestinal tumors (GIT) in MLH1-/- mice and accelerated the time to deathSlide9
Microsatellite instability (MSI) due to loss of MMR results in mutations in growth-regulatory genesSlide10
The majority of MSI-high sporadic colon tumors are due to the inactivation MLH1 and most inactivations are due to MLH1 promoter hypermethylationSlide11
Absence of MLH1 protein despite wild-type MLH1-coding sequences suggest silencing of MLH1 alleles in 4 MSI-positive sporadic tumor cell linesSlide12
Loss of MLH1 expression is associated with methylation of the MLH1 gene promoterSlide13
Summary of molecular pathways leading to development of CRCSlide14
Treatment â Fluorouracil treatment (in addition to surgery)not advised in MSI-high stage II CRC patientsSlide15
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