&lt;p&gt;Novel variants of unknown significance in the &lt;em&gt;PMS2&lt;/em&gt; gene identified in patients with hereditary colon cancer&lt;/p&gt;

Liccardo, Raffaella; Ragione, Carlo Della; Mitilini, Nunzio; Rosa, Marina De; Izzo, Paola; Duraturo, Francesca

doi:10.2147/cmar.s167348

Cited by 10 publications

(7 citation statements)

References 26 publications

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“…29 A recent study demonstrated that PMS2 gene could manifest LS phenotype in other ways. 30 In addition, our study reported similar numbers of absent MLH1/PMS2 and MSH2/MSH6 proteins, and it may be associated with protein heterodimers, MSH2 dimerizes with MSH6 and MLH1 dimerizes with PMS2 form the functional complex Escherichia coli MutS homologs α (MutSα) and E.coli MutL homologs α (MutLα), respectively. 31 We were surprised to find that the combined deficiency of MSH2 and MSH6 proteins was higher than MSH6 protein alone.…”

Section: Discussionsupporting

confidence: 57%

<p>Evaluation of Concordance Between Deficient Mismatch Repair and Microsatellite Instability Testing and Their Association with Clinicopathological Features in Colorectal Cancer</p>

Bai¹,

Wang²,

Cheng³

et al. 2020

CMAR

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Background: Microsatellite instability (MSI) is one of the most important molecular characteristics of colorectal cancer (CRC), which mainly results from defective DNA mismatch repair (MMR). This study was performed to investigate the concordance between deficient MMR and MSI testing, and to evaluate the association of these two results with clinicopathological characteristics in Chinese CRC patients. Methods: A total of 738 CRC patients were included. Tumor tissues and paired peripheral blood specimens were obtained. Screening for MMR was investigated using immunohistochemical (IHC) technique, and multiple polymerase chain reaction-capillary electrophoresis (PCR-CE) method was performed to detect the MSI status. All clinicopathological data, immunohistochemistry and microsatellite instability analyses were then statistically analyzed. Results: Of the 738 (17.75%) CRC patients, 131 expressed as deficient mismatch repair (dMMR) status, and postmeiotic segregation increased 2 (PMS2) deficiency was the most frequent deficiency among these four MMR proteins. MSI-high (MSI-H) status occurred in 74 of the 738 (10.03%) CRC patients, 55 of whom showed instability at all six mononucleotides repeat markers. dMMR was significantly associated with MSI-H and moderate concordance was observed between IHC and PCR-CE in evaluating deficient MMR/MSI through Kappa test. Statistically, dMMR was significantly associated with younger age, right-sided colon and poor differentiation. MSI-H was associated with younger age, rightsided colon, poor differentiation, mucinous type and tumor, node, metastasis (TNM) stage II. Conclusion: A moderate concordance between deficient MMR and MSI testing indicates that both IHC and PCR-CE methods should be routinely tested to provide reliable data for clinical treatment decisions.

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Section: Discussionsupporting

confidence: 57%

<p>Evaluation of Concordance Between Deficient Mismatch Repair and Microsatellite Instability Testing and Their Association with Clinicopathological Features in Colorectal Cancer</p>

Bai¹,

Wang²,

Cheng³

et al. 2020

CMAR

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“…Recent studies have associated mutS homolog 3 (Msh3) variants, which play key roles in mismatch repair alongside other genes, with Lynch syndrome [45]. Our protein studies in GASH/Sal hamsters showed that the ability of the Msh3 variant to bind and therefore repair DNA may be considerably impaired, and hence the increase in Msh3 expression may be a cellular mechanism of compensation for its functional loss.…”

