Abstract
Lynch syndrome is a cancer-predisposing syndrome inherited in an autosomal dominant manner, wherein colon cancer and endometrial cancer develop frequently in the family, it results from a loss of function of one of four different protein (MLH1, MSH2, MSH6, and PMS2), which are the products of mismatch repair genes. An abnormal EPCAM gene at the position adjacent to the MSH2 gene also inhibits MSH2 expression and causes Lynch syndrome.
Mismatch repair proteins are involved in repairing of incorrect pairing, including point mutations and deletion/insertion of simple repetitive sequences, so-called microsatellites, that can arise during DNA replication. MSH2 forms heterodimers with MSH6 or MSH3 (MutSĪ±, MutSĪ², respectively) and is involved in mismatch-pair recognition and initiation of repair. MLH1 forms a complex with PMS2 and functions as an endonuclease. If the mismatch repair system is thoroughly working, genome integrity is maintained at a high level. Lynch syndrome is a state of mismatch repair deficiency (MMRd) due to a monoallelic abnormality of the mismatch repair genes. The phenotype indicating the mismatch repair deficiency can be frequently observed as a microsatellite instability (MSI) in tumors.
Generally, Lynch syndrome develops in adulthood, but MMR gene abnormalities are observed in children with different genotypes and phenotypes. Children with germline biallelic mismatch repair gene abnormalities were reported to develop conditions such as gastrointestinal polyposis, colorectal cancer, brain cancer, leukemia, and so on. This condition is called constitutional mismatch repair deficiency (CMMRD).
In addition, for promoting cancer genome medicine in a new era, such as by utilizing immune checkpoints, it is important to understand the genetic and genomic molecular background, including the status of mismatch repair deficiency.
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Abbreviations
- CMMR-D:
-
Constitutional mismatch repair deficiency
- CNS:
-
Central nervous system
- CTE:
-
Congenital tufting enteropathy
- CTLA-4:
-
Cytotoxic T-lymphocyte-associated protein 4
- IHC:
-
Immunohistochemical staining
- ISI:
-
Immune checkpoint inhibitor
- MLPA:
-
Multiple ligation-dependent probe amplification
- MMR:
-
Mismatch repair
- MSI:
-
Microsatellite instability
- PCNA:
-
Proliferating cellular nuclear antigen
- PD-1:
-
Programmed cell death protein 1
- RFC:
-
Replication factor
- TMB:
-
Tumor mutational burden
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Acknowledgments
This work was supported in part by a grant from the Japanese Ministry of Education, Science, Sports and Culture of Japan (19K07763).
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Tamura, K. (2020). Molecular Mechanism of Lynch Syndrome. In: Tomita, N. (eds) Lynch Syndrome. Springer, Singapore. https://doi.org/10.1007/978-981-15-6891-6_1
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