First description of mutational analysis of MLH1, MSH2 and MSH6 in Algerian families with suspected Lynch syndrome

Ziada-Bouchaar, Hadia; Sifi, Karima; Filali, T.; Hammada, T.; Satta, Dalila; Abadi, N.

doi:10.1007/s10689-016-9917-1

Cited by 9 publications

(7 citation statements)

References 43 publications

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“…In addition, a team in our lab have identi ed in a LS family with discordant twins, an MSH2 pathogenic mutation (c.1552C > T;p.Q518X) previously reported only in a Portuguese LS family and shared with all investigated family members suggesting that this variant is a causal mutation [28]. Furthermore, an Algerian recent study have reported the MSH2 (c.728G > A) mutation in two cases (44 and 38 years old) with CCR belonging to the same family [61]. MSH2 (c.728G > A) variant seems to be identi ed only in Mediterranean countries.…”

Section: Discussionmentioning

confidence: 79%

A rare MSH2 variant as a candidate marker for Lynch Syndrome II screening in Tunisia: A case of Diffuse Gastric Carcinoma

Kabbage¹,

Aissa-Haj²,

Othman³

et al. 2021

Preprint

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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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Section: Discussionmentioning

confidence: 79%

A rare MSH2 variant as a candidate marker for Lynch Syndrome II screening in Tunisia: A case of Diffuse Gastric Carcinoma

Kabbage¹,

Aissa-Haj²,

Othman³

et al. 2021

Preprint

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“…The hallmark of the syndrome is the presence of microsatellite instability (MSI) in the tumor. Several studies from the Middle East reported Lynch syndrome families, and the clinical features of Lynch syndrome families appear to be similar to those seen in Western families [ 4 ].…”

Section: What Proportion Of Crc In the Middle East Is Familial Or Hermentioning

confidence: 99%

A new hereditary colorectal cancer network in the Middle East and eastern mediterranean countries to improve care for high-risk families

et al. 2017

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Colorectal cancer (CRC) has a very high incidence in the western world. Data from registries in the Middle East showed that the incidence of CRC is relatively low in these countries. However, these data also showed that CRC incidence has increased substantially over the past three decades and that a high proportion of cases are diagnosed at an early age (<50 years). In view of these findings, more attention should be paid to prevention. Because of the often limited financial resources, focused screening of individuals with hereditary CRC, in particular those with Lynch syndrome, appears to be the most cost-effective strategy. During recent meetings of the Palestinian Society of Gastroenterology and the Mediterranean Task force for Cancer Control (MTCC) in Jericho, and the Patient’s Friends Society of Jerusalem in Hebron the issue of hereditary CRC in the Middle East was discussed and the idea was conceived to establish a network on hereditary colorectal cancer (HCCN-ME) with the goal of improving care for high-risk groups in the Middle East and (Eastern) Mediterranean Countries.

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“…In addition, a team in our lab have identified in a LS family with discordant twins, an MSH2 pathogenic mutation (c.1552C>T;p.Q518X) previously reported only in a Portuguese LS family and shared with all investigated family members suggesting that this variant is a causal mutation [ 29 ]. In addition, an Algerian recent study have screened MLH1 , MSH2 and MSH6 genes among 21 families from East of Algeria and have identified the MSH2 (c.728G>A) mutation in two cases (44 and 38 years old) with CCR belonging to the same family with colon cancer family history [ 62 ]. The MSH2 (c.728G>A) variant seems to be identified only in Mediterranean countries.…”

Section: Discussionmentioning

confidence: 99%

A Rare MSH2 Variant as a Candidate Marker for Lynch Syndrome II Screening in Tunisia: A Case of Diffuse Gastric Carcinoma

Kabbage

Aissa-Haj

Othman

et al. 2022

Genes

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Several syndromic forms of digestive cancers are known to predispose to early-onset gastric tumors such as Hereditary Diffuse Gastric Cancer (HDGC) and Lynch Syndrome (LS). LSII 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 of both HDGC and LS II syndromes. We selected the index case “JI-021”, which was a woman diagnosed with a Diffuse Gastric Carcinoma and fulfilling the international guidelines for both HDGC and LSII syndromes. For DNA repair, a custom panel targeting 87 candidate genes recovering the four DNA repair pathways was used. Structural bioinformatics analysis was conducted to predict the effect of the revealed variants on the functional properties of the proteins. DNA repair genes panel screening identified two variants: a rare MSH2 c.728G>A classified as a variant with uncertain significance (VUS) and a novel FANCD2 variant c.1879G>T. The structural prediction model of the MSH2 variant 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. It 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. Our results showed that the MSH2 p.R243Q variant is likely pathogenic and is involved in the MSH2-MLH1 complex stability, and molecular modeling analysis highlights 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 the Mediterranean region. These findings emphasize the importance of testing DNA repair genes for patients diagnosed with diffuse GC with suspicion of LSII and colorectal cancer allowing better clinical surveillance for more personalized medicine.

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First description of mutational analysis of MLH1, MSH2 and MSH6 in Algerian families with suspected Lynch syndrome

Cited by 9 publications

References 43 publications

A rare MSH2 variant as a candidate marker for Lynch Syndrome II screening in Tunisia: A case of Diffuse Gastric Carcinoma

A rare MSH2 variant as a candidate marker for Lynch Syndrome II screening in Tunisia: A case of Diffuse Gastric Carcinoma

A new hereditary colorectal cancer network in the Middle East and eastern mediterranean countries to improve care for high-risk families

A Rare MSH2 Variant as a Candidate Marker for Lynch Syndrome II Screening in Tunisia: A Case of Diffuse Gastric Carcinoma

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