News

Interpretation of (tumor) copy number alterations and fusions is now available in the public version of the MTBP. These events can be introduced by using the free text box interface, together with the tumor mutations (if any). See the help popup for more details about the accepted formats. These events must be stated at the gene level (for instance "amplification of MYC"), and the system assumes that such alteration is unequivocal (for instance, that the number of gained copies is significant). 

david.tamborero@scilifelab.se

We have released some new visualization features for the reports of the public version of the MTBP provided here. The most remarkable is that now the data can be displayed through two different views; the first is the so-called alteration-centric report, which is the one provided so far by the public portal. This report groups the variants in different tables according to their functional relevance classification. Therefore, each variant can appear only once in this view. All the biomarkers associated with that alteration (if any) are aggregated according to their actionability tier in the last column of the tables.

 

In addition, the user can now select a second view, the so-called biomarker-centric view (see image below). This report groups the gene alterations in different tables according to the actionability tier of their associated biomarkers (if any). Therefore, a given alteration can appear in more than one table if that alteration is associated with different actionability tiers. Of note, remember that the public version of the MTBP only shows biomarkers (prognosis, diagnosis and drug response) gathered by external knowledgebases (such as OncoKB or CIViC), and other clinical flags (such as variants matching with clinical trial opportunities) are not provided here.

 

david.tamborero@scilifelab.se

For those users logged in the public MTBP, there is now the option to share the reports stored in the user's repository (remember that only a valid email is necessary to create an account). For that, use the 'Share' tag (see red square in the image below) to make the link of the corresponding report publicly accessible. Click the 'Stop Sharing' to make the report private again.

 

david.tamborero@scilifelab.se

We have added an icon below the gene symbol in case that more than one alteration is observed in that gene. The details of the additional alteration(s) can be seen by clicking in the corresponding icon. Note that to observe multiple alterations in the same gene may be a relevant finding to interpret the results, and the aim of this icon is to ensure that this is not overlooked when reviewing the report.

david.tamborero@scilifelab.se

Note that the public version of the MTBP integrates several knowledgebases developed by international initiatives and open for research purposes; the list of the specific resources and respective versions employed in a given analysis can be found by clicking in the ‘pipeline version’ at the top right corner of the provided report. Of note, the public MTBP is no longer using the biomarker database originally developed for the Cancer Genome Interpreter (PMID: 29592813), as the content of this resource is currently not subject to updates.

david.tamborero@scilifelab.se

We have added some icons in the reports to indicate the type of biomarker(s) that are matched with each variant (for each given tier of actionability).

A variant can be a biomarker of drug(s) sensitivity and/or drug(s) resistance (icon of the drug with a '+' or a '-', respectively; or with the combined '+/-' if both are described for that variant), and/or a diagnostic and/or prognostic biomarker (icon with the 'D' or the 'P', respectively). These icons are aimed for a more efficient visualization, but note that the details of each biomarker are provided in the popup with the supporting assertions.
 

david.tamborero@scilifelab.se

We have recenty published a paper in Nature Cancer where we share our experience in using the MTBP to allocate patients into clinical trials hosted by the Cancer Core Europe network. This paper includes the details on how the annotation and classification of the variants is performed by the portal and how these results are linked to clinical interventions of interest in the reports.

Please remember that the public website of the MTBP provided via https://www.mtbp.org/ gives only access to a lightweight version of the analytical pipeline, with limited features as compared to the system used for clinical projects, and thus the use of this public version must be limited to research purposes only (see disclaimer).

david.tamborero@scilifelab.se

We have recently updated the content of the knowledgebases employed by the public version of the MTBP. Note that this requires a number of manual steps to accurately aggregate their different data models, which we do via periodical data releases, except in the case of OncoKB, in which the information provided by their public API is harmonized on the fly. Please remember that the versions of the tools and databases employed in each MTBP analysis are included in the top right corner of the resulting report, under the “pipeline version” link.

david.tamborero@scilifelab.se

Moderate changes made to the News, FAQ, Welcome and About section of site made over the last month. The MTBP team has gone through some growth recently, inspiring a slight makeover of the user interface. Please feel free to click around and let us know what you think.

ali.razzak@scilifelab.se

The reports provided by the public MTBP website flag those genes that are recommended for reporting secondary findings according to the American College of Medical Genetics and Genomics (ACMG). We have recently updated the ACMG gene list to the v3.0 release published here. This annotation in the MTBP reports can help to evaluate genetic counseling needs for variants uploaded by the user that are known/suspected to be germline and have evidence supporting their loss-of-function effect, as provided by the MTBP functional annotation (see a dummy report screenshot below). Please note that the public MTBP provides a general interpretation of genomic variants intended for research purposes that can not substitute the judgement of a medical professional, who must review all the available data according to his/her own criteria.

david.tamborero@scilifelab.se

The public MTBP website now accepts uploading VCF files in the GRCh38/hg38 build. In this case, the coordinates of the variants are converted to GRCh37/hg19 before they are passed to the MTBP analytical pipeline, since this is the only genome assembly that is supported at the moment. Note that this means that the MTBP reports will show the genomic coordinates of the variants in the GRCh37/hg19 system. Genomic coordinates are lifted by an ad-hoc script with the same conversion mapping as the UCSC liftOver tool.

david.tamborero@scilifelab.se

The public version of the MTBP now queries the OncoKB content via its web API (https://www.oncokb.org/swagger-ui/index.html). This requires the use of a user’s token that is obtained after applying for a OncoKB license, which is free for research use (https://www.oncokb.org/apiAccess). Note that the token can be found in your OncoKB account settings once the account has been created. The token can be then passed to the MTBP public website when uploading the variants to be analysed (see red rectangle in the image below).

