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• Whole exome sequencing on primary retinoblastoma tissues and matching lymphocyte DNA.

  Retinoblastoma is a rare childhood cancer initiated by RB1 mutation or MYCN amplification, while additional alterations may be required for tumor development. However, the view on single nucleotide variants is very limited. To better understand oncogenesis, we determined the genomic landscape of retinoblastoma. We performed exome sequencing of 71 retinoblastomas and matched blood DNA. Next, we determined the presence of single nucleotide variants, copy number alterations and viruses. Aside from RB1, recurrent gene mutations were very rare. Only a limited fraction of tumors showed BCOR (7/71, 10%) or CREBBP alterations (3/71, 4%). No evidence was found for the presence of viruses. Instead, specific somatic copy number alterations were more common, particularly in patients diagnosed at later age. Recurrent alterations of chromosomal arms often involved less than one copy, also in highly pure tumor samples, suggesting within-tumor heterogeneity. Our results show that retinoblastoma is among the least mutated cancers and signify the extreme sensitivity of the childhood retina for RB1 loss. We hypothesize that retinoblastomas arising later in retinal development benefit more from subclonal secondary alterations and therefore, these alterations are more selected for in these tumors. Targeted therapy based on these subclonal events might be insufficient for complete tumor control.

  Study EGAS00001001690

• Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy

  We studied a group of melanoma patients treated with neoadjuvant BRAF/MEK-targeted therapy (NCT02231775, n=51), and observed significantly higher rates of major pathologic response (MPR= <10% viable tumor at resection) and improved recurrence-free survival (RFS) in females versus males (MPR-66% versus 14%, p=0.001; RFS-64% versus 32% at 2 years, p=0.021). Findings were validated in a several additional cohorts 2-4 patients with unresectable metastatic melanoma treated with BRAF and/or MEK-targeted therapy (n=664 patients in total), demonstrating improved progression-free survival (PFS) and overall survival (OS) in females versus males in several of these studies. Studies in pre-clinical models demonstrated significantly impaired anti-tumor activity in male versus female BRAF/MEK-treated mice (p=0.006), with significantly higher expression of androgen receptor (AR) in tumors of male and female BRAF/MEK-treated mice versus control (p=0.0006 and 0.0025). Pharmacologic inhibition of AR signaling improved responses to BRAF/MEK-targeted therapy in male and female mice (p=0.018 and p=0.003), whereas induction of AR signaling (via testosterone administration) was associated with significantly impaired response to BRAF/MEK-targeted therapy in males and females (p=0.021 and p<0.0001).

  Study EGAS00001006196

• Transcriptomics identifies blunted immunomodulatory effects of vitamin D in people with multiple sclerosis

  Vitamin D deficiency is a risk factor for developing multiple sclerosis (MS). However, the immune effects of vitamin D in people with MS are not well understood. We analyzed transcriptomic datasets generated by RNA sequencing of immune cell subsets (CD4+, CD8+ T cells, B cells, monocytes) from 33 healthy controls and 33 untreated MS cases. We utilized a traditional bioinformatic pipeline and weighted gene co-expression network analysis (WGCNA) to determine genes and pathways correlated with endogenous vitamin D. In controls, CD4+ and CD8+ T cells had 1079 and 1188 genes, respectively, whose expressions were correlated with plasma 25-hydroxyvitamin D level (P<0.05). Functional enrichment analysis identified association with TNF-alpha and MAPK signaling. In CD4+ T cells of controls, vitamin D level was associated with expression levels of several genes proximal to multiple sclerosis risk loci (P=0.01). Genes differentially associated with endogenous vitamin D by case-control status were enriched in TNF-alpha signaling via NF-κB. WGCNA suggested a blunted response to vitamin D in cases relative to controls. Collectively, our findings provide further evidence for the immune effects of vitamin D, and demonstrate a differential immune response to vitamin D in cases relative to controls, highlighting a possible mechanism contributing to MS pathophysiology.

