Phenotypic and genotypic heterogeneity of Lynch syndrome: a complex diagnostic challenge

Lynch, Henry T.; Lanspa, Stephen J.; Shaw, Trudy G.; Casey, Murray Joseph; Rendell, Marc; Stacey, Mark; Townley, Theresa; Snyder, Carrie; Hitchins, Megan P.; Bailey-Wilson, Joan E.

doi:10.1007/s10689-017-0053-3

Cited by 23 publications

(14 citation statements)

References 104 publications

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“…Gene variants that result in pathogenic (i.e., disease-causing) mutations in one of the four primary MMR genes, MSH2, MSH6, MLH1, and PMS2, result in an autosomal dominant hereditary cancer condition known as Lynch syndrome (LS), further underscoring the clinical relevance of intact MMR in the cell [275][276][277]. LS patients and families have a high lifetime risk for various cancers, including an 80% risk for colorectal cancer, a 60% risk for endometrial cancer, and a lower risk for gastric, biliary tract, brain, and other cancers [275,[278][279][280].…”

Section: Contribution Of Gene Editing Technologies To Mmr Biologymentioning

confidence: 99%

Exploiting DNA Endonucleases to Advance Mechanisms of DNA Repair

Thompson

Sobol

Prakash

2021

Biology

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The earliest methods of genome editing, such as zinc-finger nucleases (ZFN) and transcription activator-like effector nucleases (TALENs), utilize customizable DNA-binding motifs to target the genome at specific loci. While these approaches provided sequence-specific gene-editing capacity, the laborious process of designing and synthesizing recombinant nucleases to recognize a specific target sequence, combined with limited target choices and poor editing efficiency, ultimately minimized the broad utility of these systems. The discovery of clustered regularly interspaced short palindromic repeat sequences (CRISPR) in Escherichia coli dates to 1987, yet it was another 20 years before CRISPR and the CRISPR-associated (Cas) proteins were identified as part of the microbial adaptive immune system, by targeting phage DNA, to fight bacteriophage reinfection. By 2013, CRISPR/Cas9 systems had been engineered to allow gene editing in mammalian cells. The ease of design, low cytotoxicity, and increased efficiency have made CRISPR/Cas9 and its related systems the designer nucleases of choice for many. In this review, we discuss the various CRISPR systems and their broad utility in genome manipulation. We will explore how CRISPR-controlled modifications have advanced our understanding of the mechanisms of genome stability, using the modulation of DNA repair genes as examples.

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Section: Contribution Of Gene Editing Technologies To Mmr Biologymentioning

confidence: 99%

Exploiting DNA Endonucleases to Advance Mechanisms of DNA Repair

Thompson

Sobol

Prakash

2021

Biology

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“…MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations among patients who met BRCA1/2 testing criteria but did not meet LS testing criteria (P =4.3×10 −7 ). It was noted that 11.9% of the 528 MMR mutation carriers had breast cancer only 63 , while 27.3% had CRC only 144 , and 27.5% presented with breast or ovarian cancer as their first primary cancer 205 .…”

Section: Lnych Syndrome (Ls)mentioning

confidence: 99%

Cancer Genetics and Epigenetics in Cancer Risk Assesment

Meiliana

Dewi

Wijaya

2021

Mol Cell Biomed Sci

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Compared to the normal tissues, cancer cells tend to have higher proliferation rate and often lost their ability to undergo apoptosis. In addition, cancer cells can separate themselves from their original tissue thus causing metastasis in other part of body. While undergoing program cell death, disordered cellular programming can happen. The main causes of this cellular programming anomaly are epigenetic and genetic alterations, which have been known as two separate mechanisms in carcinogenetic. A recent outcome of whole exome sequencing of thousands of human cancers has been the unexpected discovery of many inactivating mutations in genes that control the epigenome. These mutations have the potential to disturb the DNA methylation patterns, histone modifications, and nucleosome positioning, hence, the causing gene expression alternation. Genetic alteration of the epigenome therefore contributes to cancer just as epigenetic process can cause point mutations and disable DNA repair functions. Epigenetic mechanisms changes could cause genetic mutations, and genetic mutations in epigenetic regulators could cause epigenome changes. Knowing that epigenome play a major role in the hierarchy of gene control mechanisms suggests that mutations might have impact on multiple pathways related to cancer phenotype. This pinpoint the fact that recently, the way the genes are organized and controlled are suggested to be a relevant factor for human carcinogenesis.Keywords: cancer genetic, cancer epigenetic, oncogens, tumor suppressor genes, driver mutation, passenger mutation

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“…Lynch Syndrome (LS) is an autosomal dominantly inherited disorder resulting from monoallelic germline aberrations in genes that are involved in DNA mismatch repair (MMR) machinery [ 1 ]. The four MMR genes that are implicated in the disorder are MLH1 , MSH2 , MSH6 and PMS2 [ 2 ]. Patients with LS inherit a pathogenic germline variant in only one allele while the remaining wild type allele is somatically inactivated by point mutations, loss of heterozygosity or epigenetic silencing due to promoter hypermethylation [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Challenges of Neoantigen Targeting in Lynch Syndrome and Constitutional Mismatch Repair Deficiency Syndrome

Abidi

Gorris

Brennan

et al. 2021

Cancers

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Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary disorders characterised by a highly increased risk of cancer development. This is due to germline aberrations in the mismatch repair (MMR) genes, which results in a high mutational load in tumours of these patients, including insertions and deletions in genes bearing microsatellites. This generates microsatellite instability and cause reading frameshifts in coding regions that could lead to the generation of neoantigens and opens up avenues for neoantigen targeting immune therapies prophylactically and therapeutically. However, major obstacles need to be overcome, such as the heterogeneity in tumour formation within and between LS and CMMRD patients, which results in considerable variability in the genes targeted by mutations, hence challenging the choice of suitable neoantigens. The machine-learning methods such as NetMHC and MHCflurry that predict neoantigen- human leukocyte antigen (HLA) binding affinity provide little information on other aspects of neoantigen presentation. Immune escape mechanisms that allow MMR-deficient cells to evade surveillance combined with the resistance to immune checkpoint therapy make the neoantigen targeting regimen challenging. Studies to delineate shared neoantigen profiles across patient cohorts, precise HLA binding algorithms, additional therapies to counter immune evasion and evaluation of biomarkers that predict the response of these patients to immune checkpoint therapy are warranted.

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Phenotypic and genotypic heterogeneity of Lynch syndrome: a complex diagnostic challenge

Cited by 23 publications

References 104 publications

Exploiting DNA Endonucleases to Advance Mechanisms of DNA Repair

Exploiting DNA Endonucleases to Advance Mechanisms of DNA Repair

Cancer Genetics and Epigenetics in Cancer Risk Assesment

Challenges of Neoantigen Targeting in Lynch Syndrome and Constitutional Mismatch Repair Deficiency Syndrome

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