Abstract
Human cells have numerous repair mechanisms to counteract various insults incurred on the DNA. Any mutation in these repair mechanisms can lead to accumulation of DNA errors and carcinogenesis. This review aims to discuss the therapeutic options in the two most common DNA repair deficient cancer syndromes, namely Lynch syndrome (hereditary non-polyposis colorectal cancer) and breast cancer susceptibility gene (BRCA) associated ovarian and breast cancer. Deficiency in DNA repair mechanisms renders these tumors with increased sensitivity to platinum agents. There has been increasing amount of information on the utility of the defects in DNA repair as targets for cancer therapy in these syndromes. Novel therapies like poly (ADP-ribose) polymerase (PARP) inhibitors are one of such example where the induction of double stranded breaks in DNA leads to tumoricidal effect in patients with homologous DNA repair deficiency. Interestingly, patients with DNA repair deficiencies tend to have a more favorable prognosis than sporadic malignancies. In microsatellite high colorectal cancer patients, this has been attributed to increased recruitment of CD8+ T lymphocytes in tumor microenvironment. However, these tumors are able to limit the host immune response by activation of immune checkpoints that seem like attractive targets of therapy in the future.
Highlights
Human cells have numerous repair mechanisms to counteract various insults incurred on the DNA
This review aims to discuss the therapeutic options in the two most common DNA repair deficient cancer syndromes, namely Lynch syndrome and breast cancer susceptibility gene (BRCA) associated ovarian and breast cancer
It is composed of four main genes—MLH1, MSH2, MSH6, PMS2—that encode the mismatch repair (MMR) proteins necessary for identification and repair of mismatched bases
Summary
Human cells are continuously exposed to countless insults, ranging from ultravoilet light and ionizing radiation to the use of alkylating and anti-tumor agents. DNA mismatch repair is a highly conserved mechanism primarily used to correct mismatched base pairs that arise as a result of replication errors or cellular damage [2] It is composed of four main genes—MLH1, MSH2, MSH6, PMS2—that encode the mismatch repair (MMR) proteins necessary for identification and repair of mismatched bases. Deficient mismatch repair causing microsatellite instability is responsible for 12–15 % of all colorectal cancers Among this group, two-thirds are due to sporadic transcriptional gene silencing while the remaining third is due to a germline loss-of-function mutation [6]. An alternative etiology for this syndrome is the germline epimutation of MLH1, a reversible hypermethylation event that involves various normal tissues [9] In another subset of Lynch Syndrome patients, constitutional, biallelic 30 exon deletion of the epithelial cell adhesion molecule can cause epigenetic silencing of the MSH2 gene and subsequent lack of MMR protein [10]. The tumor spectrum in Lynch Syndrome is broad, with following cancers listed in order of decreasing frequency: colorectal, endometrial, gastric, biliopancreatic, and uroepithelial [14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