We encourage the users of the public MTBP to follow this process. However, OncoKB developers have kindly facilitated that in case that the token is not introduced, the public MTBP website will still show the OncoKB variant annotation with slightly less detailed content. We thank the OncoKB team for this effort.

david.tamborero@scilifelab.se

We have updated our FAQs section, with specific content of the interest of the public MTBP website users.

david.tamborero@scilifelab.se

The public version of the MTBP annotates the (predominant) mechanism of action of cancer genes according to several knowledge sources. In addition, we have just updated this information according to manual curation efforts performed in the context of Cancer Core Europe (one of the ‘private’ ongoing MTBP projects, see here). This update affects the annotation of POLE and POLD1, which now also includes the label of essential genes. This detail is important for interpreting the variants found in these genes, as although they are considered tumor suppressors, mutations leading to their complete loss-of-function cannot be assumed to drive oncogenic traits (but actually are more likely to be detrimental for the tumor cells viability).

As a result, MTBP reports in the public portal will only classify as functionally relevant those specific POLE/POLD1 mutations known to interfere with their proofreading activity (and associated with an extensive increase in tumor mutation burden) without leading to a catastrophic event. Other variants (such as those of null consequence type likely leading to the complete loss-of-function of the encoded allele) will appear as of unknown functional relevance if no reported effect stating otherwise is available (see example below).

david.tamborero@scilifelab.se

The MTBP annotates the relevance of the analysed gene variants by using a variety of in-house tools and publicly available resources (referenced in the MTBP reports as appropriate). Among the latter, the portal employs a number of knowledgebases gathered by international efforts and open for the (non-commercial) access and feedback of the community.

These knowledgebases are under continuous updates, and we aim for the public version of the portal to be aligned with those. However, aggregating the content of these external resources requires first to harmonize their different variant representation and data models, which in the MTBP is implemented by an in-house semi-automatic pipeline. However, manual efforts to map certain terms are still required, which thus impedes doing the process in real-time. Instead, updating the knowledgebases content in the MTBP is performed via periodical harmonized (external) data releases, which we try to do regularly.

Note also that these updates have been halted for certain knowledgebases due to recent changes in their respective license policies, which we are currently working to address. Importantly, the version/date of each of the resources employed for the MTBP analyses is under version control, and the details are provided in the top right corner of the given report (see image).

david.tamborero@scilifelab.se

We have recently updated one of the variant mapping tools employed by the public MTBP system (the Ensembl Variant Effect Predictor). This new version raises a default error when a larger number of variants is inputted if they are not ordered by chromosome position. However, we did not have this in place for variants passed via the ‘free text’ box of the public MTBP interface, which therefore caused a run error. This issue has now been fixed.  

david.tamborero@scilifelab.se

The results of the functional and predictive variant analyses provided by the public MTBP portal are now both included in a single document (two different html reports for each were used before).

On the one hand, the evidence supporting a functional (or neutral) role of a given variant to (putatively) acquire tumor traits is shown in the ‘Functional relevance evidence’ column. Of note, the functional interpretation is variant/allele centric and thus no further considerations (e.g. the sample’s cancer type) are taken into account here (e.g. an allele loss-of-function is always classified as so regardless of the context in which it is observed). Biomarker information is also integrated for the functional relevance interpretation, under the premise that a specific variant acting as a cancer biomarker is a functionally relevant event by definition.

In addition, variant information that is not conclusive (or relevant) for the functional classification but has been curated by one the employed knowledgebases (such as in an inconclusive ClinVar assertion or reported with a low allele frequency in population genomics databases) is now also included in this column (previously, such information was only shown in the advanced gene-variant view).

On the other hand, information about the predictive relevance (cancer prognosis, diagnostic and/or drug response) of the variant is now included in a new column named ‘Reported biomarker(s)’. In the public version of the MTBP, this analysis is solely based on the biomarkers reported by several public knowledgebases (CIViC, OncoKB and CancerGenomeInterpreter), which are updated in the portal on a regular basis (but not accessed in real time). Please note that this information is automatically aggregated by the annotation pipeline, as opposed to the MTBP instances employed by clinical projects such as Cancer Core Europe, in which the main actionability flags are manually curated based on in-house criteria. The public MTBP report provides a summary of the available information and the access to the corresponding knowledgebase entry for each given assertion via interactive popups (see image below).  

Of note, the biomarker interpretation is a phenotype-centric analysis, and thus considerations such as the cancer match (i.e. whether the biomarker has been described for the sample’s cancer type or a subtype thereof) and the current clinical relevance of that biomarker (such as ‘reported by early clinical trials’) are taken into account here. In detail, the matched biomarkers are automatically tiered following a modified version of the ESMO-ESCAT scale of actionability.

david.tamborero@scilifelab.se