A new strategy to screen MMR genes in Lynch Syndrome: HA-CAE, MLPA and RT-PCR

2009 ◽  
Vol 45 (8) ◽  
pp. 1485-1493 ◽  
Author(s):  
Lucia Perez-Cabornero ◽  
Eladio Velasco ◽  
Mar Infante ◽  
David Sanz ◽  
Enrique Lastra ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Rt Pcr ◽  
Mmr Genes ◽  
New Strategy

scholarly journals Insertion of an SVA Element in MSH2 as a Novel Cause of Lynch Syndrome

2020 ◽  
Author(s):  
Ciyu Yang ◽  
Yirong Li ◽  
Magan Trottier ◽  
Michael Farrell ◽  
Vikas Rai ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Pcr Analysis ◽  
Rt Pcr ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Antisense Orientation ◽  
The Family ◽  
Long Range Pcr ◽  
Early Onset Colorectal Cancer ◽  
Generation Sequencing

Germline mutations in the DNA mismatch repair (MMR) genes cause Lynch syndrome (LS). Insertions of retrotransposons in MMR genes have been reported as a rare cause of LS. Here, we present a novel SINE-VNTR-Alu (SVA) insertion in exon 12 of MSH2 in an individual with early-onset colorectal cancer and strong LS family history. RT-PCR analysis indicated a larger aberrant MSH2 transcript in one of the family members. MSK-IMPACT next-generation sequencing testing and long-range PCR revealed an insertion in MSH2 exon 12 at the c.1972 position in an antisense orientation. The insertion was further characterized as an SVA element approximately 3 kb in length, belonging to the SVA_F1 family of retrotransposons.

scholarly journals Diagnostic Application ofhMLH1Methylation in Hereditary Non-Polyposis Colorectal Cancer

2004 ◽  
Vol 20 (4-5) ◽  
pp. 277-282 ◽  
Author(s):  
Nagahide Matsubara
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Genetic Test ◽  
Screening Program ◽  
Immunohistochemical Analysis ◽  
Germline Mutations ◽  
Clinical Criteria ◽  
Pathological Analysis ◽  
Mmr Genes ◽  
New Strategy

Colorectal cancer (CRC) due to mismatch repair (MMR) defect has distinct characteristics among unselected CRCs. These CRCs are biologically less aggressive and, thus, showing better prognosis but less sensitive to the 5FU-based chemotherapy. CRCs with MMR defect derive from both hereditary and sporadic reasons. Germline inactivation of MMR genes (hMLH1, hMSH2, hMSH6, andhPMS2) underlies the hereditary CRC with MMR defect (Lynch syndrome) and epigenetic silencing ofhMLH1gene causes the sporadic CRC with MMR defect. Hereditary and sporadic CRC with MMR defect can be detectable by microsatellite instability (MSI) test or immunohistochemical analysis among general CRCs. Lynch syndrome can be diagnosed by the clinical criteria or by genetic test to detect pathogenic germline mutations in MMR genes. However, both clinical criteria and genetic test are inadequate for the diagnosis of Lynch syndrome. Since genetic test for the diagnosis of the Lynch syndrome is expensive and not always identify pathogenic germline mutations, effective and inexpensive screening program is desirable. Here we propose a possible application of methylation test combined with MSI or pathological analysis as an effective and a cost-saving new strategy for screening of Lynch syndrome.

scholarly journals A rare large duplication of MLH1 identified in Lynch syndrome

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Abhishek Kumar ◽  
Nagarajan Paramasivam ◽  
Obul Reddy Bandapalli ◽  
Matthias Schlesner ◽  
Tianhui Chen ◽  
...  
Keyword(s):  
Amino Acid ◽  
Lynch Syndrome ◽  
Splice Site ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Splice Donor Site ◽  
Laboratory Diagnostics ◽  
Mmr Genes ◽  
Base Pair Deletion ◽  
Splice Site Variant

