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• Whole-genome plasma sequencing reveals focal amplifications as a driving force in metastatic prostate cancer

  Genomic alterations in metastatic prostate cancer remain incompletely characterized. Here we analyze 493 prostate cancer cases from the TCGA database and perform whole-genome plasma sequencing on 95 plasma samples derived from 43 patients with metastatic prostate cancer. From these samples, we identify established driver aberrations in a cancer-related gene in nearly all cases (97.7%), including driver gene fusions (TMPRSS2:ERG), driver focal deletions (PTEN, RYBP, SHQ1), and driver amplifications (AR, MYC). In serial plasma analyses, we observe changes in focal amplifications in 40% of cases. The mean time interval between new amplifications was 26.4 weeks (range: 5-52 weeks), suggesting that they represent rapid adaptations to selection pressure. An increase in neuron-specific enolase is accompanied by clonal pattern changes in the tumor genome, most consistent with subclonal diversification of the tumor. Our findings suggest a high plasticity of prostate cancer genomes with newly occurring focal amplifications as a driving force in progression

  Study EGAS00001001018

• MutWP5__CRUK_Mutographs_of_Cancer__Breast__Reduction_Mammoplasty___Exome__Novaseq_

  Cancer is a genetic disease caused by an accumulation of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from breast tissue to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. We will sample from a wide age range of individuals (<20 to >60 years old) to determine whether these processes differ in pre- and post-menopausal women. We will also be comparing the tissue from healthy individuals (samples from breast reduction surgery) to those at elevated risk of breast cancer (mastectomy from BRCA1/2 patients) and those who have breast cancer (adjacent normal, distal normal, and tumour tissue from mastectomy). This will allow us to determine how these processes are different between these groups of individuals, and gain insight into the earliest stages of tumor development.

  Study EGAS00001003527

• Recurrent adeno-associated virus 2-related insertional mutagenesis in human hepatocellular carcinomas

  Hepatocellular carcinomas (HCC) are liver tumors related to various etiologies including alcohol intake, hepatitis B (HBV) or C (HCV) virus infection. Additional risk factors remain to be identified, particularly in patients who develop HCC without cirrhosis. We identified clonal integration of adeno-associated virus type 2 (AAV2) in 11 out of 193 HCC. These AAV2 integrations occurred within known cancer driver genes, namely, CCNA2 (Cyclin A2, 4 cases), TERT (Telomerase Reverse-Transcriptase, 1 case), CCNE1 (Cyclin E1, 3 cases), TNFSF10 (Tumor Necrosis Factor member 10, 2 cases) or KMT2B (Lysine (K)-Specific Methyltransferase 2B, 1 case) leading to over-expression of the target genes. Tumors with viral integration mainly developed in non-cirrhotic liver (9 out of 11 cases) and without known risk factors (6 out of 11) suggesting a pathogenic role of AAV2 in these patients. In conclusion, AAV2 is a DNA virus associated with oncogenic insertional mutagenesis in human HCC.

  Study EGAS00001001284

• Subtype specific progression from DCIS to invasive breast cancer

  Breast cancer consists of at least five main molecular “intrinsic” subtypes, which are reflected in both pre-invasive and invasive disease. Although previous studies have suggested that many of the molecular features of invasive breast cancer are established early, it is unclear what mechanisms drive progression, and whether the mechanisms of progression are dependent or independent of subtype. We have generated mRNA, miRNA and DNA copy number profiles from a total of 59 in situ lesions and 85 invasive tumors, in order to comprehensively identify those genes, signaling pathways, processes, and cell types that are involved in breast cancer progression. Our work provides evidence that there are molecular features associated with disease progression that are unique to the intrinsic subtypes. We additionally establish subtype-specific signatures that are able to identify a small proportion of pre-invasive tumors with expression profiles that resemble invasive carcinoma, indicating a higher likelihood of future disease progression.

  Study EGAS00001001866

• Longitudinal Single-Cell Profiling Reveals Molecular Heterogeneity and Tumor-Immune Evolution in Refractory Mantle Cell Lymphoma

  The mechanisms driving therapeutic resistance and poor outcomes of mantle cell lymphoma (MCL) are incompletely understood. We characterize the cellular and molecular heterogeneity within and across patients and delineate the dynamic evolution of tumor and immune cell compartments at single cell resolution in longitudinal specimens from ibrutinib-sensitive patients and non-responders. Temporal activation of multiple cancer hallmark pathways and acquisition of 17q are observed in a refractory MCL. Multi-platform validation is performed at genomic and cellular levels in PDX models and larger patient cohorts. We demonstrate that the molecular targeting of BIRC5/survivin, locates at 17q and upregulates in resistant MCL tumor cells, results in marked tumor inhibition in preclinical models. In addition, we discovere notable differences in the tumor microenvironment including progressive dampening of CD8+ T cells and aberrant cell-to-cell communication networks in refractory MCLs. This study reveales diverse and dynamic tumor and immune programs underlying therapy resistance in MCL.

