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• Aberrant RNA-splicing (neojunctions) offers a new source for targets, and our neoantigen discovery platform (SNIPP) characterizes a novel class of clonally-expressed splicing-derived neoantigens that elicit a CD8+ T-cell-mediated tumor killing response.

  RESULTS: Our pipeline identified 789 public neojunctions, with 32 neojunctions concurrently identified in transcriptomic and proteomic glioma data and predicted to be presented by HLA-A*02:01 with high confidence. IVS and subsequent 10x VDJ scRNA-seq identified TCR clonotypes reactive against neojunctions in RPL22 (n=7) and GNAS (n=1), the latter being highly intratumorally-conserved (detected in > 90% of spatially-mapped biopsies across 17/56 patients (26.78%)). TCR-transduced T-cells demonstrated recognition and immunogenic activation against endogenously processed and presented neoantigens in multiple GBM PDX cell lines. Furthermore, IDH1-mutant oligodendroglioma samples demonstrated significantly elevated expression of neojunctions over IDH1-mutant astrocytoma and IDH1wt subtypes. Differential gene expression (DESeq2) identified decreased expression of splicing factors due to oligodendroglioma-specific co-deletion of Chromosomes 1p/19q. siRNA knockdown of these splicing factors (e.g. SF3A3, SNRPD2) in IDH1wt glioma cells resulted in significantly increased expression of corresponding neojunctions.

  Study EGAS00001007986

• Multi-Omic Microbiome Study-Pregnancy Initiative (MOMS-PI)

  The Vaginal Microbiome Consortium team at Virginia Commonwealth University has conducted the Multi-Omic Microbiome Study: Pregnancy Initiative (MOMS-PI) in collaboration with the Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) to better understand how microbiome and host profiles change throughout pregnancy and influence the establishment of the nascent microbiome in neonates. The team particularly focused on elucidation of the role of the microbiome and its components in the etiology of preterm birth, which occurs in over 10% of pregnancies and which is the leading cause of death in neonates. Samples from 1594 women and their neonates were collected throughout pregnancy, at delivery and postpartum. The group has generated a comprehensive dataset of multiple omics technologies. This longitudinal, large-scale effort was designed to provide a large-scale resource for the scientific community. The study also permits characterization of temporal dynamics of the microbiome in pregnancy and factors associated with preterm birth.

  Study phs001523

• PD-1 antibody-bound progenitor-exhausted CD8+ T cells in lymph nodes boost PD-1-blockade anti-tumor immunity in gastrointestinal cancer

  While progenitor-exhausted T cells (Tpex) expressing TCF1 and PD-1 are crucial for the therapeutic effect of immune checkpoint inhibitors (ICIs; therapeutic anti-PD-1 antibodies), the dynamics of ICI-bound Tpex are not fully understood. In this study, we investigated ICI-bound T cells in detail using combined sequencing analysis at the single cell level. By analyzing samples from gastrointestinal cancer patients with or without ICI treatment, we found that Tpex were enriched in proximal lymph nodes (LNs) and proliferated at a high rate after ICI treatment. Importantly, ICI high-bound Tpex in LNs shared T-cell receptor clonotypes with intratumoral exhausted CD8+ T cells (Tex), suggesting their migration to tumor sites after ICI treatment. These findings indicate that ICIs initially target PD-1+CD8+ Tpex in LNs, prompting their proliferation. Subsequently, these cells migrate to tumors and differentiate into Tex, thereby exerting anti-tumor immunity.

  Study JGAS000720

• Unraveling the heterogeneity of multiple myeloma identifies therapy resistant subpopulation with vulnerability to the splicing pathway intervention

  Intra-tumor heterogeneity underlies the therapy resistance of multiple myeloma (MM). However, its details remain unknown. Here, we performed single-cell RNA sequencing coupled with VDJ targeted sequencing on highly purified bone marrow lineage marker-negative CD38+ MM cells from patients at diagnosis and in remission. This approach successfully subdivided MM cells into distinct clusters, unraveling their heterogeneity and plasticity on the axis of cell surface CD138 expression. Notably, unique clusters were identified in the minor CD138-negative population that resisted therapies. CRISPR/Cas9 screening of upregulated genes in the resistant population identified their vulnerability to the splicing pathway inhibition, among which RNA-binding protein 39 (RBM39) appeared to be overexpressed in the resistant population and involved in aberrant splicing. Genetic and pharmacological inhibition of RBM39 exerted a profound synthetic lethal effect on them. Our results unveil an uncharacterized subpopulation associated with therapy resistance and provide a novel therapeutic strategy targeting the splicing pathway in MM.

