Frameshift mutational target gene analysis identifies similarities and differences in constitutional mismatch repair‐deficiency and Lynch syndrome

Maletzki, Claudia; Huehns, Maja; Bauer, Ingrid; Ripperger, Tim; Mork, Maureen M.; Vilar, Eduardo; Klöcking, Sabine; Zettl, Heike; Prall, Friedrich; Linnebacher, Michael

doi:10.1002/mc.22632

Cited by 15 publications

(19 citation statements)

References 33 publications

(81 reference statements)

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“…In addition, the frameshifts are not assumed to be tolerated in the sense that they are not changed. However, if they are not removed immediately by selecting against but could be preserved in the evolutionary history, they are assumed to be repairable [116][117][118][119][120]. At present, we are investigating the mechanism of how a frameshift mutation is repaired [121].…”

Section: Discussionmentioning

confidence: 99%

Frameshift and wild-type proteins are highly similar because the genetic code and genomes were optimized for frameshift tolerance

Wang

Dong

Chen

et al. 2016

Preprint

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Frameshift mutation yields truncated, dysfunctional product proteins, leading to loss-of-function, genetic disorders or even death. Frameshift mutations have been considered as mostly harmful and of little importance for the molecular evolution of proteins. Frameshift protein sequences, encoded by the alternative reading frames of a coding gene, have been therefore considered as meaningless. However, existing studies had shown that frameshift genes/proteins are widely existing and sometimes functional. It is puzzling how a frameshift kept its structure and functionality while its amino-acid sequence is changed substantially. Here we demonstrate that the protein sequences of the frameshifts are highly conservative when compared with the wild-type protein sequence, and the similarities among the three protein sequences encoded in the three reading frames of a coding gene are defined mainly by the genetic code. In the standard genetic code, amino acid substitutions assigned to frameshift codon substitutions are far more conservative than those assigned to random substitutions. The frameshift tolerability of the standard genetic code ranks in the top 1.0-5.0% of all possible genetic codes, showing that the genetic code is optimal in terms of frameshift tolerance. In some higher species, the shiftability is further optimized at gene- or genome-level by a biased usage of codons and codon pairs, in which frameshift-tolerable codons/codon pairs are overrepresented in their genomes.

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Section: Discussionmentioning

confidence: 99%

Frameshift and wild-type proteins are highly similar because the genetic code and genomes were optimized for frameshift tolerance

Wang

Dong

Chen

et al. 2016

Preprint

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“…In fact, MSI might be associated with disease progression in MF, as it has been more frequently detected in tumor-stage MF (47%) than in early-stage MF (20%) 2 . It is possible, though, that MSI in MF might occur during somatic cancer evolution in MF without being the disease driver 9, 10Table IVSummary of microsatellite instability and MMR defects in MF2, 6, 7, 8Microsatellite instabilityFrequency, %MSI-L20 2 MSI-H8 2 Early-stage MF (T1-2)20 2 Tumor-stage MF (T3)47 2 Molecular defects Loss of MLH1 expression46 6 ; promoter hypermethylation in 64 2 ; possible resistance to PUVA or ECP 8 Loss of MSH2 expression35 6 ; predilection for T-cell lymphoma 7 ; possible response to PUVA or ECP 8

ECP , Extracorporeal photopheresis; MF , mycosis fungoides; MMR ; mismatch repair; MSI-H , high levels of microsatellite instability; MSI-L , low levels of microsatellite instability; PUVA , psoralen plus ultraviolet A.

…”

Section: Discussionmentioning

confidence: 99%

A possible association between mycosis fungoides and Muir-Torre syndrome: Two disorders with microsatellite instability

Lewis

Duvic

2017

JAAD Case Reports

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“…A panel of non-coding and coding MS marker was analyzed as described before [31]. MSI is de ned by mono-and/or bialellic band shifts usually characterized by deletions (indicated with minus symbol + number).…”

Section: Fragment Length Analysis Of Cms Target Genesmentioning

confidence: 99%

Combined Vaccine-Immune-Checkpoint Inhibition Constitutes a Promising Strategy for Treatment of dMMR Tumors

Salewski

Kuntoff

Kuemmel

et al. 2020

Preprint

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Background: Mlh1-knock-out-driven mismatch-repair-deficient (dMMR) tumors can be targeted immunologically. By applying therapeutic tumor vaccination, tumor growth is delayed but escape mechanisms evolve, characterized by the upregulation of immune-checkpoint molecules (LAG-3, PD-L1). To counteract immune escape, we investigated the therapeutic activity of a combined tumor vaccine-immune checkpoint inhibitor therapy using α-PD-L1 monoclonal antibody clone 6E11.Design: In this trial, Mlh1-knock-out mice with established gastrointestinal tumors received single or thrice injections of α-PD-L1 monoclonal antibody clone 6E11 (2.5 mg/kg bw, q2w, i.v.) either alone or in combination with the vaccine. Longitudinal flow cytometry and PET/CT imaging studies were followed by ex vivo functional immunological and gene expression assays.Results: 6E11 monotherapy slightly increased median overall survival (mOS: 6.0 weeks vs. control 4.0 weeks). Increasing the number of injections (n=3) improved therapy outcome (mOS: 9.2 weeks) and was significantly boosted by combining 6E11 with the vaccine (mOS: 19.4 weeks vs. 10.2 weeks vaccine monotherapy). Accompanying PET/CT imaging confirmed treatment-induced tumor growth control, with the strongest inhibition in the combination group. Three mice (30%) achieved a complete remission and showed long-term survival. Decreased levels of circulating splenic and intratumoral myeloid-derived suppressor cells (MDSC) and decreased numbers of immune-checkpoint-expressing splenic T cells (LAG-3, CTLA-4) accompanied therapeutic effects. Gene expression and protein analysis of residual tumors revealed downregulation of PI3K/Akt/Wnt and TGF-signaling, leading to T cell infiltration and reduced numbers of macrophages, neutrophils, and MDSC.Conclusions: By successful uncoupling of the PD-1/PD-L1 axis, we provide further evidence for the safe and successful application of immunotherapies to combat dMMR-driven malignancies that warrants further investigation.

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Frameshift mutational target gene analysis identifies similarities and differences in constitutional mismatch repair‐deficiency and Lynch syndrome

Cited by 15 publications

References 33 publications

Frameshift and wild-type proteins are highly similar because the genetic code and genomes were optimized for frameshift tolerance

Frameshift and wild-type proteins are highly similar because the genetic code and genomes were optimized for frameshift tolerance

A possible association between mycosis fungoides and Muir-Torre syndrome: Two disorders with microsatellite instability

Combined Vaccine-Immune-Checkpoint Inhibition Constitutes a Promising Strategy for Treatment of dMMR Tumors

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