  Study EGAS00001007254

• Clinical outcomes and immune correlates of response to nivolumab plus chemoradiotherapy in women with locally-advanced cervical cancer – NiCOL study

  Concurrent chemoradiotherapy (CRT) with blockade of the PD-1 pathway may enhance immune-mediated tumor control through increased phagocytosis, cell death, and antigen presentation. The NiCOL phase 1 trial was designed to determine safety, tolerance, and immune correlates of response to the PD-1 blocking antibody, nivolumab, with and following concurrent CRT in 16 women with locally advanced cervical cancer (LACC). Three patients experienced grade 3 dose-limiting toxicities. The overall response rate was 93.8% [95%CI: 69.8%-99.8%] with a 2-year PFS of 75% [95% CI: 56.5%-99.5%]. Compared to patients with progressive disease (PD), progression-free (PF) subjects showed a brisker stromal immune infiltrate, higher proximity of tumor-infiltrating CD3+ T cells to PD-L1+ tumor cells and of Foxp3+ T cells to proliferating CD11c+ myeloid cells. PF had higher baseline levels of PD-1 on EMRA CD4+ T cells and ICOS-L on tumor-associated macrophages (TAMs) vs PD, which instead displayed enhanced PD-L1 expression on TAMs and higher, circulating frequencies of proliferating Tregs at baseline. Concomitant nivolumab plus definitive CRT is safe and associated with encouraging PFS rates. Further validation in the subset of LACC displaying pre-existing, adaptive immune activation is warranted.

  Study EGAS00001007297

• WES of 2 human osteosarcoma and corresponding cell lines

  Progress in the systemic control of osteosarcoma has been limited over the past decades thus indicating the urgent clinical need for the development of novel treatment strategies. Therefore, we have recently developed new preclinical models to study promising novel agents for the treatment of pediatric osteosarcoma. The checkpoint kinase (chk) inhibitor prexasertib (LY2606368) and its salt form (LSN2940930) have recently been shown to be active in adult and pediatric malignancies, including sarcoma. We have now tested the potency of prexasertib in clonogenic survival assays in two new lines of primary patient-derived osteosarcoma cells and in two established osteosarcoma cell lines as a single agent and in combination with cisplatin and the poly ADP-ribose polymerase (PARP) inhibitor talazoparib. Prexasertib alone results in strongly reduced clonogenic survival at low nanomolar concentrations and acts by affecting cell cycle progression, induction of apoptosis and induction of double-stranded DNA breakage at concentrations that are well below clinically tolerable and safe plasma concentrations. In combination with cisplatin and talazoparib, prexasertib acts in a synergistic fashion. Chk1 inhibition by prexasertib and its combination with the DNA damaging agent cisplatin and the PARP-inhibitor talazoparib thus emerges as a potential new treatment option for pediatric osteosarcoma which will now have to be tested in preclinical primary patient derived in vivo models and clinical studies.

  Study EGAS00001003923

• PAX5 biallelic genomic alterations define a novel subgroup of B cell precursor acute lymphoblastic leukemia

  Chromosomal rearrangements and specific aneuploidy patterns are initiating events and define subgroups in B cell precursor acute lymphoblastic leukemia (BCP-ALL). Here we analyzed 250 BCP-ALL cases and identified a novel subgroup (‘PAX5-plus’, n=19) by distinct DNA methylation and gene expression profiles. All patients in this subgroup harbored mutations in the B-lineage transcription factor PAX5, with p.P80R as hotspot. Mutations either affected two independent codons, consistent with compound heterozygosity, or suffered LOH predominantly through chromosome 9p aberrations. These biallelic events resulted in disruption of PAX5 transcriptional programs regulating B cell differentiation and tumor suppressor functions. Homozygous CDKN2A/B deletions and RAS activating hotspot mutations were highly enriched as cooperating events in the genomic profile of PAX5-plus ALL. Together this defined a specific pattern of triple alterations, exclusive to the novel subgroup. PAX5-plus ALL was observed in pediatric and adult patients. Although restricted by the limited sample size, a tendency for more favorable clinical outcome was observed with 10 of 12 adult PAX5-plus patients achieving long-term survival. PAX5-plus represents the first BCP-ALL subgroup defined by sequence alterations in contrast to gross chromosomal events and exemplifies how deregulated differentiation (PAX5), impaired cell cycle control (CDKN2A/B) together with sustained proliferative signaling (RAS) cooperatively drives leukemogenesis.

