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• Mutations in the SIX1/2 pathway and the DROSHA/DGCR8 miRNA microprocessor complex underlie high-risk blastemal type Wilms tumors

  Blastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. In order to find novel therapeutic leads for this subgroup of patients, we analyzed 58 such Wilms tumors by exome and transcriptome analysis and validated our findings in larger independent cohorts. Recurrent mutations identified either somatically or in the germline included a hotspot mutation (Q177R) in the homeodomain of SIX1 and SIX2 in tumors with high proliferative potential, mutations in microprocessor genes like DROSHA, DGCR8, DICER1 and DIS3L2, and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations had a strong effect on miRNA profiles in tumors, which we confirmed in cell lines transfected with mutant DROSHA.

  Study EGAS00001000906

• The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer

  Reactivation of telomerase reverse transcriptase (TERT) expression enables cells to overcome replicative senescence and escape apoptosis, fundamental steps in the initiation of human cancer. Multiple cancer types, including up to 83% of glioblastomas (GBM), harbor highly recurrent TERT promoter mutations of unknown function but specific to two nucleotide positions. We identify the functional consequence of these mutations in GBM to be recruitment of the multimeric GABP transcription factor specifically to the mutant promoter. Allelic recruitment of GABP is consistently observed across four cancer types, highlighting a shared mechanism underlying TERT reactivation. Tandem flanking native ETS motifs critically cooperate with these mutations to activate TERT, likely by facilitating GABP heterotetramer binding. GABP thus directly links TERT promoter mutations to aberrant expression in multiple cancers.

  Study EGAS00001001242

• Molecular sub-classification of hormone receptor-positive breast cancer

  Patients with estrogen and/or progesterone receptor-positive breast cancer benefit from hormonal treatment, yet high global death burdens due to high prevalence and long-term recurrence risk call for biomarkers to guide additional treatment approaches. From a prospective, observational study of postmenopausal early breast cancer patients treated with tamoxifen or aromatase inhibitors gene expression analyses of 612 tumors was performed using the NanoString® Breast Cancer 360 panel. We identified novel gene expression signatures, i.e. BRCAness and Tumor Inflammation Signature (associated with high tumor lymphocyte infiltration), that may aid to select high-risk patients in order to improve adjuvant treatment by targeting DNA repair deficiency or immune-checkpoints in addition to standard chemo-endocrine treatment. The overall goal is to foster novel concepts for a stratified early breast cancer management.

  Study EGAS00001004594

• Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome

  Patients with short QT syndrome (SQTS) may present with syncope, ventricular fibrillation or sudden cardiac death. Six SQTS susceptibility genes, encoding cation channels, explain less than 25% of SQTS cases. Here we identify a missense mutation in the anion exchanger (AE3)-encoding SLC4A3 gene in two unrelated families with SQTS. The mutation causes reduced surface expression of AE3 and reduced membrane bicarbonate transport. Slc4a3 knockdown in zebrafish causes increased cardiac pHi, short QTc, and reduced systolic duration, which is rescued by wildtype but not mutated SLC4A3. Mechanistic analyses suggest that an increase in pHi and decrease in [Cl-]i shortened the action potential duration. However, other mechanisms may also play a role. Altered anion transport represents a mechanism for development of arrhythmia and may provide new therapeutic possibilities.

  Study EGAS00001002632

• Multiple migrations to the Philippines during the last 50,000 years

  A key link to understand human history in Island Southeast Asia is the Philippine archipelago and its poorly investigated genetic diversity. We collected and analyzed the most comprehensive set of population-genomic data for the Philippines, 1028 individuals covering 115 indigenous communities. We demonstrate that the Philippines were populated by at least five waves of human migration. The Cordillerans migrated into the Philippines prior to the arrival of rice agriculture, where some remain to be the least admixed East Asians carrying an ancestry shared by all Austronesian-speaking populations; thereby challenging an exclusive Out-of-Taiwan model of joint farming-language-people dispersal. Altogether, our findings portray Philippines as a crucial gateway, with a multilayered history, that ultimately changed the genetic landscape of the Asia-Pacific region.

