Molecular pathology of Lynch syndrome

Abstract

Lynch syndrome (LS) is characterised by predisposition to colorectal, endometrial, and other cancers and is caused by inherited pathogenic variants affecting the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. It is probably the most common predisposition to cancer, having an estimated prevalence of between 1/100 and 1/180. Resources such as the International Society for Gastrointestinal Hereditary Cancer's MMR gene variant database, the Prospective Lynch Syndrome Database (PLSD), and the Colon Cancer Family Register (CCFR), as well as pathological and immunological studies, are enabling advances in the understanding of LS. These include defined criteria by which to interpret gene variants, the function of MMR in the normal control of apoptosis, definition of the risks of the various cancers, and the mechanisms and pathways by which the colorectal and endometrial tumours develop, including the critical role of the immune system. Colorectal cancers in LS can develop along three pathways, including flat intramucosal lesions, which depend on the underlying affected MMR gene. This gives insights into the limitations of colonoscopic surveillance and highlights the need for other forms of anti-cancer prophylaxis in LS. Finally, it shows that the processes of autoimmunisation and immunoediting fundamentally constrain the development of tumours in LS and explain the efficacy of immune checkpoint blockade therapy in MMR-deficient tumours.

DNA Mismatch Repair and its Role in Huntington’s Disease

“…Because of their overlapping substrate recognition specificities, MutS␣ can largely compensate for the absence of MutS␤, and the overwhelming majority of mispairs are recognized and rectified by a MutS␣-initiated pathway. Hence, MutS␣ is critical for mutation avoidance, and its inactivation (by mutations in MSH2 or MSH6) is a risk factor for carcinogenesis [13,14]. By contrast, loss of MutS␤ function (by inactivation of MSH3) has not been conclusively linked to an elevated cancer risk in humans [45].…”

“…MMR defects result in a 100-1000 fold elevation in mutation rate in most organisms [3][4][5][6][7], and modulation of MMR has been suggested to be a powerful evolutionary survival mechanism [11,12]. Loss of MMR function in humans is the cause of Lynch syndrome, a hereditary cancer predisposition condition that is characterized by an increased risk of gastrointestinal, uterine, and ovarian tumors [13,14]. More recently, biallelic inactivation of MMR has been linked to constitutive mismatch repair deficiency syndrome (CMMR-D), a rare childhood/young adult condition associated with a higher propensity for developing colorectal, brain, and blood cancers [15][16][17].…”

The diversity of tumours with microsatellite instability: molecular mechanisms and impact upon microsatellite instability testing and mismatch repair protein immunohistochemistry

“…Inactivation of important tumour suppressors via such MSI events is believed to be a major mechanistic pathway that initiates or promotes tumorigenesis 7,8 . Further adding to such tumorigenic effect, cells with the MSI phenotype have also been shown to have reduced susceptibility to certain DNA damage‐induced apoptosis 9,10 . Another important functional consequence of MSI relates to the fact that the MSI‐specific frameshift mutations generate new amino acid sequences in the C‐terminal part of the proteins, which prematurely terminate where a novel stop codon appears.…”

Acetylation and Deacetylation of DNA Repair Proteins in Cancers

“…MSH2-MSH6 heterodimeric complex acted as a bidirectional ATPase with ability to change ADP and ATP ratio in DNA damage repair (28). MSH6 mutation might associate with hereditary non-polyposis colorectal and endometrial cancer (29,30). However, whether acetylation modification on MSH6 interferes with ATPase activity and MMR efficiency still needs further elucidation.…”