Genetic changes of MLH1 and MSH2 genes could explain constant findings on microsatellite instability in intracranial meningioma

Abstract

Postreplicative mismatch repair safeguards the stability of our genome. The defects in its functioning will give rise to microsatellite instability. In this study, 50 meningiomas were investigated for microsatellite instability. Two major mismatch repair genes, MLH1 and MSH2, were analyzed using microsatellite markers D1S1611 and BAT26 amplified by polymerase chain reaction and visualized by gel electrophoresis on high-resolution gels. Furthermore, genes DVL3 (D3S1262), AXIN1 (D16S3399), and CDH1 (D16S752) were also investigated for microsatellite instability. Our study revealed constant presence of microsatellite instability in meningioma patients when compared to their autologous blood DNA. Altogether 38% of meningiomas showed microsatellite instability at one microsatellite locus, 16% on two, and 13.3% on three loci. The percent of detected microsatellite instability for MSH2 gene was 14%, and for MLH1, it was 26%, for DVL3 22.9%, for AXIN1 17.8%, and for CDH1 8.3%. Since markers also allowed for the detection of loss of heterozygosity, gross deletions of MLH1 gene were found in 24% of meningiomas. Genetic changes between MLH1 and MSH2 were significantly positively correlated (p = 0.032). We also noted a positive correlation between genetic changes of MSH2 and DVL3 genes (p = 0.034). No significant associations were observed when MLH1 or MSH2 was tested against specific histopathological meningioma subtype or World Health Organization grade. However, genetic changes in DVL3 were strongly associated with anaplastic histology of meningioma (χ = 9.14; p = 0.01). Our study contributes to better understanding of the genetic profile of human intracranial meningiomas and suggests that meningiomas harbor defective cellular DNA mismatch repair mechanisms.

Mismatch Repair Pathway, Genome Stability and Cancer

“…At last we would like to present our research involving MSI in human meningiomas (Pykett et al, 1994;Pećina-Šlaus et al, 2010Pećina-Šlaus et al, , 2016 in which we evidenced the appearance of constant rate of MSI loci for genes DVL3, AXIN1, and CDH1 in 38% of meningiomas. The presence of MSI in meningioma has been noted by other authors although in lower percentage (Sobrido et al, 2000;Chen et al, 2012;Pećina-Šlaus et al, 2017) indicating the involvement of MMR machinery. Furthermore, by using microsatellite markers D1S1611 and BAT26, we tested our cohort of meningiomas for the two major MMR genes, MLH1 and MSH2, and found LOH of MLH1 gene in 24% of investigated cases.…”

Neurofibromatosis Type 2 (NF2) and the Implications for Vestibular Schwannoma and Meningioma Pathogenesis

“…Indeed, MEK 1 and 2 inhibitors are being studied for NF2-related vestibular schwannomas [ 68 ]. In addition, one might be able to leverage microsatellite instability in meningiomas [ 69 ] and changes in MLH1 and the MSH2 genes may pave the way of trailing immunotherapy in recurrent meningiomas [ 23 , 70 ]. As previously discussed in the Children’s Tumor Foundation forum, Dr. M. Wootton, CEO of NF2 Therapeutics, mentioned that they have a monkey model of NF2 gene replacement, and based on this, he went on to state that the first human clinical trials for this NF2 transgene may start in 2022 or 2023.…”

Immunohistochemical Expression Pattern of Mismatch Repair Genes in the Short-term Streptozotocin-induced Diabetic Rat Kidneys

“…15 MMR inactivation is strongly associated with different types of tumors, including hereditary and sporadic renal carcinoma. [16][17][18][19][20][21][22] Till now, these genes have been analyzed predominantly in the context of carcinogenesis and the evidence about MMR gene expression and function in different other pathologies, including DM, is missing. MutL homolog 1 (MLH1) is a component of a system of 7 DNA MMR proteins that works coordinately through several steps to initiate repair of DNA mismatches.…”

“…Impaired MMR function caused by gene mutation or hypermethylation of their promotor space leads to microsatellite instability and a higher incidence of spontaneous mutations 15. MMR inactivation is strongly associated with different types of tumors, including hereditary and sporadic renal carcinoma 16–22. Till now, these genes have been analyzed predominantly in the context of carcinogenesis and the evidence about MMR gene expression and function in different other pathologies, including DM, is missing.…”