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• Adipose Tissue Omics In Obesity

  This project used a multi-omics approach to study the adipose tissue transcriptome in humans with and without obesity. Our human cohort included males and females between the ages of 18-80 who underwent elective abdominal surgery at the University of Michigan and the Ann Arbor Veterans Affairs Healthcare System.Patients with advanced cancer or immuncompromised status were excluded. Visceral adipose tissue (VAT/omental) and subcutaneous adipose tissue (SAT/abdominal wall) were collected from subjects with obesity (BMI>=35) at the beginning of elective surgical procedures, placed on ice, and transported back to the laboratory for immediate processing. For adipose tissue stromal cells (ASC) isolation, adipose tissue was digested with Type II collagenase (2 mg/mL in PBS/2% BSA) at 37oC, 60min, centrifuged at 250 rcf, and the stromal-vascular cell pellet was retrieved, plated overnight, and the adherent cells passaged three times to enrich for ASC, which were then frozen in DMEM/F12, 15% fetal calf serum, and 10% DMSO in liquid nitrogen until use. Single nuclear sequencing was performed on preparations from intact adipose tissue. Bulk RNA sequencing and single cell sequencing were performed on ASC isolated from intact adipose tissue and cultured in 2D and 3D culture systems. We currently apply bulk, single cell, and single nuclear sequencing analyses to these tissues. One component of this project studies single nuclear sequencing in nuclei isolated from intact adipose tissues from human subjects with obesity, focusing on depot comparisons (VAT vs. SAT). This cohort also permits comparisons of adipose tissue transcriptomes between male and female subjects, controlling for age and BMI. Primary findings to date include identification of multiple ASC, adipocyte, and endothelial cell (EC) subpopulations, T-cell, and macrophage (MAC) populations that are in concordance with and expand upon other published datasets. Of two dominant ASC subpopulations, one (inflammatory-mesothelial, IM- ASC) is present in VAT, but absent in SAT, while the other (fibroadipogenic, FA-ASC) is present in both VAT and SAT. We identified multiple EC subtypes with features of lymphatic, venous, and arterial EC, and a PRDM16 expressing population with features of an EC progenitor. Immune cell populations match recent experimental validation of lipid-activated macrophage (LAM) phenotypes, TIM4 macrophages, and a prominent population of MRC1/CD206+ resident AT macrophages with expression signatures related to glucocorticoid activation. These data support depot-specific differences in ASC subpopulations and previously unrecognized EC heterogeneity within human AT, with the potential to shed light on functional differences in AT depot and disease state. Planned future studies include ATAC-Seq and other omics analyses. Another component of this project studies transcriptional responses of ASC in vitro to various stimuli, including different matrix environments. Current data includes bulk RNA Sequencing of human ASC from VAT and SAT differentiated into mature adipocytes in hydrogels of differing stiffness (3%, 5%, 10%) to define transcriptional responses to matrix environments of different stiffness. Primary findings to date include enrichment of adipogenesis and lipid and oxidative metabolic gene pathways in adipocytes in 5% relative to 3% hydrogels, while fibrotic gene pathways have been enriched in 3% hydrogels. These data demonstrate that intermediate density matrix promotes a more adipogenic, less fibrotic adipocyte phenotype geared towards increased lipid and aerobic metabolism. Planned future studies include expansion of intact tissues from our cohort studied with single nuclear sequencing, as well as further study of ASC responses in vitro to different biologic stimuli, including different matrix environments.

  Study phs003390

• whole genome sequence data of multifocal hepatocellular carcinoma

  Background & Aims: The differentiation of distinct multifocal hepatocellular carcinoma (HCC): multicentric disease vs. intrahepatic metastases, in which the management and prognosis varies substantively, remains problematic. We aim to stratify multifocal HCC and identify novel diagnostic and prognostic biomarkers by performing whole genome and transcriptome sequencing, as part of a multi-omics strategy Methods: A complete collection of tumour and somatic specimens (intrahepatic HCC lesions, matched non-cancerous liver tissue and blood) were obtained from representative patientswith multifocal HCC exhibiting two distinct postsurgical courses. Whole-genome and transcriptome sequencing with genotyping were performed for each tissue specimen to con-trast genomic alterations, including hepatitis B virus integrations, somatic mutations, copy number variations, and structural variations. We then constructed a phylogenetic tree to visualise individual tumour evolution and performed functional enrichment analyses on select differentially expressed genes to elucidate biological processes involved in multifocal HCC development. Multi-omics data were integrated with detailed clinicopathological information to identify HCC biomarkers, which were further validated using a large cohort of HCC patients (n = 174).Results: The multi-omics pro?ling and tumour biomarkers could successfully distinguish the two multifocal HCC types, while accurately predicting clonality and aggressiveness. The dual speci?city protein kinase TTK, which is a key mitotic checkpoint regulator with links to p53 signaling, was further shown to be a promising overall prognostic marker for HCC in the large patient cohort.Conclusions: Comprehensive multi-omics characterisation of multifocal tumour evolution may improve clinical decision-making, facilitate personalised medicine, and expedite identi?cation of novel biomarkers and therapeutic targets in HCC.

