From the Guidelines
Yes, MSH2 is a tumor suppressor gene, as evidenced by its critical role in DNA mismatch repair, and mutations in this gene can lead to Lynch syndrome, significantly increasing the risk of various cancers, including colorectal, endometrial, and ovarian cancers, as reported in the most recent study 1.
Tumor Suppressor Function
MSH2 plays a crucial role in DNA mismatch repair, a cellular mechanism that corrects errors occurring during DNA replication. When MSH2 functions normally, it helps prevent mutations from accumulating in the genome by identifying and repairing mismatched DNA base pairs.
Clinical Implications
Mutations in the MSH2 gene can lead to Lynch syndrome, which significantly increases the risk of developing colorectal cancer and other cancers, including endometrial, ovarian, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin cancers, as highlighted in 1 and 1.
Genetic Testing
Genetic testing for MSH2 mutations is available and recommended for individuals with a strong family history of colorectal cancer or other Lynch syndrome-associated cancers, as emphasized in 1.
Key Points
- MSH2 is a tumor suppressor gene involved in DNA mismatch repair.
- Mutations in MSH2 can lead to Lynch syndrome, increasing the risk of various cancers.
- Genetic testing for MSH2 mutations is recommended for individuals with a strong family history of colorectal cancer or other Lynch syndrome-associated cancers.
- The tumor suppressor function of MSH2 is demonstrated by its role in preventing mutations from accumulating in the genome, as reported in 1.
From the Research
Role of MSH2 in Tumor Suppression
- MSH2 is a key component of the mismatch repair system, which plays a crucial role in maintaining genome stability by correcting replication errors 2, 3, 4.
- Mutations in the MSH2 gene have been associated with an increased risk of cancer, particularly in Lynch syndrome, a cancer-predisposing syndrome characterized by a high risk of colon and endometrial cancer 2.
- The MSH2 protein forms heterodimers with MSH6 or MSH3 and is involved in mismatch-pair recognition and initiation of repair, highlighting its importance in preventing genetic instability and tumorigenesis 2, 3.
Mechanisms of Tumor Suppression
- MSH2 has been shown to exert a novel epigenomic function in gastric cancer, where it regulates cell adhesion pathways and sensitivity to BET inhibition 3.
- The protein also plays a role in signaling cell-cycle arrest in response to short telomeres, which can act as a potent anticancer barrier 5.
- Additionally, MSH2 has been found to be stabilized by OTUB1, which blocks ubiquitination and prevents degradation, highlighting the importance of precise regulation of MSH2 proteostasis in maintaining genome stability 6.
Consequences of MSH2 Deficiency
- MSH2 deficiency has been associated with a mutator phenotype and increased cancer susceptibility, as well as deficient cell adhesion pathway expression and enhanced tumorigenesis 3, 4.
- Loss of MSH2 has also been shown to abolish the anticancer and pro-aging activity of short telomeres, highlighting the importance of MSH2 in the organismal response to dysfunctional telomeres 5.
- Furthermore, MSH2-deficient cancers have been found to display addiction to BAZ1B and consequent synthetic lethality to BET inhibition, identifying a potential therapeutic strategy for MSH2-deficient gastric malignancies 3.