The functional relevance of variants refers to their biological role for promoting disease phenotypes. This analysis can inform -among ohers- patient stratification to clinical trials with categorical inclusion criteria (such as FGFR3 “activating mutations” or BRCA1/2 “loss-of-function”) and the need for genetic counseling referral (in case that germline pathogenic variants in cancer-predisposing genes are observed).
The predictive relevance analysis matches functionally relevant variants to biomarkers of disease diagnosis, prognosis and drug response reported at present. In the public portal, biomarker data is retrieved from publicly available knowledgebases. Besides on-label prescribing, this informs off-label and investigational drug opportunities that could be considered according to current knowledge.
Results of the MTBP analyses are structured in HTML reports where variants are classified according to their functional relevance, and those described as cancer biomarkers are ranked according to their level of actionability. These documents provide detailed variant annotation, evidence supporting each given assertion and access to original data sources through interactive elements. This is aimed to empower in-depth review of available information.
The MTBP uses a comprehensive set of expert curated databases collecting clinical and preclinical knowledge associated to genomic events (such as their role in disease pathogenicity or anti-cancer drugs response). Assertions supported by lower quality data (e.g. not well-powered studies) and/or without consensus are not used to classify the variants (but provided as additional descriptives).
The MTBP uses public knowledgebases developed by international efforts that (a) formalize the variant information by using pre-defined criteria; (b) are based on published biomedical literature (including conference communications for most recent reports); (c) are committed to periodical updates; and (d) are open for the use and review of the community (see individual resources for licensing details).
Some bona fide assumptions are used to estimate the relevance of particular events without reported effects. These assumptions are based on stringent criteria, as the recommendations to consider mutations of null consequence type as loss-of-function events developed by the study of Mendelian gene variants.
The portal is developed under the Cancer Core Europe umbrella, which is formed by seven leading European oncology centers with the aim of implementing new therapeutic strategies involving knowledge, data and technology sharing. Variants are classified by their functional and predictive relevance following international guidelines as available or developing in-house expert consensus otherwise.
The public version of the portal does not incorporate information that cannot be retrieved from a generic input (such as the germline and/or tumor origin of the variants or their allele frequency) or implement features dependant on project specifications (such as matching variants with clinical trials of interest). Instead, the public MTBP provides an analytical framework to analyse cancer variants that supports (but does not substitute) the healthcare professional judgement.
The MTBP queries current clnical and preclinical knowledge across a comprehensive set of databases gathering information associated with genomic events. In addition, estimations according to latest guidelines and computational calculations are used for those variants with no other available evidences.
The MTBP performs periodical semi-automatic updates of the content of the knowledgebases. In addition, new analytical features will be incorporated as part of the development of the technology, which is ensured by the adoption of the portal by the Cancer Core Europe as well as by other local initiatives