  Study EGAS00001002338

• Subtyping Sub-Saharan Esophageal Squamous Cell Carcinoma by Comprehensive Molecular Analysis

  Esophageal squamous cell carcinoma (ESCC) occurs as much as 20x more frequently in sub-Saharan Africa than Western countries. Through the UNC-Malawi project collaboration we obtained whole-exome matched tumor/normal and RNA sequencing of 59 ESCC from Malawi between 2011-2012. DNA analysis revealed similar mutations as other cohorts, while RNA analysis revealed three distinct subtypes. Mutational signature analysis revealed a pattern of mutation not previously reported in other cohorts or more broadly. Taken together this suggests the high prevalence of ESCC in the region is secondary to an as yet identified mutagen.

  Study phs001448

• A non-canonical lymphoblast in refractory childhood T-cell leukaemia

  Refractory cancers may arise either through the acquisition of resistance mechanisms by cancer cells or represent distinct diseases. The origin of childhood T-cell acute lymphoblastic leukaemia (T-ALL) that does not respond to initial treatment, i.e. refractory disease, is unknown. Refractory T-ALL carries a poor prognosis and cannot be predicted at diagnosis. Here, we performed single cell mRNA sequencing of T-ALL from children who did or did not respond to initial treatment. We identified a transcriptionally distinctive blast population, exhibiting features of innate-like lymphocytes, as the major source of refractory disease.

  Study EGAS50000000767

• Breast Cancer - Very young women

  This project will focus on sequencing of breast cancer from young age cancer patients characterized by age at diagnosis under 35. Based on the incidence rate by Korean National Cancer Incidence Database, breast cancer is the most common solid tumors among young adults aged 15-34 excepting thyroid cancer (Cancer statistics in Korea (2012)). This project just started from the mid of 2015. National cancer center in Korea are collecting more than 100 tumor specimens from breast cancer patients aged 20-34. Genetic features of young patients will be investigated with somatic mutation pattern, structural variations, and canonical pathways.

  Study EGAS00001001908

• Health Effects of Arsenic Longitudinal Study

  The Health Effects of Arsenic Longitudinal Study (HEALS), a multidisciplinary and large prospective cohort study in Araihazar, Bangladesh, was established to evaluate the effects of full-dose range arsenic (As) exposure on various health outcomes. We applied array-based genotyping technologies to baseline DNA samples from a subset of the HEALS study and linked those genotypes to data on arsenic species measured in urine. We used these data to identify regions influencing arsenic metabolism (AS3MT and FTCD). We also applied array-based DNA methylation technologies to baseline DNA samples from a subset of individuals from HEALS. These data were linked to data on arsenic concentration (in both urine and drinking water) to identify regions of the genome where DNA methylation is impacted by arsenic exposure.

  Study phs003839

• APOBEC mutagenesis is a common process in normal human small intestine

  The single base substitution mutational signatures SBS2 and SBS13, likely caused by APOBEC cytosine deaminases, are common in many human cancer types. However, the stimulus activating APOBEC mutagenesis is unknown and understanding of when it occurs in the progression from normal to cancer cell is limited. Here, as part of a wider survey of human tissues, we whole genome sequenced 342 microdissected normal epithelial crypts from the small intestines of 39 individuals. SBS2/13 mutations were present in 17% normal small intestine crypts and were likely due to APOBEC3A activity. Localised clusters of SBS2/13 mutations (kataegis) were also commonly found. APOBEC mutation burdens were variable between individuals and between crypts from the same individual. Crypts with SBS2/13 often had immediate crypt neighbours without SBS2/13, suggesting that the underlying cause of SBS2/13 is cell-intrinsic rather than a widely distributed microenvironmental exposure, or needs to be permitted by cell-intrinsic conditions. APOBEC mutagenesis occurred throughout the human lifespan, including in young children, and was episodic with a small number of episodes occurring during the life history of a single cell. The results indicate that APOBEC mutagenesis is more common in the small intestine epithelium than in many other cell types, and is an episodic process in vivo initiated or permitted by cell intrinsic factors.

