Lollipops in the Clinic: Information Dense Mutation Plots for Precision Medicine

Jay, Jeremy J.; Brouwer, Cory

doi:10.1371/journal.pone.0160519

Cited by 114 publications

(104 citation statements)

References 7 publications

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“…Furthermore, mapping the mutations and its statistics on a linear gene product (proteins of interest) was done with a ‘lollipop’ mutation diagram generator (49). Based on the knowledge from the human MMR-D counterpart and general involvement in tumorigenesis, the genes for further analysis were chosen with high probability to mutate.…”

Section: Methodsmentioning

confidence: 99%

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice

Gladbach

Wiegele

Hamed

et al. 2019

Preprint

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28 29 Abbreviations: CMMR-D -constitutional mismatch repair deficiency, cMS -coding 30 microsatellite, MB -Megabase, MMR -mismatch repair, MMR-D -mismatch repair 31 deficiency, TMB -tumor mutational burden, GIT -gastrointestinal tumor, SNV -single 32 nucleotide variant, WES -whole exome sequencing 33 34 Keywords: Tumor mutational burden, exclusive/ shared mutations, predicted tumor antigens Mutations in MLH1 -/tumors 3 35Abstract 36 MLH1 knock out mice represent a preclinical model that resembles features of the human 37 counterpart. As these mice develop mismatch repair deficient (MMR-D) neoplasias in a 38 sequential twin-peaked manner (first lymphomas, then gastrointestinal tumors) we aimed at 39 identification of the underlying molecular mechanisms. Using whole-exome sequencing, we 40 focused on (I) shared and (II) mutually exclusive mutations and described the processes of 41 ongoing mutational events in tumor-derived cultures. 42 A heterogeneous genetic landscape was found, with few mutations shared among different 43 neoplasias (ARID1A and IDH2). Mutations in tumor suppressor genes SMAD4 and POLE 44 were mutually exclusive in lymphomas, most likely contributing to a more aggressive in vivo 45 phenotype. Comparing the mutational profile of selected primary tumors and their 46 corresponding cell line upon in vitro culture revealed continuous increased numbers of 47 somatic gene mutations. The same was true for coding microsatellite mutations in selected 48 MMR-D target genes, showing a gradual increase during in vitro passage. With respect to this 49 latter type of mutations, partial overlap was detectable, yet recognizing shared vaccination 50 antigens. The two most promising candidates are AKT3, a RAC-gamma serine/threonine-51 protein kinase with relevance in maintenance of cellular homeostasis and the endonuclease 52 ERCC5 (Excision Repair 5), involved in DNA excision repair. 53 Novel results of a comparison between spontaneously developing lymphomas and 54 gastrointestinal tumors as models for MMR-D driven tumorigenesis are reported. In addition 55 to identification of ARID1A as a potentially causative mutation hotspot, our comprehensive 56 characterization of the mutational signature is a starting point for immune-based approaches 57 to therapy. 58 59 Mutations in MLH1 -/tumors 4 60 Author Summary 61 This study describes the mutational spectrum of MLH1 -/--associated tumors, spontaneously 62 developing in mice. While these tumors arise at the bottom of the same germline mutation, 63 the clinical presentations as well as resulting molecular alterations are heterogeneous, and 64 thus likely being directly linked. Highly aggressive lymphomas, developing early in life are 65 ultra-hypermutated and harbor mutations in tumor suppressor genes SMAD4 and POLE. 66 Gastrointestinal tumors develop later in life and show different mutations. By performing in-67 depth whole exome sequencing analysis, we here identified for the first time a common 68 mutational hotspot. ARID1A constitutes a potentially causative mutati...