Abstract Background The most frequently identified strong cancer predisposition mutations for colorectal cancer (CRC) are those in the mismatch repair (MMR) genes in Lynch syndrome. Laboratory diagnostics include testing tumors for immunohistochemical staining (IHC) of the Lynch syndrome-associated DNA MMR proteins and/or for microsatellite instability (MSI) followed by sequencing or other techniques, such as denaturing high performance liquid chromatography (DHPLC), to identify the mutation. Methods In an ongoing project focusing on finding Mendelian cancer syndromes we applied whole-exome/whole-genome sequencing (WES/WGS) to 19 CRC families. Results Three families were identified with a pathogenic/likely pathogenic germline variant in a MMR gene that had previously tested negative in DHPLC gene variant screening. All families had a history of CRC in several family members across multiple generations. Tumor analysis showed loss of the MMR protein IHC staining corresponding to the mutated genes, as well as MSI. In family A, a structural variant, a duplication of exons 4 to 13, was identified in MLH1. The duplication was predicted to lead to a frameshift at amino acid 520 and a premature stop codon at amino acid 539. In family B, a 1 base pair deletion was found in MLH1, resulting in a frameshift and a stop codon at amino acid 491. In family C, we identified a splice site variant in MSH2, which was predicted to lead loss of a splice donor site. Conclusions We identified altogether three pathogenic/likely pathogenic variants in the MMR genes in three of the 19 sequenced families. The MLH1 variants, a duplication of exons 4 to 13 and a frameshift variant, were novel, based on the InSiGHT and ClinVar databases; the MSH2 splice site variant was reported by a single submitter in ClinVar. As a variant class, duplications have rarely been reported in the MMR gene literature, particularly those covering several exons.

Inflammatory Chemokines Expression Variations and Their Receptors in APP/PS1 Mice

2021 ◽  
pp. 1-10
Author(s):  
Adrián Jorda ◽  
Martin Aldasoro ◽  
Constanza Aldasoro ◽  
Soraya L. Valles
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Chemokine Receptors ◽  
Presenilin 1 ◽  
Wild Type ◽  
Rt Pcr ◽  
New Strategy ◽  
Inflammatory Chemokines ◽  
Inflammatory Changes ◽  
Old Mice

Background: In Alzheimer’s disease (AD), an increase in inflammation is distinctive. Amyloid precursor protein plus presenilin-1 (APP/PS1 mice) is a model for this illness. Chemokines secreted by central nervous system (CNS) cells could play multiple important roles in AD. Data looking for the chemokines involved in inflammatory mechanisms are lacking. To understand the changes that occur in the inflammation process in AD, it is necessary to improve strategies to act on specific inflammatory targets. Objective: Chemokines and their receptors involved in phagocytosis, demyelination, chemotaxis, and coagulation were the objective of our study. Methods: Female APPswe/PS1 double-transgenic mice (B6C3-Tg) were used and cortex brain from 20–22-month-old mice obtained and used to quantify chemokines and chemokine receptors expression using RT-PCR technique. Results: Significant inflammatory changes were detected in APP/PS1 compared to wild type mice. CCR1, CCR3, CCR4, and CCR9 were elevated, and CCR2 were decreased compared with wild type mice. Their ligands CCL7, CCL11, CCL17, CCL22, CCL25, and CXCL4 showed an increase expression; however, changes were not observed in CCL2 in APP/PS1 compared to wild type mice. Conclusion: This change in expression could explain the differences between AD patients and elderly people without this illness. This would provide a new strategy for the treatment of AD, with the possibility to act in specific inflammatory targets.

scholarly journals Early detection of superspreaders by mass group pool testing can mitigate COVID-19 pandemic

2020 ◽  
Author(s):  
Maxim B Gongalsky
Keyword(s):  
New York ◽  
Early Detection ◽  
Group Testing ◽  
Scale Model ◽  
Rt Pcr ◽  
Infected People ◽  
Group Matrix ◽  
New Strategy ◽  
Mass Group ◽  
Log Normal

Background Most of epidemiological models applied for COVID-19 do not consider heterogeneity in infectiousness and impact of superspreaders, despite the broad viral loading distributions amongst COVID-19 positive people (1-1 000 000 per mL). Also, mass group testing is not used regardless to existing shortage of tests. I propose new strategy for early detection of superspreaders with reasonable number of RT-PCR tests, which can dramatically mitigate development COVID-19 pandemic and even turn it endemic. Methods I used stochastic social-epidemiological SEIAR model, where S-suspected, E-exposed, I-infectious, A-admitted (confirmed COVID-19 positive, who are admitted to hospital or completely isolated), R-recovered. The model was applied to real COVID-19 dynamics in London, Moscow and New York City. Findings Viral loading data measured by RT-PCR were fitted by broad log-normal distribution, which governed high importance of superspreaders. The proposed full scale model of a metropolis shows that top 10% spreaders (100+ higher viral loading than median infector) transmit 45% of new cases. Rapid isolation of superspreaders leads to 4-8 fold mitigation of pandemic depending on applied quarantine strength and amount of currently infected people. High viral loading allows efficient group matrix pool testing of population focused on detection of the superspreaders requiring remarkably small amount of tests. Interpretation The model and new testing strategy may prevent thousand or millions COVID-19 deaths requiring just about 5000 daily RT-PCR test for big 12 million city such as Moscow. Though applied to COVID-19 pandemic the results are universal and can be used for other infectious heterogenous epidemics. Funding No funding