  Dataset EGAD00001008764

• Copy numbers in resectable gastric cancer treated with surgery alone

  Purpose: Gastric cancer is a heterogeneous disease requiring stratification to recognize its underlying biology and variable clinical outcome. The Cancer Genome Atlas (TCGA) recognizes four molecular subgroups: Epstein-Barr virus positive (EBV+) and microsatellite instable (MSI) with superior survival compared to genomically stable (GS) and chromosomal instable (CIN). Since classification criteria to distinguish GS from CIN were not defined, alternative markers such as Lauren’s histopathology or CDH1/p53 immunohistochemistry are commonly applied. Here we compared survival of gastric cancer subgroups determined by four methods. Experimental Design: EBV- and microsatellite stable tumors from a total of 309 patients treated with surgery alone were assigned to subgroups by: (i) specific copy number aberrations as determined by TCGA (GS or CIN), (ii) genome instability index (GII; high or low), (iii) Lauren’s classification (diffuse or intestinal), and (iv) CDH1/p53 immunohistochemistry (IHC; aberrant CDH1, normal-, or aberrant p53 expression). Subgroups were associated with cancer-related survival (CRS). Results: Five-year CRS was 42.0% for diffuse and 49.5% for intestinal type tumors, and 57.8% for GS and 41.6% for CIN tumors. Classification by GII or CDH1/p53 IHC did not correlate with CRS. The combination of TCGA and Lauren classifications resulted in four distinct subgroups. Five-year CRS for GS-intestinal (n=24), GS-diffuse (n=57), CIN-intestinal (n=142) and CIN-diffuse (n=86) was 61.4%, 56.5%, 47.6%, and 31.5%, respectively. Conclusions: TCGA’s GS and CIN have additional prognostic value to Lauren’s diffuse and intestinal subgroups in gastric cancer. GS-intestinal, GS-diffuse, CIN-intestinal and CIN-diffuse constitute biologically distinct entities and are suggested as stratification variables for future studies.

  Study EGAS00001007394

• BIRC5 Upregulation Enhances DNMT3A-Mutant T-ALL Cell Survival and Pathogenesis

  The goal of this study was to determine how patients with T-ALL who have DNA methyltransferase 3 alpha (DNMT3A) mutations develop resistance to therapy. Since DNMT3A is a methyltransferase, we examined the effect of those mutations on epigenetic regulation using whole genome bisulfite sequencing (WGBS). We also assessed any changes in gene expression using RNA-sequencing. We found that T-ALL patients with DNMT3A mutations are resistant to apoptosis and some chemotherapies. WGBS showed that DNMT3A mutated patients clustered together by their epigenetic profile, which was associated with hypomethylation at TERT and HOX genes. RNA sequencing identified differences in JAK/STAT signaling.

  Study phs003623

• THE GENOMIC LANDSCAPE OF ACTINIC KERATOSIS

  Actinic keratoses (AK) are lesions of epidermal keratinocyte dysplasia and are precursors for invasive cutaneous squamous cell carcinoma (CSCC). Identifying the specific genomic alterations driving progression from normal skin-AK-invasive CSCC is challenging due to the massive ultraviolet radiation-induced mutational burden characteristic at all stages of this progression. Here, we report the largest AK whole exome sequencing study to date and perform mutational signature and candidate driver gene analysis on these lesions. We demonstrate in 37 AK, from both immunosuppressed and immunocompetent patients, that there are significant similarities to CSCC in terms of mutational burden, copy number alterations, mutational signatures and patterns of driver gene mutations. We identify 44 significantly mutated AK driver genes and confirm that these genes are similarly altered in CSCC. We identify the azathioprine mutational signature in all AK from patients exposed to the drug, providing further evidence for its role in keratinocyte carcinogenesis. CSCC differ from AK in having higher levels of intra-sample heterogeneity. Alterations in signaling pathways also differ, with immune-related signaling and TGF-β signaling significantly more mutated in CSCC. Integrating our findings with independent gene expression datasets confirms that dysregulated TGF-β signaling may represent an important event in AK-CSCC progression.

