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• Splicing signature analysis of RNU4-2, RNU5A-1 and RNU5B-1

  Pathogenic variants in the snRNA RNU4-2 were recently described as a frequent cause of neurodevelopmental disorders. In our study we further delineate the phenotype associated with RNU4-2 and we also identify pathogenic variants in RNU5A-A and RNU5B-1. Capture-based RNA-Seq were performed to compare splicing pattern between affected and control individuals. A strong signature based on alternative 5' splice site usage was found for RNU4-2 patients, and we suggest an either 5' or 3' signature depending on the variant's localiztion in U5 genes.

  Study EGAS50000000889

• Genetics of Mood Disorders: Aging and Emotion Regulation Brain Circuitry in Bipolar

  This single-site study is designed to investigate age-related changes in structure and function of a ventral prefrontal cortex (VPFC) neural system, that subserves emotion processing and regulation, during mid to later adulthood in individuals with bipolar disorder (BD), compared to healthy controls (HC). It is a 5-year study of age-related changes in mood, emotion regulation and related symptoms and behaviors using multimodality imaging measures [structural magnetic resonance imaging (MRI) of gray matter, diffusion tensor imaging (DTI) of white matter, and functional MRI measures of functional connectivity and of brain responses during implicit and explicit emotion regulation] comparing BD and HC groups ages 40-79 years, 50% female; a subgroup will be reassessed and rescanned after 2 years to study brain and associated behavioral changes over time. We will explore relationships between brain aging with risk factors implicated in progression. This will include genes, as well as adverse outcomes of progression such as suicide ideation and behavior. As there has been little study of effects of aging of the VPFC emotional circuitry in healthy individuals, findings could provide new insights into brain circuitry and emotional regulation in older adults. In addition to the importance of contributing to understanding BD, as BD is unique in having both elevated and depressive episodes, its study can provide a model for understanding progressive emotion dysregulation to both intervention and prevention that can be better targeted specifically for older individuals with BD. A de-identified blood sample will be sent to the Repository and Genomics Resource.

  Study phs001631

• Genetic Underpinnings of Ethnic Disparities in Bone Toxicities Between Hispanic and Non-Hispanic Children Treated for Acute Lymphoblastic Leukemia

  Acute lymphoblastic leukemia (ALL) is the most common malignancy among children and young adolescents. More than 90% of children are cured with a combination of multiple chemotherapeutic drugs. Some may suffer from debilitating toxicities due to the cytotoxic drugs, necessitating pharmacogenetic research to search for genetic markers predictive of treatment toxicities, so that treatment can be better tailored based on patients' genetic makeup. Bone toxicities, including osteonecrosis and fractures, most often due to glucocorticoids, are the most common complications in ALL, which have long-lasting detrimental impact on the still developing skeletons in children. In DFCI ALL Consortium Protocol 05-001, a multi-center clinical trial for childhood ALL conducted in Canada and the US, we found that Hispanic children had less drug toxicities to their bones than non-Hispanic children. Although reasons for the observed ethnic differences are largely unknown, patients' inherited genetic background may be at play. This study seeks to perform a novel pharmacogenomic study based on multi-site clinical trials DFCI ALL Consortium Protocol 05-001 and 11-001 to identify genetic underpinnings of ethnic disparities in bone toxicities.

  Study phs002317

• Mid-pass Whole-genome Sequencing in a Malagasy Cohort Uncovers Body Composition Associations

  The majority of human genomic research studies have been conducted in European-ancestry cohorts, reducing the likelihood of detecting potentially novel and globally impactful findings. Here, we present mid-pass whole-genome sequencing data and a genome-wide association study in a cohort of 264 self-reported Malagasy individuals from three locations on the island of Madagascar. We describe genetic variation in this Malagasy cohort, providing insight into the shared and unique patterns of genetic variation across the island. We observe phenotypic variation by location, and find high rates of hypertension particularly in the Southern Highlands sampling site as well as elevated self-reported malaria prevalence in the West Coast site relative to other sites. After filtering to a subset of 214 minimally-related individuals, we find a number of genetic associations with body composition traits, including many variants that are only observed in African populations or populations with admixed African ancestry from the 1000 Genomes Project. This study highlights the importance of including diverse populations in genomic research for the potential to gain novel insights, even with small cohort sizes. This project was conducted in partnership and consultation with local stakeholders in Madagascar and serves as an example of genomic research that prioritizes community engagement and that has potential impacts on our understanding of human health and disease.

  Study EGAS50000000496

• Differential methylation positions

  This dataset includes an analyzed DMP file that provide the information about differential methylation positions based on Illumina Infinium MethylationEPIC BeadChip. All samples (5 lung cancer cases vs. 5 benign lung disease controls) were obtained from bronchial washings at the site of the lesion under bronchoscopy manipulation. Of the five lung cancer cases, 3 are adenocarcinoma and 2 are squamous carcinoma.