Section: Discussionmentioning

confidence: 85%

Analysis of gene variants in the GASH/Sal model of epilepsy

et al. 2020

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Epilepsy is a complex neurological disorder characterized by sudden and recurrent seizures, which are caused by various factors, including genetic abnormalities. Several animal models of epilepsy mimic the different symptoms of this disorder. In particular, the genetic audiogenic seizure hamster from Salamanca (GASH/Sal) animals exhibit sound-induced seizures similar to the generalized tonic seizures observed in epileptic patients. However, the genetic alterations underlying the audiogenic seizure susceptibility of the GASH/Sal model remain unknown. In addition, gene variations in the GASH/Sal might have a close resemblance with those described in humans with epilepsy, which is a prerequisite for any new preclinical studies that target genetic abnormalities. Here, we performed whole exome sequencing (WES) in GASH/Sal animals and their corresponding controls to identify and characterize the mutational landscape of the GASH/Sal strain. After filtering the results, moderate-and high-impact variants were validated by Sanger sequencing, assessing the possible impact of the mutations by "in silico" reconstruction of the encoded proteins and analyzing their corresponding biological pathways. Lastly, we quantified gene expression levels by RT-qPCR. In the GASH/Sal model, WES showed the presence of 342 variations, in which 21 were classified as high-impact mutations. After a full bioinformatics analysis to highlight the high quality and reliable variants, the presence of 3 high-impact and 15 moderate-impact variants were identified. Gene expression analysis of the high-impact variants of Asb14 (ankyrin repeat and SOCS Box Containing 14), Msh3 (MutS Homolog 3) and Arh-gef38 (Rho Guanine Nucleotide Exchange Factor 38) genes showed a higher expression in the GASH/Sal than in control hamsters. In silico analysis of the functional consequences indicated that those mutations in the three encoded proteins would have severe functional alterations. By functional analysis of the variants, we detected 44 significantly enriched pathways, including the glutamatergic synapse pathway. The data show three high-impact mutations with a major impact on the function of the proteins encoded by these genes, although no mutation in these three genes has been associated with some type of epilepsy until now. Furthermore, GASH/Sal animals also showed gene variants associated with different types of epilepsy that has been extensively documented, as well as mutations in other genes that PLOS ONE PLOS ONE | https://doi.

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“…This variant was identified in three affected patients with LS-related cancer. Point variants in other MMR genes (MLH1, MSH6, PMS2, MLH3, and MSH3) [8][9][10]20], and large rearrangements in these genes (MLH1, MSH2, MSH6, and PMS2) [11,12,21] were not identified in these patients. MSI analysis revealed instability in two dinucleotide repeats, D5S346 and D18S58 (of which only one repeat is of the Bethesda panel), and then a MSI-Low status.…”

Section: Discussionmentioning

confidence: 81%

“…LS is an autosomal dominant condition caused by a defect in one of the MMR genes and is characterized by a high lifetime risk of tumor development, especially colorectal cancer (20-70%), endometrial cancer (15-70%), and other extracolonic tumors (15%) [7]. The molecular characterization of LS patients relies on the identification of point mutations and large rearrangements in the coding regions of the MMR genes, MLH1, MSH2, PMS2, and MSH6 [8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

MSH2 Overexpression Due to an Unclassified Variant in 3’-Untranslated Region in a Patient with Colon Cancer

et al. 2020

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Background: The loss or low expression of DNA mismatch repair (MMR) genes can result in genomic instability and tumorigenesis. One such gene, MSH2, is mutated or rearranged in Lynch syndrome (LS), which is characterized by a high risk of tumor development, including colorectal cancer. However, many variants identified in this gene are often defined as variants of uncertain significance (VUS). In this study, we selected a variant in the 3′ untranslated region (UTR) of MSH2 (c*226A > G), identified in three affected members of a LS family and already reported in the literature as a VUS. Methods: The effect of this variant on the activity of the MMR complex was examined using a set of functional assays to evaluate MSH2 expression. Results: We found MSH2 was overexpressed compared to healthy controls, as determined by RTqPCR and Western blot analyses of total RNA and proteins, respectively, extracted from peripheral blood samples. These results were confirmed by luciferase reporter gene assays. Conclusions: We therefore speculated that, in addition to canonical inactivation via a gene mutation, MMR activity may also be modulated by changes in MMR gene expression.

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<p>Novel variants of unknown significance in the <em>PMS2</em> gene identified in patients with hereditary colon cancer</p>

Cited by 10 publications

References 26 publications

<p>Evaluation of Concordance Between Deficient Mismatch Repair and Microsatellite Instability Testing and Their Association with Clinicopathological Features in Colorectal Cancer</p>

<p>Evaluation of Concordance Between Deficient Mismatch Repair and Microsatellite Instability Testing and Their Association with Clinicopathological Features in Colorectal Cancer</p>

Analysis of gene variants in the GASH/Sal model of epilepsy

MSH2 Overexpression Due to an Unclassified Variant in 3’-Untranslated Region in a Patient with Colon Cancer

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