Implication of DNA repair genes in Lynch-like syndrome

Xicola, Rosa M.; Clark, Julia; Carroll, Timothy; Alvikas, Jurgis; Marwaha, Priti; Regan, Meredith M.; López-Giráldez, Francesc; Choi, Jungmin; Emmadi, Rajyasree; Alagiozian-Angelova, Victoria; Kupfer, Sonia S.; Ellis, Nathan A.; Llor, Xavier

doi:10.1007/s10689-019-00128-6

Cited by 29 publications

(31 citation statements)

References 44 publications

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“…By performing MCM8 gene editing in a cellular model and ectopic reintroduction of the identified genetic variants, we were able to demonstrate its plausible effect on DNA repair efficiency. Besides, although several genes implicated in DNA repair are spotlighted as probable causes of the underlying mechanisms of LLS CRC ( 24 ), this study differs from previous reports in the fact of performing a thorough functional characterization of the proposed candidate gene. Additionally, although HR and MMR systems are inextricably linked ( 25 ), we were capable of suggesting that both systems could be impaired by biallelic pathogenic variants in MCM8 .…”

Section: Discussionmentioning

confidence: 73%

Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome

Golubicki¹,

Bonjoch²,

Acuña-Ochoa³

et al. 2020

JCI Insight

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Section: Discussionmentioning

confidence: 73%

Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome

Golubicki¹,

Bonjoch²,

Acuña-Ochoa³

et al. 2020

JCI Insight

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“…Other candidate genes with potentially pathogenic germline variants reported in patients with MSI/dMMR tumors (without germline MMR gene mutations) include MSH3 , EXO1, FAN1 , MLH3 , POLD1 , RFC1 , RPA1, SETD2 , BUB1 , BARD1 , WRN , MCPH1 , and REV3L [ 214 , 215 , 216 , 217 , 218 ]. MSH3 biallelic variants leading to MSH3 deficiency are associated with the microsatellite instability of di- and tetranucleotides (EMAST, Elevated Microsatellite instability at Selected Tetranucleotide Repeats) [ 214 ] but the stability of mononucleotide repeats.…”

Section: Diagnosis Of Lynch Syndromementioning

confidence: 99%

Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors

Leclerc

Vermaut²,

Buisine

2021

Cancers

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Microsatellite instability (MSI) is a hallmark of Lynch syndrome (LS)-related tumors but is not specific to it, as approximately 80% of MSI/mismatch repair-deficient (dMMR) tumors are sporadic. Methods leading to the diagnosis of LS have considerably evolved in recent years and so have tumoral tests for LS screening and for the discrimination of LS-related to MSI-sporadic tumors. In this review, we address the hallmarks of LS, including the clinical, histopathological, and molecular features. We present recent advances in diagnostic and screening strategies to identify LS patients. We also discuss the pitfalls associated with the current strategies, which should be taken into account to improve the diagnosis of LS and avoid inappropriate clinical management.

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“…The defects are often caused by mutations in the coding regions of MMR genes or by the promoter methylation of these genes. However, in many cases, despite the presence of a hypermutable phenotype in a patient, no mutations/hypermethylation of MMR genes can be detected [14,15].…”

Section: Of 10mentioning

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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Implication of DNA repair genes in Lynch-like syndrome

Cited by 29 publications

References 44 publications

Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome

Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome

Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors

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

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