Solving the genetic aetiology of hereditary gastrointestinal tumour syndromes- a collaborative multicentre endeavour within the project Solve-RD.

Patients and families with suspected, but genetically unexplained (unsolved) genetic tumour risk syndromes lack appropriate treatment and prevention, leading to preventable morbidity and mortality. To tackle this problem, patients from the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) are analysed in the European Commission's research project "Solving the unsolved rare diseases" (Solve-RD). The aim is to uncover known and novel cancer predisposing genes by reanalysing available whole-exome sequencing (WES) data of large cohorts in a combined manner, and applying a multidimensional omics approach. Around 500 genetically unsolved cases with suspected hereditary gastrointestinal tumour syndromes (polyposis, early-onset/familial colorectal cancer and gastric cancer) from multiple European centres are aimed to be included. Currently, clinical and germline WES data from 294 cases have been analysed. In addition, an extensive molecular profiling of gastrointestinal tumours from these patients is planned and deep learning techniques will be applied. The ambitious, multidisciplinary project is accompanied by a number of methodical, technical, and logistic challenges, which require the development and implementation of new analysis tools, the standardisation of bioinformatics pipelines, and strategies to exchange data and knowledge. and Outlook. The first re-analysis of 229 known and proposed cancer predisposition genes allowed solving 2-3% of previously unsolved GENTURIS cases. The integration of expert knowledge and new technologies will help to identify the genetic basis of additional unsolved cases within the ongoing project. The ERN GENTURIS approach might serve as a model for other genomic initiatives.

Sommer AK ，Te Paske IBAW ，Garcia-Pelaez J ，Laner A ，Holinski-Feder E ，Steinke-Lange V ，Peters S ，Valle L ，Spier I ，Huntsman D ，Solve-RD-GENTURIS group ，Oliveira C ，de Voer RM ，Hoogerbrugge N ，Aretz S ... -  《-》

Boosting care and knowledge about hereditary cancer: European Reference Network on Genetic Tumour Risk Syndromes.

Vos JR ，Giepmans L ，Röhl C ，Geverink N ，Hoogerbrugge N ，ERN GENTURIS ... -  《-》

Solve-RD: systematic pan-European data sharing and collaborative analysis to solve rare diseases.

For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient's data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe.

Zurek B ，Ellwanger K ，Vissers LELM ，Schüle R ，Synofzik M ，Töpf A ，de Voer RM ，Laurie S ，Matalonga L ，Gilissen C ，Ossowski S ，'t Hoen PAC ，Vitobello A ，Schulze-Hentrich JM ，Riess O ，Brunner HG ，Brookes AJ ，Rath A ，Bonne G ，Gumus G ，Verloes A ，Hoogerbrugge N ，Evangelista T ，Harmuth T ，Swertz M ，Spalding D ，Hoischen A ，Beltran S ，Graessner H ，Solve-RD consortium ... -  《-》

Inherited colorectal cancer syndromes.

Kastrinos F ，Syngal S 《-》

Exome sequencing in diagnostic evaluation of colorectal cancer predisposition in young patients.

Tanskanen T ，Gylfe AE ，Katainen R ，Taipale M ，Renkonen-Sinisalo L ，Mecklin JP ，Järvinen H ，Tuupanen S ，Kilpivaara O ，Vahteristo P ，Aaltonen LA ... -  《-》