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• The dataset of Southeast Borneo individuals (Banjar and Ngaju ethnic groups) was used as comparative data to determine the Asian parental population of the Malagasy. Our study found strong support for an origin of the Asian ancestry of Malagasy among the Banjar.

  Malagasy genetic diversity results from an exceptional proto-globalisation process that took place over a thousand years ago across the Indian Ocean. Previous efforts to locate the Asian origin of Malagasy have highlighted Borneo broadly as a potential source, but so far no firm source populations have been identified. Here, we have generated genome-wide data from two Southeast Borneo populations, the Banjar and the Ngaju, together with published data compiled from populations across the Indian Ocean region. We find strong support for an origin of the Asian ancestry of Malagasy among the Banjar. This group emerged from the long-standing presence of a Malay Empire trading post in Southeast Borneo, which favoured admixture between the Malay and an autochthonous Borneo group, the Ma’anyan. Reconciling genetic, historical and linguistic data, we show that the Banjar, in Malay-led voyages, were the most probable Asian source among the analysed groups in the founding of the Malagasy gene pool.

  Study EGAS00001001841

• Mapping the breast cancer metastatic cascade onto circulating tumour DNA using genetic and epigenetic clonal tracking

  Circulating tumour DNA (ctDNA) allows tracking the evolution of human cancers at high resolution, overcoming many limitations of tissue biopsies. However, exploiting ctDNA to determine how a patient’s cancer is evolving in order to aid clinical decisions remains difficult. This is because ctDNA is a mix of fragmented alleles, and the contribution of different cancer cell subpopulations from distinct lesions to ctDNA remains largely unknown. Profiling of ctDNA almost invariably requires prior knowledge of what genomic alterations to track. Here we leverage on a rapid autopsy programme to demonstrate that unbiased genomic characterisation of several metastatic sites and concomitant ctDNA profiling at whole-genome resolution reveals the extent to which ctDNA is representative of widespread disease. We also present a ctDNA methylation profiling method that allows tracking evolutionary changes in the cancer cell population at single-molecule resolution without prior knowledge. These results have critical implications for the use of liquid biopsies to monitor cancer evolution in humans and potentially guide treatment.

  Study EGAS00001004014

• Comprehensive pharmacogenomic characterization of gastric cancer

  Gastric cancer is among the most lethal human malignancies. Previous studies have identified molecular aberrations that constitute dynamic biological networks and genomic complexities of gastric tumors. However, the clinical translation of molecular-guided targeted therapy is hampered by challenges. Notably, solid tumors often harbor multiple genetic alterations, complicating the development of effective treatments. To address such challenges, we established a comprehensive dataset of molecularly annotated patient derivatives coupled with pharmacological profiles for 60 targeted agents to explore dynamic pharmacogenomic interactions in gastric cancers. We identified lineage-specific drug sensitivities based on histopathological and molecular subclassification, including substantial sensitivities toward VEGFR and EGFR inhibition therapies in diffuse- and signet ring-type gastric tumors, respectively. We identified potential therapeutic opportunities for WNT pathway inhibitors in ALK-mutant tumors, a significant association between PIK3CA-E542K mutation and AZD5363 response, and transcriptome expression of RNF11 as a potential predictor of response to gefitinib. Collectively, our results demonstrate the feasibility of drug screening combined with tumor molecular characterization to facilitate personalized therapeutic regimens for gastric tumors.

  Study EGAS00001004106

• Molecular origins of mpMRI visibility

  Multiparametric magnetic resonance imaging (mpMRI) has transformed the landscape of prostate cancer (PCa) management. Prostate Imaging Reporting and Data System (PI-RADSv2) scores reflect function and correlate phenotypic features with tumor aggressiveness, is an independent predictor of biochemical recurrence, and may distinguish low-risk tumors requiring no treatment from high-risk tumors requiring aggressive management. We hypothesize that differences in functional mpMRI of prostate tumors reflect the genetic and epigenetic heterogeneity of PCa. We profiled the genomes and transcriptomes of 40 Gleason score 3+4 tumors, of which 20 tumors were mpMRI invisible (not PI-RADSv2 3-5) and 20 tumors were visible (PI-RADSv2 5). Genomes of visible tumors were more unstable than those of invisible tumors. We identified 62 enriched transcripts, including numerous snoRNAs, Relaxin 1 and SCHLAP1, in visible tumors. These data suggest a confluence of aggressive pathological and microenvironmental phenomenon in PI-RADSv2 5 tumors reminiscent of nimbosus, while linking the molecular profiles of tumor aggressiveness with their functional features on mpMRI.

  Study EGAS00001003179

• Molecular stratification of endometrioid ovarian carcinoma predicts clinical outcome

  Endometrioid ovarian carcinoma (EnOC) is an under-investigated type of ovarian carcinoma. Here, we report the largest genomic study of EnOCs to date, performing whole exome sequencing of 112 cases following rigorous pathological assessment. High frequencies of mutation were detected in CTNNB1(43%), PIK3CA(43%), ARID1A(36%), PTEN(29%), TP53(26%) and SOX8(19%), a novel target of recurrent mutation in EnOC. POLE and mismatch repair protein-encoding genes were mutated at lower frequency (6%, 18%) with significant co-occurrence. A molecular taxonomy was constructed using a novel algorithm (PRISTINE), identifying clinically distinct EnOC subtypes: TP53m cases demonstrated greater genomic complexity, were frequently FIGO stage III/IV at diagnosis (48%) and incompletely debulked (44%), and demonstrated inferior survival; conversely, CTNNB1m cases demonstrated low complexity and excellent clinical outcome, were predominantly stage I/II at diagnosis (89%) and completely resected (87%). Tumour complexity provides further resolution within the TP53wt/CTNNB1wt group. Moreover, we identify the WNT, MAPK/RAS and PI3K pathways as good candidate targets for molecular therapeutics in EnOC.

  Study EGAS00001004366

• Salivary Gland Cancer TSO500 dataset

  Salivary gland cancer (SGC) is a rare cancer for which systemic treatment options are limited. Therefore, it is important to characterize its genetic landscape in search for actionable aberrations. This research aimed to identify these actionable aberrations by NGS-based analysis of DNA (single and multiple nucleotide variants, copy number variants, microsatellite instability and tumor mutational burden) in a large cohort of SGC patients. DNA was extracted from archival tissue of 119 patients with various SGC subtypes and sequenced using a targeted NGS panel encompassing 523 cancer related genes (TruSight Oncology 500, TSO500). The 119 patients included 46 AdCC patients, 43 SDC patients, 15 MEC patients, 9 AciCC patients and 6 patients with other subtypes (1 secretory carcinoma, 1 polymorphic adenocarcinoma (PAC), 1 adenocarcinoma NOS, 1 myoepithelial carcinoma, 1 epithelial/myoepithelial carcinoma and 1 mixed PAC/myoepithelial carcinoma). Median exon coverage ranged from 80-904 (median 308) unique reads and the median percentage of exon coverage with at least 100 unique reads was median 96.6% in these 119 samples.

  Study EGAS00001006232

• Genotype data from 'Dense sampling of ethnic groups within African countries reveals fine-scale genetic structure and extensive historical admixture.'

  Previous studies have highlighted how African genomes have been shaped by a complex series of historical events. Despite this, genome-wide data has only been obtained from a small proportion of present-day ethnolinguistic groups. By analysing new autosomal genetic variation data of 1333 individuals from over 150 ethnic groups from Cameroon, Republic of the Congo, Ghana, Nigeria and Sudan, we demonstrate a previously underappreciated fine-scale level of genetic structure within these countries, for example correlating with historical polities in western Cameroon. By comparing genetic variation patterns among populations, we infer that many northern Cameroonian and Sudanese groups share genetic links with multiple geographically disparate populations, likely resulting from long-distance migrations. In Ghana and Nigeria, we infer signatures of intermixing dated to over 2000 years ago, corresponding to reports of environmental transformations possibly related to climate change. We also infer recent intermixing signals in multiple African populations, including Congolese, that likely relates to the expansions of Bantu language-speaking peoples.

  Study EGAS00001006944

• Deep whole genome ctDNA chronology of treatment-resistant prostate cancer

  Circulating tumor DNA (ctDNA) in blood plasma is an emerging tool for clinical cancer genotyping and longitudinal disease monitoring. We performed deep whole-genome sequencing of serial plasma and synchronous metastases in patients with aggressive prostate cancer. We comprehensively assess all classes of genomic alterations and demonstrate that ctDNA harbors multiple dominant populations whose evolutionary histories frequently indicate whole-genome doubling and shifts in mutational processes. Although tissue and ctDNA showed concordant clonally-expanded cancer driver alterations, each individual metastasis contributed only a minor share of total ctDNA. By comparing serial ctDNA before and after clinical progression on potent androgen receptor (AR) pathway inhibitors, we reveal population restructuring converging solely on AR augmentation as the dominant genomic driver of acquired treatment-resistance. Finally we leverage nucleosome footprints in ctDNA to infer mRNA abundance in synchronously biopsied metastases, including treatment-induced changes in AR pathway transcriptional activity.

  Dataset EGAD00001008460

• TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.

  We examined tumours from a large cohort of patients with metastatic urothelial bladder cancer (mUC) treated with an anti–PD-L1 agent (atezolizumab) and identified major determinants of clinical response and immune escape. Whole transcriptome profiles were generated for 368 patients using TruSeq RNA Access technology (Illumina). Somatic mutations were determined via whole exome sequencing for a subset of these patients. - Response was associated with CD8+ T effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden (TMB). On the other hand, lack of response was associated with a transforming growth factor β (TGF-β) signature, particularly in patients with CD8+ T cells preferentially residing in collagen-rich matrix surrounding tumours. Integration of these three independent biological features provided the best basis for understanding outcome in this setting. -

  Study EGAS00001002556

• Accurate Immune Repertoire Sequencing Reveals Malaria Infection Driven Antibody Lineage Diversification in Young Children

  This study describes a novel Immune Repertoire Sequencing technique, termed Molecular Identifier Clustering-based Immune Repertoire Sequencing (MIDCIRS), to reduce sequencing error while maintaining extremely high coverage and applies this technique to investigate the differential immune response to malaria between infants and toddlers. Despite a lower somatic hypermutation load, we found an unexpectedly high level of competency within the infant antibody repertoire, particularly the ability to diversify B cell clonal lineages upon acute infection. Detailed clonal lineage analysis encompassing lineages containing sequences from both pre- and acute malaria timepoints revealed an increase in somatic hypermutations upon acute infection. Further analysis on pre-malaria memory B cell containing lineages in toddlers who had previously been exposed to malaria provides evidence for the capacity of memory B cells to continue to mutate and isotype switch.

  Study phs001209