  Dataset EGAD00001006894

• Whole genome sequencing of tumor samples from advanced pre-treated NSCLC patients recruited in a phase I/II single-arm trial utilising CVA21, an oncolytic coxsackie virus, in combination with pembrolizumab.

  Acquired or de novo resistance to immune checkpoint inhibitors occurs in the majority of advanced non-small cell lung cancers (NSCLC). There is an unmet need to improve outcomes for patients with this condition. Oncolytic viruses represent an attractive treatment approach due to their dual activity in inducing tumor cell lysis directly and potentially augmenting anti-tumor immunity. Here, we present the safety, efficacy and translational findings from a phase I/II single-arm trial utilising CVA21, an oncolytic coxsackie virus, in combination with pembrolizumab in patients with advanced pre-treated NSCLC. We performed paired biopsies pre- and post-treatment in 10 patients who received intravenous CVA21 and pembrolizumab, 8 of whom had prior treatment with immune checkpoint inhibitor (ICI) therapy. Whole genome sequencing and spatial proteomics were performed to comprehensively characterise the response to CVA21. Combination CVA21/pembrolizumab (anti PD-1) therapy was well tolerated with no serious treatment-related adverse events. Partial responses were seen in two patients with prior acquired anti-PD-1 resistance and disease stabilisation in 6 patients, giving a clinical benefit rate of 80%. High baseline tumor mutational burden and PD-L1 expression were observed in patients with better response to treatment. Interestingly, an increase in antigen presentation and CD8+ T cell infiltration was observed on treatment compared with baseline in patients with better progression-free survival. This study demonstrates the potential of CVA21 to modulate the immunogenicity of tumor cells and remodelling the tumor microenvironment, providing novel insights for patient selection for trials involving novel immunotherapeutic approaches.

  Study EGAS00001008258

• Whole-Genome Sequencing (WGS) of a Malignant Granular Cell Tumor (GCT) with Metabolic Response to Pazopanib

  We report one case study of a malignant granular cell tumor patient with metabolic response to pazopanib. In this study, we used whole-genome sequencing of the tumor with the matched blood to characterize the somatic mutation profile in this tumor. This is the first reported whole-genome sequencing study of the rare malignant granular cell tumor.

  Study phs000978

• Mixture of 2 (closer mtDNA)

  Mixture of 2 unrelated individuals (of close mtDNA haplogroup) sequenced by 10x as a scRNA-seq. The dataset was then processed by Cell Ranger and deconvoluted to yield each individuals genetic profile. The clustering of SNPs is submitted as the processed file. The Sequencing fastqs are submitted as unprocessed files.

  Dataset EGAD00001008727

• Multiple Myeloma ChipSeq data on six histone modifications

  The data contained in this dataset is ChipSeq BAM files aligned to reference genome hg38. The ChipSeq was based on a combination of six histone modifications as follows: H3K4me1, H3K4me3, H3K9me3, H3K27me3, H3K27Ac and H3K36me3. The samples are patient-derived xenografts generated by passaging primary patient CD138+ selected cells through the SCID-rab myeloma mouse model.

  Dataset EGAD00001008353

• Pairs of whole genome sequencing repeated measurement sample pairs

  This dataset includes 186 whole genome sequencing samples which combine to create 93 pairs. Each pair is comprised of two sequencing experiments carried out on the same donor to the NIHR BioResource Rare Disease cohort. These samples have been used to validate the Telomerecat method (a method for estimating telomere length from whole genome sequencing).

  Dataset EGAD00001003809

• Exome sequencing of advanced hepatocellular carcinoma

  The aim of our project is to decipher the genomic of advanced hepatocellular carcinoma using whole exome sequencing. To this purpose, we aim to compare genetic landscape of advanced hepatocellular carcinoma with early tumor in order to understand the mechanisms of tumor progression. This work will also help to identify new therapeutic targets potentially useful to treat patients at advanced stage. This dataset contain whole exome sequencing aligned reads for 41 tumor with matched normal samples

  Dataset EGAD00001004555

• Childhood arthritis DNA (2020-01-15)

  The aim of this study is to describe the transcriptome of single arthritic cells. . This dataset contains all the data available for this study on 2020-01-15.

  Dataset EGAD00001005785

• TenK10K Phase 1: Whole Genome Sequencing tandem repeats multi-sample VCFs

  Tandem repeat variants were called for 1,925 samples from phase 1 of the TenK10K project. Variant calling from WGS alignments to the GRCh38 reference assembly was completed with ExpansionHunter v5. This dataset is comprised of autosomal tandem repeat variants provided as multisample compressed VCF format files. SNV-derived principal component scores used in the manuscript (Tanudisastro et al.) are also provided in this dataset.