  Study EGAS00001003209

• Extracellular transcriptome in seminal plasma for non-invasive prostate cancer diagnosis

  A diagnostic non-invasive biomarker test for prostate cancer at an early stage, with high sensitivity and specificity, would improve diagnostic decision making. Extracellular RNAs present in seminal plasma might contain biomarker potential for the accurate detection of clinically significant prostate cancer. So far, the extracellular messenger RNA (mRNA) profile of seminal plasma has not been interrogated for its biomarker potential in the context of prostate cancer. Here, we investigate the mRNA transcriptome in seminal plasma samples obtained from prostate cancer patients (n=25), patients with benign prostate hyperplasia (n=26) and individuals without prostatic disease (n=6). Seminal plasma harbors a complex mRNA repertoire that reflects prostate as its tissue of origin. The endogenous RNA content is higher in the prostate cancer samples compared to the control samples. Prostate cancer antigen 3 (PCA3), a long non-coding RNA with prostate cancer-specific overexpression, and ATP-binding cassette transporter 1 (ABCA1), known to be involved in the prostate cancer pathogenesis, were more abundant in the prostate cancer group. In addition, twelve high confidence fusion transcripts could be detected in prostate cancer samples, including the bona-fide prostate cancer fusion transcript TMPRSS2-ERG. Our findings provide proof-of-principle that the extracellular transcriptome of seminal plasma can reveal information of an underlying prostate cancer.

  Study EGAS00001005277

• Towards standardized whole exome sequencing (WES) for cancer patients: lessons from a multicentric pilot study

  A growing number of druggable targets and national initiatives for precision oncology necessitate broader genomic profiling for many cancer patients. Whole exome sequencing (WES) offers unbiased analysis of the entire coding sequence, segmentation-based detection of copy number alterations (CNAs), and accurate determination of complex biomarkers including tumor mutational burden (TMB), homologous recombination repair deficiency (HRD), and microsatellite instability (MSI). To assess the inter-institution variability of clinical WES, we performed a comparative pilot study between German Centers of Personalized Medicine (ZPMs) from five participating institutions. Tumor and matched normal DNA from 30 patients were analyzed using custom sequencing protocols and bioinformatic pipelines. Calling of somatic variants was highly concordant with a sensitivity between 91-95% and a positive predictive value (PPV) of 82-95% compared with a three-institution consensus and full agreement for 16 of 17 druggable targets. Deviations were observed for cases with low VAF or coverage, differing annotations, and different filter protocols. CNAs showed overall agreement in 76% for the genomic sequence with high wet-lab variability. Complex biomarkers correlated strongly between institutions (HRD: 0.79-1, TMB: 0.97-0.99) and all institutions agreed on microsatellite instability. This study will contribute to the development of quality control frameworks for comprehensive genomic profiling and sheds light onto parameters that require stringent standardization.

  Study EGAS00001007363

• Carbamazepine-induced hypersensitivity reactions in Europeans

  An antiepileptic drug carbamazepine is well tolerated by the majority of patients, but can cause severe and potentialy fatal hypersensitivity reactions in a small number of individuals. The aim of this study was to identify genetic predictors of hypersensitivity reactions to carbamazepine. We undertook a genome-wide association study (GWAS) in 22 patients of European ancestry with carbamazepine-induced hypersensitivity syndrome (HSS) and compared our data with genotypes from a healthy population within the WTCCC. We performed imputation of classical HLA alleles according to a recently described method (Science. 2010 Dec 10;330(6010):1551-7. Epub 2010 Nov 4). GWAS statistical analysis was performed using logistic regression with an additive model of inheritance.

  Study EGAS00000000037

• WNT-signaling and Dupuytren's Disease

  The EGA hosts the summary genotype results of the GWAS in 856 patients with Dupuytren's disease and 2,836 population based controls from 'LifeLines' cohort study

  Study EGAS00000000043