  Study JGAS000723

• Variant allele frequency changes in TP53 predict pembrolizumab response in patients with metastatic urothelial carcinoma

  Prognoses for patients with metastatic urothelial carcinoma (mUC) have strikingly improved with pembrolizumab, an immune checkpoint inhibitor (ICI), but clinical benefits are limited to a subset of patients. Therefore, a non-invasive biomarker to predict pembrolizumab response is urgently required. We retrospectively examined genomic alterations in 25 plasma circulating tumor DNA (ctDNA) samples using a targeted sequencing of 77 genes from 16 mUC patients during pembrolizumab treatment. Eleven (68.8%) patients had two or more genomic alterations, including TP53 mutations (as defined by ctDNA-positive status). The proportion of responders to pembrolizumab in the ctDNA-positive group was higher than the ctDNA-negative group (72.7% vs. 20.0%). Furthermore, among all detected genomic alterations, variant allele frequency decreases in TP53 during pembrolizumab treatment were mainly associated with therapeutic response. Collectively, we suggest that profiling of ctDNA in plasma, especially TP53, is useful for predicting and monitoring therapeutic responses to pembrolizumab in mUC patients.

  Study JGAS000622

• Loss of presentation of estimated neoantigens from mutated genes in ctDNA was essential for fostering primary to recurrent tumors in postoperative colorectal cancer cases

  Specific parameters regarding mutations at primary sites for the detection of postoperative recurrence using circulating tumor (ct)DNA liquid biopsy are lacking. In the current retrospective study, we conducted target resequencing of ctDNA using 47 plasma samples and established a cancer panel carrying the commonly mutated genes between primary and recurrent tumors. We found that mutated genes in ctDNA indicated immune-resistance traits with respect to the impaired ability to present neoantigens by loss of expression or binding affinity to HLA in the primary tumor. Compared with the estimated neoantigens from all mutated genes in primary tumors, the neoantigen peptides from commonly mutated genes between primary and recurrent tumors showed abundant and significant expression with no binding affinity to HLA. Therefore, ctDNA mutations can be frequently and postoperatively detected to identify recurrence; however, these mutated genes were derived from immune-tolerated clones owing to the loss of neoantigen presentation in primary CRC tumors.

  Study JGAS000549

• Somatic mutations in ALS genes in the motor cortex of sporadic ALS patients

  Several lines of evidence suggest that amyotrophic lateral sclerosis (ALS) pathology starts focally and spreads within the central nervous system (CNS). We leveraged DNA and RNA sequencing data from ALS autopsy tissue to explore the presence of somatic mosaic variants in sporadic ALS (sALS) cases. Deep targeted sequencing of known ALS disease genes from motor cortex tissue revealed enrichment of somatic variants in sALS compared to familial ALS (fALS) with a monogenic cause and an increased pathogenicity of mosaic mutations in known ALS mutational hot spots. Experimental validation of the variants identified that the somatic FUS variant p.E516X leads to nucleo-cytoplasmic mislocalization and aggregation. Additionally, somatic variant calling from single-cell RNA-sequencing data of sALS tissue showed an accumulation of somatic variants in excitatory neurons. Collectively, using a multi-modal approach, our findings suggest that somatic mutations within the motor cortex, especially in excitatory neurons, may contribute to the development of sALS.

  Study EGAS00001008104

• Whole genome sequencing of patients with or at risk for HCC

  Liver cancer is a major cause of cancer mortality worldwide. Screening individuals at high risk, including those with cirrhosis and viral hepatitis, provides an avenue for improved survival, but current screening methods are inadequate. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome analyses to evaluate 724 individuals from the United States, the European Union, or Hong Kong with hepatocellular carcinoma (HCC) or who were at average or high-risk for HCC. Using a machine learning model that incorporated multifeature fragmentome data, the sensitivity for detecting cancer was 88% in an average-risk population at 98% specificity and 85% among high-risk individuals at 80% specificity. We validated these results in an independent population. cfDNA fragmentation changes reflected genomic and chromatin changes in liver cancer, including from transcription factor binding sites. These findings provide a biological basis for changes in cfDNA fragmentation in patients with liver cancer and provide an accessible approach for noninvasive cancer detection.

  Study EGAS00001007249

• single cell sequencing of resting and Influenza-stimulated mononcluear phagocytes of African and Europeans with varying degree of ex-vivo susceptibility to Influenza

  There is considerable inter-individual immunological and clinical variability upon influenza A virus (IAV) infection in humans; yet, the factors underlying such heterogeneity remain elusive. Here, using an ex vivo cellular model that captures natural variation in the transcriptional responses of monocytes to IAV, we find significant differences in viral mRNA levels between individuals of African and European ancestry. Using single cell analyses, we show that the overall number of cells that will ultimately become infected, rather than the amount of viral transcript expression per cell, is the main driver of the surprisingly higher IAV mRNA levels detected in European cells. Finally, we identify 135 genes, including the interferon-stimulated genes IFITM3, MX1, and OAS3, for which basal mRNA expression levels associate with IAV mRNA levels post infection. Our findings reveal that basal differences in activation of IRF/STAT-induced antiviral mechanisms may contribute to individual and population disparities in susceptibility to IAV infection.

  Study EGAS00001005000

• Inferring expressed genes by whole-genome sequencing of plasma DNA

  The analysis of cell-free DNA (cfDNA) in plasma represents a rapidly advancing field in medicine. cfDNA consists predominantly of nucleosome-protected DNA shed into the bloodstream by cells undergoing apoptosis. We performed whole-genome sequencing (WGS) of plasma DNA and identified two discrete regions at transcription start sites (TSS) where the nucleosome occupancy results in different read-depth coverage patterns in expressed and silent genes. By employing machine learning for gene classification we found that the plasma DNA read depth patterns from healthy donors reflected the expression signature of hematopoietic cells. In cancer patients with metastatic disease, we were able to classify expressed cancer driver genes in regions with somatic copy number gains with high accuracy. We could even determine the expressed isoform of genes with several TSSs as confirmed by RNA-Seq of the matching primary tumor. Our analyses provide functional information about the cells releasing their DNA into the circulation.

  Study EGAS00001001754

• cfRRBS on cfDNA from pediatric cancer

  In the clinical management of pediatric solid tumors, histological examination of tumor tissue obtained by a biopsy remains the gold standard to establish a conclusive pathological diagnosis. The DNA methylation pattern of a tumor is known to correlate with the histopathological diagnosis across cancer types and is showing promise in the diagnostic workup of tumor samples. This methylation pattern can be detected in the cell-free DNA. Here, we provide proof-of-concept of histopathologic classification of pediatric tumors using cell-free reduced representation bisulfite sequencing (cf-RRBS) from retrospectively collected plasma and cerebrospinal fluid samples. We determined the correct tumor type in 49 out of 60 (81.6%) samples starting from minute amounts (less than 10 ng) of cell-free DNA. We demonstrate that the majority of misclassifications were associated with sample quality and not with the extent of disease. Our approach has the potential to help tackle some of the remaining diagnostic challenges in pediatric oncology in a cost-effective and minimally invasive manner.

  Study EGAS00001004194

• Human Pancreatic Beta Cell lncRNAs Control Cell-Specific Regulatory Networks

  Recent studies have uncovered thousands of long non-coding RNAs (lncRNAs) in human pancreatic β cells. β cell lncRNAs are often cell type specific and exhibit dynamic regulation during differentiation or upon changing glucose concentrations. Although these features hint at a role of lncRNAs in β cell gene regulation and diabetes, the function of β cell lncRNAs remains largely unknown. In this study, we investigated the function of β cell-specific lncRNAs and transcription factors using transcript knockdowns and co-expression network analysis. This revealed lncRNAs that function in concert with transcription factors to regulate β cell-specific transcriptional networks. We further demonstrate that the lncRNA PLUTO affects local 3D chromatin structure and transcription of PDX1, encoding a key β cell transcription factor, and that both PLUTO and PDX1 are downregulated in islets from donors with type 2 diabetes or impaired glucose tolerance. These results implicate lncRNAs in the regulation of β cell-specific transcription factor networks.

  Study EGAS00001002865

• H014: HES5 mediates NOTCH signaling by interaction with AKT to drive liver carcinogenesis

  Notch signaling plays a pivotal role in liver development and aberrant Notch signaling may lead to hepatocellular (HCC) or cholangiocellular carcinoma (CCA) development. Using whole exome sequencing of 54 human HCC samples, we discovered 19 somatic missense mutations in 15 different Notch pathway genes affecting 24.6% (14 of 57) of patients. Prediction of functional impact of these Notch pathway mutations revealed HES5-R31G to have high relevance. We found HES5 to be strongly activated by Notch signaling. In vitro, HES5 reduced cell migration and clonogenicity and in vivo, HES5 inhibited MYC-dependent liver tumor formation. But together with AKT, HES5 increased liver tumor formation in a mouse model. HES5 directly binds to AKT and AKT expression leads to increase HES5 protein levels. Furthermore, HES5 exhibits a negative feed-back loop by inhibiting NOTCH1 and HES1 gene expression. In contrast, HES5-R31G appears to be non-functional possibly by loss of nuclear translocation

  Study EGAS00001003329

• Understanding human fetal pancreas development using subpopulation sorting and RNA sequencing

  To decipher the populations of cells present in the human fetal pancreas and their lineage relationships, we developed strategies to isolate pancreatic progenitors, endocrine progenitors and endocrine cells. Transcriptome analysis of the individual populationsrevealed a large degree of conservation among vertebrates in the drivers of gene expression changes occurring at different steps of differentiation, althoughnotably, sometimes, different members of the same gene family are expressed. The transcriptome analysis establishes a resource to identify novel genes and pathways involved in human pancreas development. Single cell profiling further captured intermediate stages ofdifferentiation and enabled us to decipher the sequence of transcriptional events occurring during human endocrine differentiation. Furthermore, we evaluate how well individual pancreatic cells derived in vitro from human pluripotent stem cells mirror the natural processoccurring in human fetuses. This comparison uncovers a few differences at the progenitor steps, a convergence at the steps of endocrine induction and the current inability to fully resolve endocrine cell subtypes in vitro.

  Study EGAS00001003127

• Tissue and plasma RNA from esophageal cancer and precursor lesions

  In the past decades, the incidence of esophageal adenocarcinoma has increased dramatically in Western populations. Better understanding of disease etiology along with the identification of novel prognostic and predictive biomarkers are urgently needed to improve the dismal survival probabilities. Here, we performed comprehensive RNA (both coding and non-coding) profiling in various samples from 17 patients diagnosed with esophageal adenocarcinoma, high-grade dysplastic or non-dysplastic Barrett’s esophagus. Per patient, a blood plasma sample, and a healthy esophageal and disease tissue sample were included. In total, this comprehensive dataset consists of 102 RNA-seq libraries from 51 samples. This unique resource allows for discovery of novel biomarkers and disease mechanisms, comparison of tissue and liquid biopsy profiles, integration of coding and non-coding RNA patterns, and can serve as a validation dataset in other RNA landscaping studies. Moreover, structural RNA differences can be identified in this dataset, including protein coding mutations fusion genes, and circular RNAs.

  Study EGAS00001004939

• whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases

  Esophageal cancer is one of the most aggressive cancers and the sixth leading cause of cancer death worldwide1. Approximately 70% of the global esophageal cancers occur in China and over 90% histopathological forms of this disease are esophageal squamous cell carcinoma (ESCC)2-3. Currently, there are limited clinical approaches for early diagnosis and treatment for ESCC, resulting in a 10% 5-year survival rate for the patients. Meanwhile, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we show a comprehensive genomic analysis in 158 ESCC cases, as part of the International Cancer Genome Consortium (ICGC) Research Projects (http://icgc.org/icgc/cgp/72/371/1001734). We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases and additional 70 ESCC cases were subjected to array comparative genomic hybridization (a-CGH) analysis.

  Study EGAS00001000709

• scRNA-seq of LN and lymphoma stroma

  The activities of non-haematopoietic cells (NHCs), including mesenchymal stromal cells and endothelial cells, in lymphomas, reportedly underlie lymphomagenesis. However, understanding of lymphoma NHCs has been hampered by unexplained NHC heterogeneity, even in normal human lymph nodes (LNs). Here, we constructed a single-cell transcriptome atlas of >100,000 NHCs collected from 27 human samples, including LNs and various nodal lymphomas, revealing 30 distinct subclusters, including some that were previously unrecognized. Notably, this atlas was highly useful for comparative analysis with lymphoma NHCs, which revealed an unanticipated landscape of subcluster-specific changes in gene expression and interaction with malignant cells in follicular lymphoma NHCs, facilitating our understanding of stromal remodelling in lymphoma and potentially suggesting novel biomarkers. Our study largely updates NHC taxonomy in human LNs and pertains to analysis of disease status, providing a rich resource and deeper insights into LN and lymphoma biology and offering to advance lymphoma management and therapy.

  Study EGAS00001005732

• Whole genome sequencing of EBV Associated Nasopharyngeal Carcinoma

  Interplay between EBV infection and acquired genetic alterations during nasopharyngeal carcinoma (NPC) development remains vague. Here we report a comprehensive genomic analysis of 70 NPCs, combining whole-genome sequencing (WGS) of microdissected tumor cells with EBV oncogene expression to reveal multiple aspects of cellular-viral co-operation in tumorigenesis. Genomic aberrations along with EBV-encoded LMP1 expression underpin constitutive NF-κB activation in 90% of NPCs. A similar spectrum of somatic aberrations and viral gene expression undermine innate immunity in 79% of cases and adaptive immunity in 47% of cases; mechanisms by which NPC may evade immune surveillance despite its pro inflammatory phenotype. Additionally, genomic changes impairing TGFBR2 promote oncogenesis and stabilize EBV infection in tumor cells. Fine-mapping of CDKN2A/CDKN2B deletion breakpoints reveals homozygous MTAP deletions in 32-34% of NPCs that confer marked sensitivity to MAT2A inhibition. Our work concludes that NPC is a homogeneously NF-κB-driven and immune-protected, yet potentially druggable, cancer.

  Study EGAS00001004705

• The landscape of chromothripsis across adult cancer types

  Chromothripsis is a recently identified mutational phenomenon, by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosome(s). Considered as an early event in tumour development, this form of genome instability plays a prominent role in tumour onset. Chromothripsis prevalence might have been underestimated when using low-resolution methods, and pan-cancer studies based on sequencing are rare. We analysed chromothripsis in 28 tumour types covering all major adult cancers (634 tumours, 316 whole-genome and 318 whole-exome sequences). We show that chromothripsis affects a substantial proportion of human cancers, with a prevalence of 49% across all cases. Chromothripsis generates entity-specific genomic alterations driving tumour development, including clinically relevant druggable fusions. Chromothripsis is linked with specific telomere patterns and univocal mutational signatures in distinct tumour entities. Longitudinal analysis of chromothriptic patterns in 24 matched tumour pairs reveals novel insights in the clonal evolution of tumours with chromothripsis. (H021)

  Study EGAS00001004250

• Phylogenetic reconstruction of adult blood cancer reveals early origins and lifelong evolution - WGS

  Mutations in cancer-associated genes drive tumour outgrowth. However, the timing of driver mutations and dynamics of clonal expansion that lead to human cancers are largely unknown. We used 580,133 somatic mutations from whole-genome sequencing of 1013 clonal haematopoietic colonies to reconstruct the phylogeny of haematopoiesis, from embryogenesis to clinical disease, in 12 patients with myeloproliferative neoplasms which are blood cancers more common in older age. JAK2V617F, the pathognomonic mutation driving the majority of these cancers, was acquired in utero or childhood, with upper estimates of age of acquisition from 33 weeks gestation to 10.8 years, in all 5 patients in whom JAK2V617F was either the only or the first driver event.  Driver mutations associated with age-related clonal haematopoiesis occurred prior to or following JAK2V617F,  as independent clonal expansions in JAK2V617F-mutated patients, and as large clonal expansions in JAK2V617F-unmutated patients . These mutations were also acquired in utero or childhood, with DNMT3A mutations occurring by 8 weeks of gestation to 7.6 years across 4 patients, and PPM1D mutation occurring by age 5.8yrs in a patient with MPN lacking phenotypic driver mutations. Sequential driver mutation acquisition was common, separated by decades across life, and often outcompeted ancestral clones. The mean latency between JAK2V617F acquisition and clinical presentation was 30 years (range 11-54 years). Rates of clonal expansion were inferred from phylogenetic trees and varied substantially (3% to 190% expansion/year), were affected by additional driver mutations, and were predictive of latency to clinical presentation. Driver mutations and rates of expansion would have been detectable in blood one to four decades before clinical presentation. This study reveals how driver mutation acquisition early in life with life-long growth and evolution underlie adult myeloproliferative neoplasms, providing opportunities for early detection and intervention and a new paradigm for cancer development.

  Dataset EGAD00001007714

• Phylogenetic reconstruction of adult blood cancer reveals early origins and lifelong evolution - TGS

  Mutations in cancer-associated genes drive tumour outgrowth. However, the timing of driver mutations and dynamics of clonal expansion that lead to human cancers are largely unknown. We used 580,133 somatic mutations from whole-genome sequencing of 1013 clonal haematopoietic colonies to reconstruct the phylogeny of haematopoiesis, from embryogenesis to clinical disease, in 12 patients with myeloproliferative neoplasms which are blood cancers more common in older age. JAK2V617F, the pathognomonic mutation driving the majority of these cancers, was acquired in utero or childhood, with upper estimates of age of acquisition from 33 weeks gestation to 10.8 years, in all 5 patients in whom JAK2V617F was either the only or the first driver event.  Driver mutations associated with age-related clonal haematopoiesis occurred prior to or following JAK2V617F,  as independent clonal expansions in JAK2V617F-mutated patients, and as large clonal expansions in JAK2V617F-unmutated patients . These mutations were also acquired in utero or childhood, with DNMT3A mutations occurring by 8 weeks of gestation to 7.6 years across 4 patients, and PPM1D mutation occurring by age 5.8yrs in a patient with MPN lacking phenotypic driver mutations. Sequential driver mutation acquisition was common, separated by decades across life, and often outcompeted ancestral clones. The mean latency between JAK2V617F acquisition and clinical presentation was 30 years (range 11-54 years). Rates of clonal expansion were inferred from phylogenetic trees and varied substantially (3% to 190% expansion/year), were affected by additional driver mutations, and were predictive of latency to clinical presentation. Driver mutations and rates of expansion would have been detectable in blood one to four decades before clinical presentation. This study reveals how driver mutation acquisition early in life with life-long growth and evolution underlie adult myeloproliferative neoplasms, providing opportunities for early detection and intervention and a new paradigm for cancer development.

  Dataset EGAD00001007715

• Identification of the Global miR-130a Targetome Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML

  In this study, we identified miR-130a as a regulator of HSC self-renewal and differentiation. To characterize gene expression changes following enforced expression of miR-130a OE, we performed RNA-seq in CD34+ cord blood (CB) cells transduced with control and miR-130a OE lentiviruses. To capture miRNA targets in an unbiased, transcriptome-wide manner, we perfomed enhanced CLIPseq procol in 2 replicates of CD34+ CB cells and Kasumi-1 cell line, which represent a model system for t(8;21) AML. We chose this cell line, as we found miR-130a to be highly expressed in this AML subtype where it is critical for maintaining the oncogenic molecular program mediated by AML1-ETO. Chimeric Ago2 eCLIPseq in CD34+ CB cells combined with Mass Spectrometry data analysis identified TBL1XR1 as a principal target of miR-130a. To elucidate gene expression changes associated with TBL1XR1 loss of function, we performed RNA-seq in CD34+CD38- CB cells transduced with control and shRNA targeted against TBL1XR1. To determine the functional significance of high miR-130a expression levels in Kasumi-1 cells on the molecular network controlled by AML1-ETO, we performed CUT&RUN assay and RNA-seq in Kasumi-1 cells following miR-130a knock-down (KD). Collectively, our findings reveal a unique role of miR-130a in regulating normal hematopoietic stem cell self-renewal and how elevated levels of miR-130a in t(8;21) AML contribute to the leukemogenesis of this AML subtype.

