Identification of novel pathogenic MSH2 mutation and new DNA repair genes variants: investigation of a Tunisian Lynch syndrome family with discordant twins

Abstract BACKGROUND Inherited syndromic forms of digestive cancers with age occurrence before 50 seem to be relatively in higher proportions in Tunisia suggesting genetic susceptibility. Several syndromic forms are known to predispose to early onset gastric tumors such as Hereditary Diffuse Gastric Cancer (HDGC) and Lynch Syndrome (LS). LS II is an extracolonic cancer syndrome characterized by a tumor spectrum including gastric cancer (GC). In the current work, our main aim was to identify the mutational spectrum underlying the genetic predisposition to diffuse gastric tumors occurring in a Tunisian family suspected with both HDGC and LS II syndromes. PATIENTS AND METHODS The index case was a woman diagnosed with Diffuse Gastric Carcinoma (DGC) fulfilling the international guidelines for both HDGC and LSII syndromes. Genomic DNA was used for the search of CDH1 and CTNNA1 germ mutations. We performed, also a DNA repair custom panel targeting candidate genes recovering the four DNA repair systems. Structural bioinformatics analysis was conducted to predict the effect of the revealed mutations. RESULTS No deleterious variants have been identified neither in CDH1 nor in CTNNA1 coding and their flanking regions. DNA repair genes panel screening identified two variants: a rare MSH2 c.728G > A classified as a variant with uncertain significance and a novel FANCD2 variant c.1879G > T. The structural prediction model of MSH2 mutation and electrostatic potential calculation showed for the first time that MSH2 c.728G > A is likely pathogenic and is involved in the MSH2-MLH1 complex stability. This mutation appears to affect the MSH2-MLH1 complex as well as DNA-complex stability. The c.1879G > T FANCD2 variant was predicted to destabilize the protein structure. CONCLUSIONS Our results showed that MSH2 p.R243Q variant is likely pathogenic and is involved in the MSH2-MLH1 complex stability with a putative impact on the binding with MLH1 by disrupting the electrostatic potential suggesting the revision of its status from VUS to likely pathogenic. This variant seems to be a shared variant in Mediterranean region. These findings emphasize the importance of testing DNA repair genes for patients diagnosed with DGC with suspicion of LSII as well as colorectal cancer allowing better clinical surveillance for more personalized medicine.

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Truncating variants in DNA-repair genes and their effect on AAO of hereditary breast cancer

10.1055/s-0038-1651801 ◽

2018 ◽

Author(s):

I Sepahi ◽

U Faust ◽

M Sturm ◽

K Bosse ◽

M Kehrer ◽

...

Keyword(s):

Breast Cancer ◽

Dna Repair ◽

Hereditary Breast Cancer ◽

Dna Repair Genes ◽

Repair Genes

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Comprehensive Analyses of Copy Number Variations In DNA Repair Genes Reveal the Role of Poly(ADP-Ribose) Polymerase in Longevity in Trees

SSRN Electronic Journal ◽

10.2139/ssrn.3751787 ◽

2020 ◽

Author(s):

Yuta Aoyagi Blue ◽

Junko Kusumi ◽

Akiko Satake

Keyword(s):

Dna Repair ◽

Copy Number ◽

Copy Number Variations ◽

Dna Repair Genes ◽

Repair Genes

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Copy number analyses of DNA repair genes reveal the role of poly(ADP-ribose) polymerase (PARP) in tree longevity

iScience ◽

10.1016/j.isci.2021.102779 ◽

2021 ◽

pp. 102779

Author(s):

Yuta Aoyagi Blue ◽

Junko Kusumi ◽

Akiko Satake

Keyword(s):

Dna Repair ◽

Copy Number ◽

Dna Repair Genes ◽

Repair Genes

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Coexistence of SOS-Dependent and SOS-Independent Regulation of DNA Repair Genes in Radiation-Resistant Deinococcus Bacteria