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Section: Methodsmentioning

confidence: 99%

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice

Gladbach

Wiegele

Hamed

et al. 2019

Preprint

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“…Here, we use lollipops-v.1.3.1 (Jay and Brouwer 2016) to plot the distribution of the 606 qualified pathogenic variants across the linear gene structure of the 11 epilepsy genes (Methods; Fig. 2).…”

Section: Identifying Missense-intolerant Subregions Of Genesmentioning

confidence: 99%

Optimizing genomic medicine in epilepsy through a gene-customized approach to missense variant interpretation

et al. 2017

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Gene panel and exome sequencing have revealed a high rate of molecular diagnoses among diseases where the genetic architecture has proven suitable for sequencing approaches, with a large number of distinct and highly penetrant causal variants identified among a growing list of disease genes. The challenge is, given the DNA sequence of a new patient, to distinguish disease-causing from benign variants. Large samples of human standing variation data highlight regional variation in the tolerance to missense variation within the protein-coding sequence of genes. This information is not well captured by existing bioinformatic tools, but is effective in improving variant interpretation. To address this limitation in existing tools, we introduce the missense tolerance ratio (MTR), which summarizes available human standing variation data within genes to encapsulate population level genetic variation. We find that patient-ascertained pathogenic variants preferentially cluster in low MTR regions (P < 0.005) of well-informed genes. By evaluating 20 publicly available predictive tools across genes linked to epilepsy, we also highlight the importance of understanding the empirical null distribution of existing prediction tools, as these vary across genes. Subsequently integrating the MTR with the empirically selected bioinformatic tools in a gene-specific approach demonstrates a clear improvement in the ability to predict pathogenic missense variants from background missense variation in disease genes. Among an independent test sample of case and control missense variants, case variants (0.83 median score) consistently achieve higher pathogenicity prediction probabilities than control variants (0.02 median score; Mann-Whitney U test, P < 1 × 10

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“…Variants in each sample were further filtered for high genotype quality (≥20), and annotated according to Human Genome Variation Society Gene scheme structure was generated by using Lollipops (Jay & Brouwer, 2016). RNA-seq data analysis was performed by using kallisto and DEseq2 (Bray, Pimentel, Melsted, & Pachter, 2016).…”

Section: Bioinformaticsmentioning

confidence: 99%

Loss ofRAD9Bimpairs early neural development and contributes to the risk for human spina bifida

et al. 2020

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DNA damage response (DDR) genes orchestrating the network of DNA repair, cell cycle control, are essential for the rapid proliferation of neural progenitor cells. To date, the potential association between specific DDR genes and the risk of human neural tube defects (NTDs) has not been investigated. Using whole‐genome sequencing and targeted sequencing, we identified significant enrichment of rare deleterious RAD9B variants in spina bifida cases compared to controls (8/409 vs. 0/298; p = .0241). Among the eight identified variants, the two frameshift mutants and p.Gln146Glu affected RAD9B nuclear localization. The two frameshift mutants also decreased the protein level of RAD9B. p.Ser354Gly, as well as the two frameshifts, affected the cell proliferation rate. Finally, p.Ser354Gly, p.Ser10Gly, p.Ile112Met, p.Gln146Glu, and the two frameshift variants showed a decreased ability for activating JNK phosphorylation. RAD9B knockdowns in human embryonic stem cells profoundly affected early differentiation through impairing PAX6 and OCT4 expression. RAD9B deficiency impeded in vitro formation of neural organoids, a 3D cell culture model for human neural development. Furthermore, the RNA‐seq data revealed that loss of RAD9B dysregulates cell adhesion genes during organoid formation. These results represent the first demonstration of a DDR gene as an NTD risk factor in humans.

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Lollipops in the Clinic: Information Dense Mutation Plots for Precision Medicine

Cited by 114 publications

References 7 publications

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice

Optimizing genomic medicine in epilepsy through a gene-customized approach to missense variant interpretation

Loss ofRAD9Bimpairs early neural development and contributes to the risk for human spina bifida

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Lollipops in the Clinic: Information Dense Mutation Plots for Precision Medicine

Cited by 114 publications

References 7 publications

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1-/-mice

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1-/-mice

Optimizing genomic medicine in epilepsy through a gene-customized approach to missense variant interpretation

Loss ofRAD9Bimpairs early neural development and contributes to the risk for human spina bifida

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Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice