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• The Acquisition of Molecular Drivers in Pediatric Therapy-Related Myeloid Neoplasms

  Pediatric therapy-related myeloid neoplasms (tMN) occur in children after exposure to cytotoxic therapy and have a dismal prognosis1-4. The somatic and germline genomic alterations that drive these myeloid neoplasms in children and how they arise have yet to be comprehensively described. We use whole exome, whole genome, and/or RNA sequencing to characterize the genomic profile of 85 pediatric tMN cases (tMDS: n=29, tAML: n=56). Our data show that Ras/MAPK pathway mutations, alterations in RUNX1 or TP53, and KMT2A rearrangements are frequent somatic drivers, and we identify cases with aberrant MECOM expression secondary to enhancer hijacking. Unlike adults with tMN5-7, we find no evidence of pre-existing minor tMN clones (including those with TP53 mutations), but rather the majority of cases were unrelated clones arising as a consequence of cytotoxic therapy. These studies also uncover rare cases of lineage switch disease rather than true secondary neoplasms.

  Study EGAS00001004850

• The genomic landscape of early stage ovarian high grade serous carcinoma

  To determine whether early-stage ovarian high grade serous carcinoma (HGSC) represents a distinct genomic entity, we collected samples from 43 patients with stage IA-IIA HGSC to identify potential differences in short genomic variants and copy number aberrations, and compared them to a cohort of 52 late-stage (stage IIIC-IV) cases. We found no significant differences in somatic mutations or focal copy number alterations between early-stage and late-stage cohorts. There was, however, a significant difference in both ploidy and copy number signature exposure between early and late-stage samples, with higher ploidy and signature 4 exposure in late-stage cases. Unsupervised hierarchical clustering revealed three clusters, which were prognostic. Together, our data suggest that early and late-stage HGSC share fundamental genomic features, but that late- stage disease appears distinct from early-stage, with evidence of whole genome duplication that may provide evolutionary benefit.

  Study EGAS00001005567

• Multimodal immunogenomic biomarker analysis of tumors from pediatric patients enrolled to a phase 1-2 study of single-agent atezolizumab

  We report herein an extensive exploratory biomarker analysis of refractory tumors taken from pediatric patients prior to receiving atezolizumab monotherapy in the phase 1-2 iMATRIX-atezolizumab trial (NCT02541604). A high percentage of CD8+ T cells and elevated protein levels of programmed cell death ligand 1 (PD-L1) were associated with progression-free survival (PFS). T-cell receptor (TCR) sequencing revealed that diverse infiltrating TCR repertoire at baseline was prognostic. We found no associations between panel-based tumor mutation burden (TMB) or specific genetic aberrations with PFS in this study. Through a pan-cancer gene co-expression network analysis, we developed a novel tumor-agnostic Pediatric Cytotoxicity and Antigen Presentation (PedCAP) signature that was associated with improved PFS in the iMATRIX-atezo study. Our study highlights features of immune response in pediatric cancers when treated with immune checkpoint inhibitors and provides a multi-biomarker pediatric immunogram framework to guide prospective clinical trials in pediatric cancers.

  Study EGAS00001006004

• Fetal origins of malignant germ cell tumours

  Germ cell tumours (GCTs) are a collection of benign and malignant neoplasms derived from primordial germ cells (PGCs). They are uniquely able to generate embryonic and extraembryonic tissues, which in malignant GCTs carries prognostic and therapeutic significance. The developmental pathways underpinning GCT initiation and histogenesis are incompletely understood. Here, we studied the phylogenetic and transcriptional diversity of 15 malignant gonadal GCTs and four normal testis biopsies by sequencing 131 whole genomes and 416 transcriptomes from 14 gonadal histologies, excised by laser capture microdissection. Our findings demonstrate that tumours were initiated by whole genome duplication likely in embryogenesis, within ~5-8 cell divisions post-PGC specification, followed by chromosome 12p gains associated with invasive disease. Of note, 12p imbalances were not only generated through GCT-typical isochromosomes, but also through non-isochromosomic configurations. Whilst tumours developed along homogenous phylogenetic pathways, they spawned manifold tissues independent of genetic subclonal diversification. A key feature of GCT tissues was the expression of fetal-specific genes. The transcriptional diversity notwithstanding, we found universal transcriptional elements correlated with hallmark 12p gains. Overall, our study reveals stereotyped phylogenies and transcriptomes underpinning the development of GCT that originate in fetal life and may lend themselves to therapeutic manipulation.