  Dataset EGAD00001008412

• WGS BAM files fromxa0Genomic Features and Classification of Homologous Recombination Deficient Pancreatic Ductal Adenocarcinoma

  Background and Aims: Homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC), remains poorly defined beyond germline(g) alterations in BRCA1, BRCA2 and PALB2. Methods: We interrogated whole genome sequencing (WGS) data on 391 patients including 49 carriers of pathogenic variants (PVs) in g_BRCA_ and PALB2. HRD classifiers were applied to the dataset and included: 1) the genomic instability score (GIS) used by Myriad MyChoice HRD assay; 2) substitution base signature 3 (SBS3); 3) HRDetect; and, 4) Structural Variant (SV) burden. Clinical outcomes and responses to chemotherapy were correlated with HRD status. Results: Biallelic tumour inactivation of g_BRCA_ or PALB2 was evident in 43/49 germline carriers identifying HRD-PDAC. HRDetect (score ?0.7) predicted gBRCA1/PALB2 deficiency with highest sensitivity (98%) and specificity (100%). HRD genomic tumour classifiers suggested that 7-10% of PDAC that do not harbor g_BRCA/PALB2_ have features of HRD. Of the somatic HRDetect cases, 69% were attributed to alterations in BRCA1/2, PALB2, RAD51C/D and XRCC2, and a tandem duplicator phenotype. TP53 loss was more common in BRCA1- compared to BRCA2-associated HRD-PDAC. HRD status was not prognostic in resected PDAC. However in advanced disease the GIS (p=0.02), SBS3 (p=0.03) and HRDetect score (p=0.005) were predictive of platinum response and superior survival. PVs in g_ATM_ (n=6) or g_CHEK2_ (n=2) did not result in HRD-PDAC by any of the classifiers. In four patients, BRCA2 reversion mutations associated with platinum resistance. Conclusions: Germline and parallel somatic profiling of PDAC outperforms germline testing alone in identifying HRD-PDAC. An additional 7-10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.

  Dataset EGAD00001007571

• Sequencing data from MethylScan assay on plasma

  Machine learning models in biomedical research are often hindered by demographic imbalances in clinical datasets, leading to biased predictions that disadvantage minority populations. Existing bias correction methods face limitations in handling the heterogeneity of biomedical data and the complexity of demographic influences. Here, we present DeBias, a computational framework for mitigating demographic biases in high-dimensional biomedical datasets. DeBias eliminates bias-associated subspaces within the entire feature space using control samples and enables global bias correction across all features, effectively preserving disease-specific signals while minimizing demographic distortions. To demonstrate its effectiveness, we applied DeBias to cfDNA methylation data for cancer detection. It achieved a >6-fold reduction in the number of features containing biases and outperformed existing methods in improving the cancer detection performance for minority populations. Our method represented a promising step toward developing machine learning models that are more accurate, reliable, and equitable for minority populations.

  Study EGAS00001008127

• The spectrum of somatic mutations in high-risk acute myeloid leukemia with -7/del(7q)

  Patients with myeloid malignancies bearing high-risk cytogenetic abnormalities lack effective therapies and have a poor overall survival. -7/del(7q) is identified in half of high-risk myeloid neoplasms. We recently identified CUX1 to be a haploinsufficient myeloid tumor suppressor gene located within the commonly deleted segment of 7q22. Here we identify the spectrum of somatic mutations that co-occur with loss of CUX1 and chromosome 7 in patients with de novo acute myeloid leukemia (AML) or a therapy-related myeloid neoplasm. -7/del(7q) leukemias have a distinct mutational profile characterized by low frequencies of alterations in major leukemogenic pathways, including genes encoding transcription factors, cohesin, and DNA-methylation-related proteins. In contrast, RAS pathway activating mutations occurred in 40% of -7/del(7q) samples, a significantly higher frequency than other AMLs and higher than previously reported. As targeted therapeutics advance, our data provide guidance for which pathways are most relevant in the treatment of adverse-risk myeloid leukemia.

  Study phs000759