The Ensembl Variant Effect Predictor

Genomic instability, which is a hallmark of cancer, is generally thought to occur in the middle to late stages of tumourigenesis, following the acquisition of permissive molecular aberrations such as TP53 mutation or whole genome doubling. Tumours with somatic POLE exonuclease domain mutations are notable for their extreme genomic instability (their mutation burden is among the highest in human cancer), distinct mutational signature, lymphocytic infiltrate, and excellent prognosis. To what extent these characteristics are determined by the timing of POLE mutations in oncogenesis is unknown. Here, we have shown that pathogenic POLE mutations are detectable in non‐malignant precursors of endometrial and colorectal cancer. Using genome and exome sequencing, we found that multiple driver mutations in POLE‐mutant cancers show the characteristic POLE mutational signature, including those in genes conventionally regarded as initiators of tumourigenesis. In POLE‐mutant cancers, the proportion of monoclonal predicted neoantigens was similar to that in other cancers, but the absolute number was much greater. We also found that the prominent CD8+ T‐cell infiltrate present in POLE‐mutant cancers was evident in their precursor lesions. Collectively, these data indicate that somatic POLE mutations are early, quite possibly initiating, events in the endometrial and colorectal cancers in which they occur. The resulting early onset of genomic instability may account for the striking immune response and excellent prognosis of these tumours, as well as their early presentation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…Copy number profiles were derived with Sequenza 31. Variant annotation was performed with using Annovar 32 or Variant Effect Predictor 33.…”

Section: Methodsmentioning

confidence: 99%

Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response

Temko

Gool

Rayner

et al. 2018

The Journal of Pathology

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“…A sensitive pipeline was used to ensure that variants were not missed (a coverage ≥15×, a minimum of two reads for an altered allele, a Phred quality ≥ zero, and no strand bias filter). Variant annotation was carried out with Variant Effect Predictor (VEP) tool from Ensembl 48 and based on the transcripts LDLR : ENTS00000558518, APOB : ENTS00000233242, PCSK9 : ENTS00000302118, and LDLRAP1 : ENTS00000374338. Reported variants were filtered based on their frequency and functional affects.…”

Section: Methodsmentioning

confidence: 99%

The Genetic Spectrum of Familial Hypercholesterolemia (FH) in the Iranian Population

Fairoozy

Futema

Vakili

et al. 2017

Sci Rep

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Familial hypercholesterolemia (FH) is an autosomal dominant disorder associated with premature cardiovascular disease (CVD). Mutations in the LDLR, APOB, and PCSK9 genes are known to cause FH. In this study, we analysed the genetic spectrum of the disease in subjects from the Iranian population with a clinical diagnosis of FH. Samples were collected from 16 children and family members from five different cities of Iran. Probands were screened for mutations in the LDLR, APOB, and PCSK9 genes using next generation sequencing, with results confirmed by Sanger sequencing. The likely pathology of identified variants was examined using in silico tools. Of the probands, 14 had a clinical diagnosis of homozygous FH and two of heterozygous FH. No mutations were found in either APOB or PCSK9, but nine probands were homozygous for seven different LDLR mutations, with p.(Trp577Arg) occurring in three and p.Val806Glyfs*11 occurring in two patients. Two mutations were novel: p.(Leu479Gln) and p.(Glu668*). Seven probands with a clinical diagnosis of FH were mutation negative. This pilot study, integrating clinical and molecular-based techniques, begins to elucidate the FH heterogeneity and the mutation spectrum in the Iranian population. Such information is important for future disease management and cost savings.

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“…Subsequently, we made use of the ENSEMBL variant database [18][19][20] as a reference database to map the SNPs with their relevant chromosome, location, gene, allele and potential functional features (intergenic SNPs were mapped to the nearest gene on the chromosome). Additionally, these shared SNPs were interpreted with the characteristics of predicted functional consequences by using RegulomeDB V.1.1 [21] to get annotation from current ENCODE data (updated with recent ENCODE releases: [22,23]), Chromatin States data from the Roadmap Epigenome Consortium and updated data for DNase footprinting, PWMs, and DNA Methylation, and finally ranked the variant lists according to predicted functional consequences attributes.…”

Section: Methodsmentioning

confidence: 99%

Systematic Analysis of GWAS Data Reveals Genomic Hotspots for Shared Mechanisms between Neurodegenerative Diseases

Naz¹,

Younesi²,

Hofmann‐Apitius³

2017

J Alzheimers Dis Parkinsonism

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The Ensembl Variant Effect Predictor

Cited by 5,695 publications

References 73 publications

Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response

Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response

The Genetic Spectrum of Familial Hypercholesterolemia (FH) in the Iranian Population

Systematic Analysis of GWAS Data Reveals Genomic Hotspots for Shared Mechanisms between Neurodegenerative Diseases

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