  Study EGAS00001005083

• Patient-derived organoids as a novel tool to study cervical cancer

  Cervical cancer is the most prevalent gynecological malignancy worldwide, often caused by infection with a high-risk human papillomavirus. Currently, there are only limited number of human-derived culture systems available that enable to study the viral infection for short-term. Here, we report on establishment of long-term human-derived organoid cultures from both healthy ecto- and endocervical epithelia that closely recapitulate the tissues of origin by maintaining the authentic histological and tissue-specific gene expression profiles. Additionally, using material from patients’ Pap-brush material, a successful panel of long-term patient-derived cancer organoids was established that maintain the causative viral infection in vitro and show differential response to common chemotherapy regimens. This study provides a promising platform for cervical cancer research and studying direct virus-host interactions.

  Study EGAS00001004439

• Mullighan - PAX5-driven Subtypes

  Using integrated genomic analysis of 1.988 childhood and adult cases, we describe a revised taxonomy of B-cell acute lymphoblastic leukemia, which incorporates 23 subtypes defined by chromosomal rearrangements, sequence mutations, or heterogeneous genomic alterations. Two subtypes have frequent alterations of the B lymphoid transcription factor gene PAX5. One, PAX5alt, has diverse PAX5 alterations, and a second subtype is defined by a single mutation, PAX5 P80R. We show that P80R impairs B lymphoid development and promotes the development of B-ALL in vivo. These results demonstrate the utility of transcriptome sequencing to classify B-ALL and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis.

  Study EGAS00001003266

• Personalised therapy with MEK inhibition leads to a sustained complete response in an adolescent patient with a recurrent malignant peripheral nerve sheath tumor

  The prognosis of recurrent malignant peripheral nerve sheath tumors (MPNST) is dismal, with surgical resection being the only definitive salvage therapy. Treatment with chemo-radiation approaches has not significantly improved patient outcomes. Similarly, trials of therapies targeting MPNST genomic drivers have thus far been unsuccessful. Improved understanding of the molecular pathogenesis of MPNST indicates frequent activation of the mitogen activated protein kinase (MAPK) cell signaling pathway. MEK inhibitors have shown activity in preclinical studies; however, their clinical efficacy has not been reported to date. We describe here a case of sustained complete response to MEK inhibition in an adolescent patient with a recurrent metastatic MPNST with multiple alterations in the MAPK pathway, guided by a precision oncology approach.

  Study EGAS00001004899

• RP-1843 Arcagen - Gastrointestinal rare cancers (GI)

  Arcagen is an EORTC/SPECTA pan-European project that aims to recruit 1000 rare cancer patients from different tumour domains of EURACAN. This study collected samples from advanced or metastatic rare cancer from patients older than 12, and analysed them using Foundation Medicine next-generation sequencing (NGS) panels (FoundationOne CDx for FFPE samples or FoundationOne Liquid CDx for blood samples). Here we are submitting two datasets that contain NGS files from gastrointestinal rare cancers (n=119): - Dataset 1 (32 patients): Mesothelioma of the peritoneum (n=21) and Pseudomyxoma peritonei/mucinous adenocarcinoma of the appendix (n=11) - Dataset 2 (87 patients): Intra-hepatic cholangiocarcinoma (n=47), Extra-hepatic, cholangiocarcinoma (n=16), Not specified Cholangiocarcinoma (n=9), Small bowel adenocarcinoma (n=6) and other rare GI cancer (n=9)

  Study EGAS00001006299

• Upper respiratory microbiome of COVID-19 patients

  Understanding the pathology of COVID-19 is a global research priority. Early evidence suggests that the microbiome may be playing a role in disease progression, yet current studies report contradictory results. Here, we examine potential confounders in COVID-19 microbiome studies by analyzing the upper respiratory tract microbiome in well-phenotyped COVID-19 patients and controls combining microbiome sequencing, viral load determination, and immunoprofiling. We found that time in the intensive care unit and the type of oxygen support explained the most variation within the upper respiratory tract microbiome, dwarfing (non-significant) effects from viral load, disease severity, and immune status. Specifically, mechanical ventilation was linked to altered community structure, lower species- and higher strain-level diversity, and significant shifts in oral taxa previously associated with COVID-19.

  Study EGAS00001004951