  Dataset EGAD00001007037

• Mult-omics Palbociclib Resistance Study in HR+/HER2– Metastatic Breast Cancer

  Resistance to CDK4/6 inhibitors and endocrine therapy (ET) are common and poorly understood since they have been real game changer in patients with HR-positive and HER2-negative MBC. A comprehensive genomic and transcriptomic analysis of pre-treatment and post-treatment tumors from patients treated with palbociclib plus ET identified novel markers associated with poor prognosis such as genomic scar features caused by homologous repair deficiency (HRD), estrogen response signatures, and four unique prognostic clusters with distinct molecular features. Tumors with TP53 mutations co-occurring with a unique HRD-high cluster responded poorly. By comparing genomic and transciptomic profiles of paired samples, tumors were found to be further enriched in HRD genomic scars and many had switched to aggressive molecular subtypes. Furthermore, we identified high frequencies of acquired genomic alterations upon disease progression in RB1, ESR1, PTEN, and KMT2C. Our findings provide new insight into potential predictive biomarkers that could be targeted to overcome resistance. (NCT03401359)

  Study EGAS00001005736

• Circulating Biomarker Laboratory within the Division of Cancer of Imperial College London

  The purpose of the Circulating Biomarker Laboratory within the Division of Cancer of Imperial College London (ICL) is to assist ICL researchers working on solid tumours or/and haematological malignancies with a particular interest in the analysis of liquid biopsies. We are focusing on isolating and analysing single circulating tumour cells (CTCs) and cell-free circulating tumour DNA (ctDNA) from cancer patients' blood samples but also pure tumour poulations from heterogeneous Formalin-fixed paraffin-embedded (FFPE) tissue specimens with a view to monitoring tumour-related changes, such as mutations and copy number alterations at a single cell level.

  Dac EGAC50000000768

• Peruvian Genome Project

  Through the Peruvian Genome Project we generate and analyze the high coverage genomes of 150 individuals where the majority have >90% Native American ancestry and explore questions at the interface of evolutionary genetics, history, anthropology, and medicine. This is the most extensive sampling of high-coverage Native American and mestizo whole genomes to date. Reference: https://doi.org/10.1073/pnas.1720798115

  Dataset EGAD00001007082

• Whole-genome plasma DNA sequencing in CRC patients under anti-EGFR therapy

  In this study we performed whole genome sequencing of plasma DNA (plasma-Seq) of 19 plasma-DNA samples from a total of 10 patients treated with anti-EGFR therapy. We demonstrated that development of resistance to anti-EGFR therapies is frequently associated with focal amplifications of KRAS, MET, and ERBB2. We also showed that focal KRAS amplifications can be acquired in tumor genomes of patients under cytotoxic chemotherapy. Furthermore, we provide evidence that specific chromosomal polysomies, such as overrepresentations of 12p and 7p, harboring KRAS and EGFR, respectively, determine responsiveness to anti-EGFR therapy.

  Dataset EGAD00001000748

• Detection of clinically relevant genetic and transcriptomic landscape in DLBCL uniformly treated by R-CHOP

  Recent studies using next-generation sequencing strategies have described the landscape of genetic alterations in diffuse large B-cell lymphoma (DLBCL). However, little is known about the clinical relevance of recurrent mutations and copy number alterations and their transcriptional footprints. This study examines the frequency, interaction and clinical impact of recurrent genetic aberrations in DLBCL using high-resolution technologies in a large population-based cohort.

  Dataset EGAD00001003783

• Genomic Evolution of Breast Cancer Metastasis and Relapse

  Recurrent breast cancer is almost universally fatal. We characterize 170 patients locally relapsed or distant metastatic cancers using massively parallel sequencing. We identify that the relapse-seeding clone disseminates late from the primary tumor. TP53 and AKT1 appear to be enriched in ER-positive cancers predisposed to relapse. Mutation acquisition continues at relapse as the same mutation signatures continue to operate and new signatures, such as that caused by radiotherapy appear de novo. In 49% of cases we identify drivers mutations private to the relapse and these are sampled from a wider range of cancer genes, including SWI-SNF complex and JAK-STAT signaling.

  Dataset EGAD00001002697