  Dataset EGAD50000002378

• Genome-Wide Pleiotropy Scan Across Multiple Cancers

  A whole-exome sequencing (WES) study was conducted in 3,233 cases diagnosed with multiple primary cancers and 3,229 matched cancer-free controls (90% non-Hispanic white, 3% African-American, 3% East Asian, and 4% Latino) selected from individuals in the Kaiser Permanente Research Bank (KPRB) who were members of the Kaiser Permanente Northern California (KPNC) health plan. Cancer-free controls were matched to cases on age at specimen collection (within 2 years), sex, genotyping array (which matched on self-reported race/ethnicity), closest distance using the first two principal components for genetic ancestry, and reagent kit. Cases and controls were drawn from two prospective KPRB cohorts: the Research Program on Genes, Environment and Health (RPGEH) and the ProHealth study. Participants were sequenced by the Regeneron Genetics Center using the Illumina NovaSeq 6000 platform, and sample preparation and quality control were performed using a high-throughput, fully-automated system [PMID: 33087929]. Reads were aligned to the GRCh38 reference genome, and variants were called using WeCall [PMID: 33087929]. Participants with sex discordance, 20x coverage at less than 80% of targeted sites, and/or contamination greater than 5% were excluded. After quality control, we retained n = 6,247 (3,111 cases, 3,136 controls) individuals for downstream analyses. Among participants selected for this WES study, n = 5,432 (2,299 cases; 3,133 controls) consented to deposition of data to the National Institutes of Health (NIH).Further quality control was applied to filter low quality variants. Genotype calls with low depth of coverage (DP) were updated to missing (DP < 7 for SNPs and DP < 10 for indels), after which sites with low allele balance (AB) - variants without at least one sample having AB ≥ 15% for SNPs or AB ≥ 20% for indels - were removed. Lastly, variants with missingness > 10% and Hardy-Weinberg equilibrium p-value < 10-15 were excluded. Further description of quality control and downstream single-variant and gene-based analyses is available in Cavazos et al, 2022 [medRxiv].

  Study phs002809

• A Single Cell Transcriptomic Analysis of Human Neocortical Development

  Defining the number, proportion, or lineage of distinct cell types in the developing human brain is an important goal of modern brain research. We produced single cell transcriptomic profiles for 40,000 cells at mid-gestation to define deep expression profiles corresponding to all known major cell types at this developmental period and compare this with bulk tissue profiles. We identified multiple transcription factors (TFs) and co-factors expressed in specific cell types, including multiple new cell-type-specific relationships, providing an unprecedented resource for understanding human neocortical development and evolution. This includes the first single-cell characterization of human subplate neurons and subtypes of developing glutamatergic and GABAergic neurons. We also used these data to deconvolute single cell regulatory networks that connect regulatory elements and transcriptional drivers to single cell gene expression programs in the developing CNS. We characterized major developmental trajectories that tie cell cycle progression with early cell fate decisions during early neurogenesis. Remarkably, we found that differentiation occurs on a transcriptomic continuum, so that differentiating cells not only express the few key TFs that drive cell fates, but express broad, mixed cell-type transcriptomes prior to telophase. Finally, we mapped neuropsychiatric disease genes to specific cell types, implicating dysregulation of specific cell types in ASD, ID, and epilepsy, as the mechanistic underpinnings of several neurodevelopmental disorders. Together these results provide an extensive catalog of cell types in human neocortex and extend our understanding of early cortical development, human brain evolution and the cellular basis of neuropsychiatric disease.

  Study phs001836

• Ewings Sarcoma Rearrangement Screen

  Cancer is driven by mutations in the genome. We will uncover the mutations that give rise to Ewing's sarcoma, a bone tumour that largely affects children. We will use second generation Illumina massively parallel sequencing, and bespoke software, to characterise the genomes and transcriptomes of Ewing's sarcoma tumours.

