Mismatch repair deficient colorectal cancer in the era of personalized treatment

Abstract

The molecular and genetic subtyping of cancer has allowed the emergence of individualized therapies. This approach could potentially deliver treatments that have both increased efficacy as well as reduced toxicity. A well-defined subtype of colorectal cancer (CRC) is characterized by a deficiency in the mismatch repair (MMR) pathway. MMR deficiency not only contributes to the pathogenesis of a large proportion of CRC, but also determines the response to many of the drugs that are frequently used to treat this disease. In this Review we describe the MMR deficient phenotype and discuss how a deficiency in this DNA repair process may impact on the management of CRC, including surgery, adjuvant chemotherapy and the choice of systemic agents for the palliation of advanced disease. We also discuss how the DNA repair defect in MMR deficient CRC could be exploited in the development of novel therapeutic strategies.

MLH1 expression predicts the response to preoperative therapy and is associated with PD-L1 expression in esophageal cancer

“…In esophageal cancer, hypermethylation of the MLH1 promoter appears to be involved in MMR deficiency (13). In colorectal cancer, MMR-deficient tumors are associated with improved survival (14,15), although they are not sensitive to 5-fluorouracil (5-FU)-based chemotherapy (12,16,17). These characteristics have not been validated adequately in esophageal cancer.…”

“…MMR-deficient cancer arises from an inherited mutation in an MMR gene or by epigenetic suppression of MMR gene expression (12). In esophageal cancer, hypermethylation of the MLH1 promoter appears to be involved in MMR deficiency (13).…”

Mikrosatelliteninstabilität

“…Abb. 4, [13]). Dabei wird die durch 5-FU verursachte DNA-Läsion durch die MutS-Homologen (MSH2/MSH6 bzw.…”

Aberrant DNA Methylation and Epigenetic Inactivation of hMSH2 Decrease Overall Survival of Acute Lymphoblastic Leukemia Patients via Modulating Cell Cycle and Apoptosis

“…Defects in MMR proteins have been found be associated with reduced or absent benefit from 5-FU adjuvant chemotherapy in clinical trials (Ribic et al, 2003). MMR impairment appears to cause reduced incorporation of 5-FU metabolites into DNA, leading to reduced G2/M arrest and apoptosis after 5-FU treatment (Meyers et al, 2005;Hewish et al, 2010). The deficiencies of MMR genes are also associated with MNNG, 6-thioguanine and cisplatin (Fiumicino et al, 2000;Meyers et al, 2001;Loo et al, 2005).…”