Mutations in Non-MMR Genes Modifying or Mimicking Lynch Syndrome Phenotype

2013 ◽  
pp. 135-169
Author(s):  
Mala Pande ◽  
Jinyun Chen ◽  
Chongjuan Wei ◽  
Yu-Jing Huang ◽  
Marsha L. Frazier
Keyword(s):  
Lynch Syndrome ◽  
Mmr Genes

SVA retrotransposon insertion in exon of MMR genes results in aberrant RNA splicing and causes Lynch syndrome

2020 ◽  
Author(s):  
Gou Yamamoto ◽  
Izumi Miyabe ◽  
Keisuke Tanaka ◽  
Miho Kakuta ◽  
Motoko Watanabe ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Rna Splicing ◽  
Mmr Genes ◽  
Retrotransposon Insertion ◽  
Aberrant Rna

Overlooking MMR deficiency in carriers of certain pathogenic variants by routine MSI and/or IHC testing in Lynch syndrome: Implications for a wider MMR deficiency testing.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16107-e16107
Author(s):  
Marija Staninova Stojovska ◽  
Katerina Kubelka Sabit ◽  
Dzengis Jasar ◽  
Rubens Jovanovic ◽  
Nadica Matevska ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Positive Result ◽  
Splice Site Mutation ◽  
The Other ◽  
Sporadic Colorectal Cancer ◽  
Site Mutation ◽  
Potential Implication ◽  
Mmr Genes ◽  
Pathogenic Variants ◽  
Mmr Deficiency

e16107 Background: DNA mismatch repair (MMR) deficiency occurs in both inherited/sporadic colorectal cancer (CRC) and endometrial cancer, but it may also be found in some other types of cancer. At present, MMR status testing in clinical practice is recommended for all CRC patients in order to identify those who should be offered genetic testing for the Lynch syndrome (LS), inform disease prognosis, and guide therapeutic management.There are two commonly accepted methods for MMR deficiency analysis, one based on the detection of microsatellite instability (MSI) by PCR and the other based on the detection of protein expression of the MMR genes using immunohistochemistry (IHC). The objective of this study was to evaluate the concordance between IHC and MSI in tumors from 18 LS patients with known pathogenic germline variants in MMR genes (MLH1, MSH2, PMS2 and MSH6). Methods: The MSI testing was performed using the five gene Bethesda panel (BAT25, BAT26, D2S123, D5S346, D17S250) while the IHC testing was done with the use of a standard 4 antibody panel (MLH1, MSH2, PMS2 and MSH6). Results: High concordance of the two methods was observed in 13/18 (72.2%) patients, mainly with disruptive mutations in the МLH1, MSH2 and PMS2 genes. Inconsistent results were obtained in 5/18 (28.8%) patients, of whom two had a positive result only with the use of the PCR method [carriers of MLH1 c.62C > T (p.Ala21Val) and c.244A > G (p.Thr82Ala) missense variants], other two had a positive result only with IHC [carriers of MSH6 c.3514dupA (p.Arg1172LysfsTer5) and c.2384T > C (p.Ile795Thr)] and one patient had normal results using both methods (carrier of MSH6 c.457+1G > T splice site mutation that results in exon 3 skipping). A positive predictive value of either MSI or IHC used as a single methods for screening was 83.3%, which indicates that a substantial number of cases with MMR tumors can be misdiagnosed by using only either one or the other of these two methods. Conclusions: These results have a potential implication not only for LS screening in CRC patients, but also for the detection of the MMR deficiency in patients with various tumors that might benefit from the checkpoint inhibitor immunotherapy. The use of extended MSI NGS panels might provide a higher sensitivity for the detection of MMR deficiency compared to the standard MSI or ICH testing.

