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• Investigating Host Genetic Risk Factors for Tuberculosis in Highly Endemic South African Populations

  It is apparent from our recent population genetic and admixture mapping work 1–3 that a substantial part of the ancestral input into the South African Coloured (SAC) population is from the San or Khoe groups, which are not well represented in publicly available genetic databases. It is a reasonable assumption that the SAC population in the Western Cape may have derived more genetic input from the present KhoeSan population in the Northern Cape than the San residing in Namibia. It was concluded by our group that it is indeed the southern African KhoeSan group, the ≠Khomani, that best represent the KhoeSan contribution seen in the SAC 4. More recently, it has been shown that there are ancestry related increases in TB susceptibility, especially with increased Bantu-speaking African and KhoeSan ancestry 5. We aim to elucidate the epidemiological and human-host genetic risk factors for TB and the immunological pathways modulating TB infection. The proposed sub-study will enroll people evaluated for TB at Northern Cape community health clinics and their contacts from their households and/or community. We will conduct a demographic interview, collect saliva, which will be used for genetic analysis, and blood to determine latent TB infection status and capture immunological responses to mycobacterial infections at the cellular level and RNA sequencing.

  Study EGAS00001007850

• Double mutant DNMT3A AML: a unique subtype

  Mutation of DNMT3A, encoding a de novo methyltransferase essential for cytosine methylation, is a common early event in clonal hematopoiesis (CH) and adult acute myeloid leukemia (AML). Spontaneous deamination of methylated cytosines damages DNA, which is repaired by the base excision repair (BER) enzymes MBD4 and TDG. Congenital MBD4-deficiency has been linked to early-onset CH and AML, and is marked by exceedingly high levels of DNA damage and mutation of DNMT3A. Strikingly, wildtype (WT) DNMT3A binds TDG, thereby potentiating its repair activity. Since TDG is the only remaining BER enzyme in MBD4-deficient AML patients capable of repairing methylation damage, we investigated whether mutant DNMT3A negatively affects the repair function of TDG. We found that, whereas WT DNMT3A stimulates TDG function, mutant DNMT3A impairs TDG-mediated repair of DNA damage in vitro. In light of this finding and to extrapolate our observations to the broader AML patient population, we investigate here the genetic profiles and survival outcomes of AML patients with single (SM) versus double mutant (DM) DNMT3A. DM DNMT3A AML patients show a characteristic driver mutation landscape and reduced overall survival when compared to SM DNMT3A AML patients. Importantly, whole-genome sequencing showed a trend for increased DNA damage in primary DM DNMT3A AML samples, especially when DNMT3A mutations are located at the DNMT3A-TDG interaction interface.

  Study EGAS00001007966

• Transcriptome sequencing of gingivo-buccal oral squamous cell carcinoma for integrative analysis: alterations in expression of genes attributable to methylation changes

  Gingivo-buccal oral squamous cell carcinoma (OSCC-GB) is the most common cancer among men in India and is associated with high mortality. Although OSCC-GB is known to be quite different from tongue cancer in its genomic presentation and its clinical behavior, it is treated identically as tongue cancer. Predictive markers of prognosis and therapy that are specific to OSCC-GB are, therefore, required. To achieve this, we have carried out transcriptome (n=72) profiling of paired tumor-normal tissues collected from OSCC-GB patients from India. RNA sequencing was performed on tumor and paired adjacent normal samples from 72 OSCC-GB patients. From each patient, total RNA was extracted from tumor and normal tissue samples using AllPrep DNA/RNA Mini Kit (QIAGEN). The quality and concentration of isolated total RNA were checked using Agilent 2100 Bioanalyzer and NanoDrop 2000 (Thermo Fisher Scientific). The OD260/OD280 ratio was ≥ 2 and RNA Integrity Number (RIN) was ≥ 7.0 for all sequenced samples. Ribosomal RNA (rRNA) was removed from the RNA samples, using Ribo-Zero Magnetic Kit (Epicentre). Sequencing libraries were prepared from rRNA depleted samples using TrueSeq RNA Sample Preparation Kit (Illumina). Each triplex cDNA library pool was sequenced as 100bp paired-end on HiSeq-2000 or HiSeq-2500 (Illumina). Protocols suggested by the manufacturers were used for all assays.

  Study EGAS00001003893

• Insular Celtic population structure and genomic footprints of migration

  Previous studies of the genetic landscape of Ireland have suggested homogeneity, with population substructure undetectable using single-marker methods. Here we have harnessed the haplotype-based method fineSTRUCTURE in an Irish genome-wide SNP dataset, identifying 23 discrete genetic clusters which segregate with geographical provenance. Cluster diversity is pronounced in the west of Ireland but reduced in the east where older structure has been eroded by historical migrations. Accordingly, when populations from the neighbouring island of Britain are included, a west-east cline of Celtic-British ancestry is revealed along with a particularly striking correlation between haplotypes and geography across both islands. A strong relationship is revealed between subsets of Northern Irish and Scottish populations, where discordant genetic and geographic affinities reflect major migrations in recent centuries. Additionally, Irish genetic proximity of all Scottish samples likely reflects older strata of communication across the narrowest inter-island crossing. Using GLOBETROTTER we detected Irish admixture signals from Britain and Europe and estimated dates for events consistent with the historical migrations of the Norse-Vikings, the Anglo-Normans and the British Plantations. The influence of the former is greater than previously estimated from Y chromosome haplotypes. In all, we paint a new picture of the genetic landscape of Ireland, revealing structure which should be considered in the design of studies examining rare genetic variation and its association with traits.