  Study EGAS00001005019

• Evolutionary predictability of genetic versus non genetic resistance to anticancer drugs in melanoma

  Therapy resistance arises from heterogeneous drug-tolerant persister cells or minimal residual disease (MRD) through genetic and nongenetic mechanisms. A key question is whether specific molecular features of the MRD ecosystem determine which of these two distinct trajectories will eventually prevail. We show that, in melanoma exposed to MAPK therapeutics, emergence of a transient neural crest stem cell (NCSC) population in MRD concurs with the development of nongenetic resistance. This increase relies on a GDNF-dependent signaling cascade, which activates the AKT survival pathway in a focal adhesion kinase (FAK)-dependent manner. Ablation of the NCSC population through FAK inhibition delays relapse in patient-derived tumor xenografts. Strikingly, all tumors that ultimately escape this treatment exhibit resistance-conferring genetic alterations and increased sensitivity to ERK inhibition. These findings identify an approach that abrogates the nongenetic resistance trajectory in melanoma and demonstrate that the cellular composition of MRD deterministically imposes distinct drug resistance evolutionary paths.

  Study EGAS00001005314

• Molecular profiling of metastatic uveal melanoma

  Metastatic uveal melanoma is less well understood than its primary counterpart, has a distinct biology compared to skin melanoma and lacks effective treatments. Here we genomically profile metastatic tumors and infiltrating lymphocytes. BAP1 alterations were overrepresented and occurred in 29/32 of cases. An outlier tumor had high mutational burden associated with UV-damage. CDKN2A deletions also occurred, which are rarely present in primaries. We profiled recurrent copy number alterations associated with metastasis and performed a focused knockdown screen on overexpressed targets. We investigated the role of BAP1 by reintroducing a functional allele into a deficient patient-derived cell line, revealing a broad shift towards a transcriptomic subtype associated with better prognosis. Tumor-infiltrating lymphocytes were in several cases tumor-reactive, but expression of the immune checkpoint receptors TIM-3, TIGIT and LAG3 was abundant. This study represents the largest whole-genome analysis of uveal melanoma to date and presents an updated view of the metastatic disease.

  Study EGAS00001004296

• Single-cell RNA-seq of bronchoalveolar lavage (BAL) fluid of late stage severe COVID-19 patients

  COVID-19-induced ‘acute respiratory distress syndrome’ (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyzed pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single cell genomics, immunohistology and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages, that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not Influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.

  Study EGAS00001005634

• Gain of function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions

  DNA methylation and Polycomb are key factors in the establishment of vertebrate cellular identity and fate. Here we report de novo missense mutations in DNMT3A, encoding the DNA methyltransferase DNMT3A, that cause microcephalic dwarfism, a hypocellular disorder of extreme global growth failure. Substitutions in the PWWP domain abrogate binding to the histone modifications H3K36me2/3, and alter DNA methylation in patient cells. Polycomb-associated DNA methylation canyons/valleys, hypomethylated domains encompassing developmental genes, become methylated with concomitant depletion of H3K27me3 and H3K4me3 bivalent marks. Such de novo DNA methylation occurs during differentiation of Dnmt3aW326R pluripotent cells in vitro, and is also evident in Dnmt3aW326R/+ dwarf mice. We therefore propose that the interaction of the DNMT3A PWWP domain with H3K36me2/3 normally limits DNA methylation of polycomb-marked regions. Our findings implicate the interplay between DNA methylation and polycomb at key developmental regulators as a determinant of organism size in mammals.

  Study EGAS00001003232

• Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer

  Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary endpoint, decreased Ki67, occurs in 12% of TNBC. Multiple different approaches identify HR deficiency in the majority of TNBC, 69% with the mutational-signature-based HRDetect assay. Cancers with mutational signatures of HR deficiency have a functional defect in HR. Following rucaparib treatment there is no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identify activity of rucaparib in cancers with mutation-signatures of HR deficiency, with rucaparib inducing expression of interferon response genes in HR deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors.

  Study EGAS00001004405