  Dataset EGAD00001010147

• Oncogene activated human breast luminal progenitors contribute basally located myoepithelial cells

  Basal-like breast cancer originates in luminal progenitors, frequently with an altered PI3K pathway, and focally in close association with genetically altered myoepithelial cells at the site of tumor initiation. The exact trajectory behind this bi-lineage phenomenon remains poorly understood. Here we used a breast cancer relevant transduction protocol including hTERT, shp16, shp53, and PIK3CA(H1047R) to immortalize FACS isolated luminal cells, and we identified a candidate multipotent progenitor. We found that the apparent luminal phenotype of these oncogene transduced progenitors was metastable giving rise to basal-like cells dependent on culture conditions.

  Study EGAS50000000505

• Aberrant expression of SLAMF6 constitutes a targetable immune escape mechanism in acute myeloid leukemia

  In this study, we demonstrate that aberrant expression of SLAMF6 on acute myeloid leukemia (AML) cells serves as a novel immune escape mechanism that can be inhibited by antibodies against the SLAMF6 dimerization site. This constitutes a novel mechanism of checkpoint inhibition, which paves the way for immunotherapy in AML and other SLAMF6-expressing cancers. This study utilizes single cell sequencing data from the AML cell line HNT-34 co-cultured with normal T cells, with and without antibody targeting SLAMF6, as well as single cell data of 38 primary AML samples.

  Study EGAS50000001085

• Spatial and temporal intra-tumoural heterogeneity in advanced High-Grade Serous Ovarian Cancer: implications for surgical and clinical outcomes

  Limited evidence exists on the extent and impact of spatial and temporal heterogeneity of high grade serous ovarian cancer (HGSOC) on tumour evolution and patients surgical and clinical outcome. We investigated this through systematic mapping of multi-site tumours at initial presentation and matched relapse from 49 chemo-naïve HGSOC patients with high tumour load, operated upfront. Our data provides a unique insight into the tumour evolution and metastatic pathways of HGSOC across time and space, how this complexity relates to surgical and clinical outcome and its consequences on clinical decision-making.

  Study EGAS00001007164

• Competitive selection of somatic mutant clones in normal human skin varies with body site

  The risk of getting non-melanoma skin cancer varies over 40-fold across the body. Here we map mutations in normal skin in high and low risk sites in normal donors and those with an increased risk of skin cancer. The density of mutations varied widely, with evidence of positive and negative genetic selection.  Regional differences in mutational signatures in high and low cancer risk sites and preferential selection of mutants of TP53 in high risk skin and FAT1 in lower risk skin were observed. 10% of clones had copy number changes in cancer associated genes and the largest had multiple driver mutations with loss of heterozygosity. In hair follicles, a proposed site of origin of skin cancers, mutations in the upper follicle resembled adjacent skin, but the lower follicle was sparsely mutated. We conclude cancer risk reflects the efficiency of transformation of oncogenic mutants rather than the density of mutant clones.

  Dataset EGAD00001006194

• Defining the metastasome in colorectal cancer: Implications for hypotheses on metastasis evolution and personalized therapy (HIPO-032)

  Personalized cancer therapy aims at individual genetic changes characterizing primary cancers. Still, however, metastasis is the major clinically unmet problem, also due to an incomplete understanding of its molecular evolution.This study is the first to define the metastasis-specific whole genome landscape of human colorectal primary vs. matched metastatic lesions.Protein coding, ncRNA genes and 3’UTRs harbored about a third each of single nucleotide variations (SNVs)/indels, 19% of them being metastasis-specific. We found novel mutational hills among ncRNAs and 3’UTRs, copy number changes able to explain changes in microRNA expression in metastases, and novel metastasis-specific mutations in the 3’UTRs on important cancer signalling genes. Some metastatic lesions showed targetable mutations not detected in the primaries. Analysis of mutual exclusivity patterns supported a model that has progressive alterations in important colorectal cancer genes and revealed new partners. Metastatic lesions were enriched in SNVs, specific structural variations, and alterations in genes affecting cell adhesion and extracellular matrix interaction.Furthermore, a hepatic stellate activation cascade was enriched in metastases, suggesting genetic programs for site-specific colonization. Allele frequency distribution and mutational signature analysis suggests a common ancestor clone to both the primary tumor and the metastasis, with additional mutagenesis ongoing in both sites independently. Taken together, our results significantly add to hypothesis generation on metastasis evolution, and suggest novel metastasis-specific genomic changes which would be missed by current personalized therapy concepts. (HIPO-032)

  Study EGAS00001002717