Genetic identification and characterization of Lynch syndrome in a multi-ethnic biobank.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1520-1520
Author(s):  
Rachel Rosenblum ◽  
Sabrina A. Suckiel ◽  
Gillian M. Belbin ◽  
Sinead Cullina ◽  
Judy H. Cho ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Diagnostic Criteria ◽  
Sequence Data ◽  
Genetic Identification ◽  
European Ancestry ◽  
Gene Variants ◽  
Loss Of Function ◽  
Mmr Genes ◽  
Pathogenic Variants ◽  
Increased Risk

1520 Background: Lynch syndrome (LS), caused by germline pathogenic variants in mismatch repair (MMR) genes, results in increased risk of colorectal, endometrial, and other cancers. LS has a prevalence of ~1 in 440 in European ancestry populations; prevalence data in other populations are limited. We identified and characterized carriers of pathogenic MMR gene variants in the multi-ethnic Bio Me Biobank in New York City. Methods: Exome sequence data from ~31,000 Bio Me participants were evaluated for known (per ClinVar) and predicted (loss-of-function) pathogenic variants in MMR genes. Population groups were defined by genetic ancestry. Participant questionnaires and electronic health records (EHRs) of carriers were reviewed for personal or family history of malignancy. Results: We identified 48 carriers of 33 distinct pathogenic variants in PMS2 (48%), MLH1 (27%), MSH6 (15%), and MSH2 (10%), for an estimated prevalence of ~1/640 in the Bio Me Biobank. Prevalence was higher among individuals of Non-Jewish European (N = 14; 1/400) and African (N = 14; 1/490) ancestries, compared to Puerto Rican (N = 8; 1/640), Ashkenazi Jewish (N = 6; 1/690), and other/mixed (N = 6) ancestries. Carriers had a median age of 56 (range 27 to 77) years and were 50% female. Overall rate of malignancy among carriers was 38%, with the lowest rate in PMS2 (26%) and the highest rate in MSH6 (57%) variant carriers. We found a high prevalence of endometrial cancer (21% of female carriers) and a lower prevalence of colorectal cancer (4% of all carriers). Only 2 carriers (4%) had a diagnosis of LS in their EHRs, and only 1 carrier met Amsterdam diagnostic criteria for LS. Conclusions: These data show that ~0.15% of participants in a multi-ethnic biobank are carriers of pathogenic MMR gene variants and suggest that the prevalence is higher in European and lower in non-European ancestry populations. Notably, most carriers do not have a clinical diagnosis of LS and do not meet diagnostic criteria for LS. Carriers demonstrate variable rates of cancer, which may contribute to under-diagnosis of LS. Genomic screening for pathogenic MMR variants may lead to earlier diagnosis of LS and improved outcomes.

scholarly journals Lynch syndrome I: A case report

2008 ◽  
Vol 61 (1-2) ◽  
pp. 79-82
Author(s):  
Vesna Zivkovic ◽  
Vuka Katic ◽  
Jasmina Gligorijevic ◽  
Zlatibor Andjelkovic ◽  
Aleksandar Petrovic ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Case Report ◽  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Clinical Stage ◽  
Family Members ◽  
Advanced Rectal Cancer ◽  
Degree Relative ◽  
Mmr Genes ◽  
Amsterdam Criteria

Introduction. Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndromes J and II, accounts for about 5-8% of colorectal cancers. Lynch syndrome I is an autosomal domi?nant inherited disorder characterized by early onset of colorectal cancer, predominance of proximal and multiple tumors, and microsatellite instability. In order to identify HNPCC, the international "Amsterdam criteria" have been used. Case report. The proband was a 40-year-old male who was admitted to hospital with a diagnosis of advanced rectal cancer. Left colectomy was carried out. A histopathologic diagnosis of poorly differentiated adenocarcinoma of clinical stage Dukes C was made. The family talking was done and it was revealed that the pro-band had five family members (one of first degree relative) with colorectal cancer, and two successive generations affected. All malignancy were diagnosed before 45 years of age. In one family member, metachronous transverse cancer was revealed 12 years after surgery for cecal adenocarcinoma. Discussion and conclusion. The main molecular cause for HNPCC is constitutional mutation in one of the mismatch repair (MMR) genes that regulate the excision of errors occurring during DNA replication. The most often are mutations of MLHI and MSH2 genes, and microsatellite instability is present in about 90-95% HNPCC. In this report, we present a case of an HNPCC patient who met the Amsterdam criteria for Lynch syndrome I. Family members that fulfill the Amsterdam criteria should be investigated for mutation in MMR genes. The genetic tests are not routinely available, so colonoscopic screening of all asymptomatic family members older than 25 has been recommended.

Sign in / Sign up

Export Citation Format

Share Document