MLH1 & its role in Lynch Syndrome and sporadic colorectal cancers By Annie Jin

Colorectal cancer (CRC) – 2 nd leading cause of cancer death in the US

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 MLH1-coding 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.)

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References (cont.) Gastroenterology, Vol. 119, No. 3, Randall W. Burt, Colon Cancer Screening, Pages , Copyright (2000) hsieh/ResearchImages/HsiehLabImage2_3389_Scheme-for-DNA[1].png