Origins of MSI cancer

Different genetic mechanisms can lead to development of MSI cancers. Whereas 70% of MSI cancers develop sporadically as a consequence of epigenetic inactivation of the MMR gene MLH1, in 30% of cases MSI cancers have a hereditary background. These cancers occur in the context of Lynch syndrome. Lynch syndrome is caused by mono-allelic germ line mutations in one of the DNA mismatch repair genes, most commonly MLH1 and MSH2. MSI cancers in Lynch syndrome develop after the inactivation of the second, still functional MMR gene allele.

Lynch syndore represents the most common inherited tumor syndrome, with an estimated prevalence of around 1:200 in the general population.

Sporadic MSI cancer

Microsatellite instability is observed in nearly all cancer types with varying frequency, being most frequent in bowel and uterus cancer. One possible explanation for high frequency of MSI in these cancer types is frequent tissue renewal requiring extremely high number of cell divisions, thereby increasing the chance for accumulation of mutations.

Mutations accumulating at short repetitive sequences (microsatellites) lead to a shift of the reading frame which results in generation of the so-called “Frame Shift Peptides” (FSP). These peptides are completely unknown to the immune system and therefore can induce strong immune reaction against MSI tumor cells. This phenomenon explains the good prognosis usually associated with MSI cancers and the striking success of immune checkpoint blockade in these cancers.

The mechanisms of microsatellite instability in sporadic scenario are often related to epigenetic alterations, such as DNA methylation. Since methylation occurs more often at older age, sporadic MSI cancers, unlike hereditary ones, are usually diagnosed in elderly patients (mostly after 70).

Lynch syndrome

Lynch syndrome is the most common cancer predisposition syndrome. Only in Germany there are about 500.000 affected individuals (for comparison, the number of HIV patients is 80.000), however the awareness about this cancer syndrome is unacceptably limited, mostly due to relatively low chance of developing cancer and limited power of clinical criteria to identify affected individuals.

Most commonly Lynch syndrome patients develop bowel cancer (therefore the historic name Hereditary Non-Polyposis Colorectal Cancer, or HNPCC syndrome), women with Lynch syndrome frequently develop cancer of uterus. However, many other Lynch syndrome cancer manifestations, such as stomach, ovarian, brain, skin cancer, have been described as well.

Microsatellite instability is the major molecular hallmark of Lynch syndrome-associated cancers. Therefore, all features of MSI cancer associated with sporadic setting, namely high mutational load, strong tumor immunogenicity and good prognosis, are also observed in Lynch syndrome. But in comparison to sporadic MSI cancer patients, Lynch syndrome patients are usually diagnosed with cancer at a younger (mostly below the age of 50).

Unlike the sporadic setting, in Lynch syndrome it is possible to predict cancer predisposition in unaffected individuals from Lynch syndrome families by testing them for pathogenic mutations. Therefore, cancer preventive strategies can be applied in order to reduce the risk of cancer or to enhance the chances of detecting cancer at an early stage.

CMMRD syndrome

Consititutional MisMatch Repair Deficiency (CMMRD) syndrome is a very rare cancer predisposition syndrome where affected individuals carry germline mutations in both alleles of an MMR gene. Therefore, patients with CMMRD have very early cancer manifestation (mostly below the age of 18).

The awareness of CMMRD syndrome is even more limited than of Lynch syndrome and the rarity of the disease makes it very hard to study. CMMRD-associated cancers are also characterized by microsatellite instability, but due to predisposition to developing multiple cancers,  high risk of secondary malignancies as well as development of very rare cancer types (glioblastoma, medulloblastoma), patients with CMMRD have a poor prognosis. Therefore, there is an unmet clinical need to develop primary prevention strategies for CMMRD patients.

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