Incomplete Segregation of MSH6 Frameshift Variants with Phenotype of Lynch Syndrome

Liccardo, Raffaella; Rosa, Marina De; Rossi, Giovanni Battista; Carlomagno, Nicola; Izzo, Paola; Duraturo, Francesca

doi:10.3390/ijms18050999

Cited by 15 publications

(16 citation statements)

References 42 publications

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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%

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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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Section: Discussionmentioning

confidence: 81%

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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“…The antibodies used were anti-MSH6, mouse monoclonal clone 44; anti-MSH2, mouse monoclonal clone G219-1129; anti-MLH1, mouse monoclonal clone M1 (Ventana); and anti-PMS2. The procedure was performed as described previously on sections of colon cancer tissues 9…”

Section: Methodsmentioning

confidence: 99%

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

Liccardo¹,

Ragione²,

Mitilini³

et al. 2019

CMAR

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Background: Lynch syndrome is associated with genetic variants in mismatch repair ( MMR ) genes. Pathogenic variants in the MLH1 and MSH2 genes occur in most families in which the phenotype is highly penetrant. These testing criteria are likely to miss individuals with Lynch syndrome due to the less penetrant MMR genes, such as MSH6, MLH3, MSH3, and PMS2 . So far, several mutations in the PMS2 gene have been described as responsible for the clinical manifestation of Lynch syndrome. Recent data have reported that families with atypical Lynch phenotype were found to have primarily monoallelic mutations in the PMS2 gene. Methods: We analyzed the PMS2 gene to detect mutations in members of 64 Lynch syndrome families by direct sequencing. Results: We report the identification of several genetic variants in patients with LS, of which three are novel variants. The carriers of these novel variants were also carried of other variants in PMS2 gene and/or in other MMR genes. Conclusion: Therefore, we think that these novel PMS2 variants may act in additive manner to manifestation LS phenotype.

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“…LS is associated with mutations in MMR genes. Most of mutations were found in the MLH1 and MSH2 genes that account for about 50 and 40% respectively of all mutations reported; about 15–20% of mutations were identified in the MSH6 and in PMS2 (33,34); few pathogenetic mutations were identified in MLH3 (15) gene and so far, only one heterozygous variant in MSH3 gene was associated with LS phenotype (16). The most pathogenetic variants in MMR genes are small insertions/deletions or large genetic rearrangements (large deletions/insertions) that, at protein level, result in premature stop codon formation (35,36).…”

Section: Clinical Diagnosis and Molecular Analysis Of Lynch Syndromementioning

confidence: 99%

“…This approach is based on the evaluation of both phenotipic and functional features (9,39). In particular, the segregation analysis should be considered the ‘gold standard’ for the validation of VUS pathogenecity (34,39).…”

Section: Clinical Diagnosis and Molecular Analysis Of Lynch Syndromementioning

confidence: 99%

Genetics, diagnosis and treatment of Lynch syndrome: Old lessons and current challenges (Review)

et al. 2019

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Lynch syndrome (LS) is an autosomal dominant genetic disorder associated with germline mutations in DNA mismatch repair (MMR) genes. The carriers of pathogenic mutations in these genes have an increased risk of developing a colorectal cancer and/or LS-associated cancer. The LS-associated cancer types include carcinomas of the endometrium, small intestine, stomach, pancreas and biliary tract, ovary, brain, upper urinary tract and skin. The criteria for the clinical diagnosis of LS and the procedures of the genetic testing for identification of pathogenetic mutations carriers in MMR genes have long been known. A crucial point in the mutation detection analysis is the correct definition of the pathogenecity associated with MMR genetic variants, especially in order to include the mutation carriers in the endoscopy surveillance programs more suited to them. Therefore, this may help to improve the LS-associated cancer prevention programs. In the present review, we also report the recent discoveries in molecular genetics of LS, such as the new roles of MMR protein and immune response of MMR repair deficiency in colorectal cancer. Finally, we discuss the main therapeutic approaches, including immunotherapy, which represent a valid alternative to traditional therapeutic methods and extend the life expectancy of patients that have already developed LS-associated colorectal cancer.

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Incomplete Segregation of MSH6 Frameshift Variants with Phenotype of Lynch Syndrome

Cited by 15 publications

References 42 publications

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

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

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

Genetics, diagnosis and treatment of Lynch syndrome: Old lessons and current challenges (Review)

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