  Study EGAS00001002769

• Mutated H3 Histones Drive Human Pre-Leukemic Hematopoietic Stem Cell Expansion And Promote Leukemic Aggressiveness

  Leukemogenesis is a stepwise progression from mutated, pre-neoplastic hematopoietic stem cells (HSCs) to full-blown leukemia. Our ability to prevent or treat acute myeloid leukemia (AML) is limited by our incomplete understanding of the epigenetic disruption that is central to this process, including improper histone methylation. Comprehensive analysis of 16 histone H3 genes in 434 primary AML samples identified Q69H, A26P, R2Q, R8H and K27M/I mutations (1.6%), and a higher incidence in secondary AML (s-AML) (9%). We establish that these mutations are important early events in leukemogenesis. They occur in pre-leukemic HSCs, increase the frequency of functional human HSCs, and alter differentiation. The mutations are present in the major leukemic clones in primary samples, and the mutant histones amplify leukemic aggressiveness with increased proliferation, expansion of leukemic progenitor and blast cells, and superior competitiveness in vivo. These effects are dependent on the specific mutation. Genome-wide analysis of K27 mutants revealed increased expression of genes involved in erythrocyte and myeloid differentiation with a corresponding decrease in histone H3 K27 tri-methylation and increase in K27 acetylation. The functional impact of histone mutations is independent of RUNX1 mutations, although they can co-occur. These data establish the involvement of H3 mutations as initial drivers of pre-cancerous stem cell expansion and leukemogenesis.

  Study EGAS00001003288

• Spatial concordance of DNA methylation classification in diffuse glioma

  Background: Intratumoral heterogeneity is a hallmark of diffuse gliomas. DNA methylation profiling is an emerging approach in the clinical classification of brain tumors. The goal of this study is to investigate the effects of intratumoral heterogeneity on classification confidence. Methods: We used neuronavigation to acquire 133 image-guided and spatially-separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma (7 IDH-wildtype and 2 IDH-mutant glioblastoma, 6 diffuse astrocytoma, IDH-mutant and 1 oligodendroglioma, IDH-mutant and 1p19q codeleted), which we characterized using DNA methylation arrays. Samples were obtained from regions with and without abnormalities on contrast enhanced T1 weighted and fluid-attenuated inversion recovery MRI. Methylation profiles were analyzed to devise a three-dimensional reconstruction of (epi)genetic heterogeneity. Tumor purity was assessed from clonal methylation sites. Results: Molecular aberrations indicated that tumor was found outside imaging abnormalities, underlining the infiltrative nature of this tumor and the limitations of current routine imaging modalities. We demonstrate that tumor purity is highly variable between samples and explains a substantial part of apparent epigenetic spatial heterogeneity. We observed that DNA methylation subtypes are often, but not always, conserved in space taking tumor purity and prediction accuracy into account. Conclusion: Our results underscore the infiltrative nature of diffuse gliomas and suggest that DNA methylation subtypes are relatively concordant in this tumor type, although some heterogeneity exists.

  Study EGAS00001005434

• 5- FU treated organoids

  5-Fluorouracil (5-FU) is a chemotherapeutic drug component that is commonly used for the treatment of solid cancers. The anticancer properties of 5-FU have been attributed to interference with nucleotide synthesis and through direct incorporation into the DNA as being a pyrimidine analog. As both mechanisms of action may have a mutational impact on surviving tumor cells, we performed three independent analyses to characterize the genomic consequences of 5-FU treatment: i) in vitro treatment of intestinal organoids with 5-FU followed by whole genome sequencing, ii) genome-wide mutation analyses in tumor samples from 5-FU treated patients with breast or colorectal cancer, and iii) analysis of paired biopsies from patients treated with 5-FU between biopsies. Our results demonstrate that both in vitro and in vivo 5-FU causes a mutational pattern that is dominated by T>G substitutions in a CTT context and with strong resemblance to COSMIC signature 17. Interestingly, this signature is also found in non 5-FU treated patients, most prominently in esophageal tumors, indicating that distinct endogenous and exogenous triggers can converge into highly similar mutational signatures. Furthermore, our results suggest that 5-FU may have adverse mutagenic effects on healthy cells and contributes to genetic variability in surviving cancer cells thereby contributing to tumor evolution.

  Study EGAS00001003592

• EGAD00000000054

  NCI-H209 is an immortal cell line derived from a bone marrow metastasis of a patient with small cell lung cancer, taken before chemotherapy. The specimen showed histologically typical small cells with classic neuroendocrine features. NCI-BL209 is an EBV-transformed B-cell line derived from the same patient as the small cell lung cancer cell line, NCI-H209

  Dataset EGAD00000000054

• Molecular Genetics of Secondary Histiocytic/Dendritic Sarcoma

  This is a comprehensive genomic analysis of a rare set of secondary histiocytic/dendritic sarcomas from the consult service of the Hematopathology section of the Laboratory of Pathology, NCI, NIH.

  Study phs001942

• Whole exome sequencing of a cold agglutinin disease patient

  We performed whole exome sequencing of bone marrow monoclear cells derived from a cold agglutinin disease patient. Aim of our study is to elucidate the pathogenesis of hemolytic anemia.

  Study JGAS000612