Cells ◽

10.3390/cells10040924 ◽

2021 ◽

Vol 10 (4) ◽

pp. 924

Author(s):

Laurence Blanchard ◽

Arjan de Groot

Keyword(s):

Dna Repair ◽

Deinococcus Radiodurans ◽

Dna Repair Genes ◽

Lesion Bypass ◽

Radiation Resistant ◽

Radiation Induced ◽

Induced Mutagenesis ◽

High Doses ◽

Translesion Polymerases ◽

Repair Genes

Deinococcus bacteria are extremely resistant to radiation and able to repair a shattered genome in an essentially error-free manner after exposure to high doses of radiation or prolonged desiccation. An efficient, SOS-independent response mechanism to induce various DNA repair genes such as recA is essential for radiation resistance. This pathway, called radiation/desiccation response, is controlled by metallopeptidase IrrE and repressor DdrO that are highly conserved in Deinococcus. Among various Deinococcus species, Deinococcus radiodurans has been studied most extensively. Its genome encodes classical DNA repair proteins for error-free repair but no error-prone translesion DNA polymerases, which may suggest that absence of mutagenic lesion bypass is crucial for error-free repair of massive DNA damage. However, many other radiation-resistant Deinococcus species do possess translesion polymerases, and radiation-induced mutagenesis has been demonstrated. At least dozens of Deinococcus species contain a mutagenesis cassette, and some even two cassettes, encoding error-prone translesion polymerase DnaE2 and two other proteins, ImuY and ImuB-C, that are probable accessory factors required for DnaE2 activity. Expression of this mutagenesis cassette is under control of the SOS regulators RecA and LexA. In this paper, we review both the RecA/LexA-controlled mutagenesis and the IrrE/DdrO-controlled radiation/desiccation response in Deinococcus.

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Patients with Systemic Sclerosis Present Increased DNA Damage Differentially Associated with DNA Repair Gene Polymorphisms

The Journal of Rheumatology ◽

10.3899/jrheum.130376 ◽

2014 ◽

Vol 41 (3) ◽

pp. 458-465 ◽

Cited By ~ 11

Author(s):

Gustavo Martelli Palomino ◽

Carmen L. Bassi ◽

Isabela J. Wastowski ◽

Danilo J. Xavier ◽

Yara M. Lucisano-Valim ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Systemic Sclerosis ◽

Blood Cells ◽

Gene Polymorphisms ◽

Peripheral Blood Cells ◽

Dna Repair Genes ◽

Repair Gene ◽

Dna Repair Gene ◽

Repair Genes

Objective.Patients with systemic sclerosis (SSc) exhibit increased toxicity when exposed to genotoxic agents. In our study, we evaluated DNA damage and polymorphic sites in 2 DNA repair genes (XRCC1Arg399Gln andXRCC4Ile401Thr) in patients with SSc.Methods.A total of 177 patients were studied for DNA repair gene polymorphisms. Fifty-six of them were also evaluated for DNA damage in peripheral blood cells using the comet assay.Results.Compared to controls, the patients as a whole or stratified into major clinical variants (limited or diffuse skin involvement), irrespective of the underlying treatment schedule, exhibited increased DNA damage.XRCC1(rs: 25487) andXRCC4(rs: 28360135) allele and genotype frequencies observed in patients with SSc were not significantly different from those observed in controls; however, theXRCC1Arg399Gln allele was associated with increased DNA damage only in healthy controls and theXRCC4Ile401Thr allele was associated with increased DNA damage in both patients and controls. Further, theXRCC1Arg399Gln allele was associated with the presence of antinuclear antibody and anticentromere antibody. No association was observed between these DNA repair gene polymorphic sites and clinical features of patients with SSc.Conclusion.These results corroborate the presence of genomic instability in SSc peripheral blood cells, as evaluated by increased DNA damage, and show that polymorphic sites of theXRCC1andXRCC4DNA repair genes may differentially influence DNA damage and the development of autoantibodies.

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