  Dataset EGAD00001000389

• Gabriella Miller Kids First (GMKF) Pediatric Research Program in Susceptibility to Ewing Sarcoma Based on Germline Risk and Familial History of Cancer

  Ewing sarcoma (EWS) is a deadly bone cancer that occurs in children and adolescents. Mounting evidence suggests that a genetic predisposition exists for this pediatric cancer, although the specific genetic contribution has yet to be identified. EWS has never been linked to a specific cancer predisposition syndrome, although several case reports have been published that describe siblings and cousins with EWS. Furthermore, neuroectodermal tumors appear to occur more commonly in families with EWS. The two consistent epidemiology findings in EWS include a very strong Caucasian predilection and increased rates of hernia in EWS patients and their family members. Finally, the role of genetic microsatellite repeats in EWS tumorigenesis has been recently described, and these GGAA microsatellites are polymorphic in repeat size and location across the genome. The study goals of this Kids First project include (1) To identify cancer predisposition genes in EWS trios increasing disease risk, (2) To identify genome-wide GGAA microsatellite repeats in EWS trios increasing disease risk, and (3) To identity de novo mutation and structural variant rates in EWS trios reflecting underlying DNA repair defects that increase disease risk. As part of the Kids First Common Fund initiative, this study proposal will further elucidate the genetic contribution to pediatric cancer development. Around 375 of these trios were selected for whole genome sequencing as part of the Gabriella Miller Kids First fund. The EWS trios have been collected as part of the Children's Oncology Group's AEPI10N5 Study ("Genetic Epidemiology of Ewing Sarcoma"), and each trio has associated phenotypic data including a detailed family history. We will interrogate the sequence data using our genomic analysis pipeline at the University of Utah and the Utah Science Technology and Research initiative's (USTAR) Center for Genetic Discovery. We will look for the genetic contribution to EWS and the sequence data with be shared in a repository designated by the Kids First Common Fund. The WGS of these ~375 EWS trios will help us to understand the genetic origins of a deadly childhood cancer and may lead to novel strategies for prevention and treatment.

  Study phs001228

• ctDNA monitoring using patient-specific sequencing and integration of variant reads - Lung cohort

  Circulating tumor-derived DNA (ctDNA) can be used to monitor cancer dynamics noninvasively. Detection of ctDNA can be challenging in patients with low-volume or residual disease, where plasma contains very few tumor-derived DNA fragments. We show that sensitivity for ctDNA detection in plasma can be improved by analyzing hundreds to thousands of mutations that are first identified by tumor genotyping. We describe the INtegration of VAriant Reads (INVAR) pipeline, which combines custom error-suppression methods and signal-enrichment approaches based on biological features of ctDNA. With this approach, the detection limit in each sample can be estimated independently based on the number of informative reads sequenced across multiple patient-specific loci. We applied INVAR to custom hybrid-capture sequencing data from 176 plasma samples from 105 patients with melanoma, lung, renal, glioma, and breast cancer across both early and advanced disease. By integrating signal across a median of >105 informative reads, ctDNA was routinely quantified to 1 mutant molecule per 100,000, and in some cases with high tumor mutation burden and/or plasma input material, to individual parts per million. This resulted in median Area Under the Curve (AUC) values of 0.98 in advanced cancers, and 0.80 in early stage and challenging settings for ctDNA detection. We generalized this method to whole-exome and whole-genome sequencing, showing that the INVAR may be applied without requiring personalized sequencing panels, so long as a tumor mutation list is available. As tumor sequencing becomes increasingly performed, such methods for personalized cancer monitoring may enhance the sensitivity of cancer liquid biopsies.

  Study EGAS00001004447

• ctDNA monitoring using patient-specific sequencing and integration of variant reads - Breast cohort

  Circulating tumor-derived DNA (ctDNA) can be used to monitor cancer dynamics noninvasively. Detection of ctDNA can be challenging in patients with low-volume or residual disease, where plasma contains very few tumor-derived DNA fragments. We show that sensitivity for ctDNA detection in plasma can be improved by analyzing hundreds to thousands of mutations that are first identified by tumor genotyping. We describe the INtegration of VAriant Reads (INVAR) pipeline, which combines custom error-suppression methods and signal-enrichment approaches based on biological features of ctDNA. With this approach, the detection limit in each sample can be estimated independently based on the number of informative reads sequenced across multiple patient-specific loci. We applied INVAR to custom hybrid-capture sequencing data from 176 plasma samples from 105 patients with melanoma, lung, renal, glioma, and breast cancer across both early and advanced disease. By integrating signal across a median of >105 informative reads, ctDNA was routinely quantified to 1 mutant molecule per 100,000, and in some cases with high tumor mutation burden and/or plasma input material, to individual parts per million. This resulted in median Area Under the Curve (AUC) values of 0.98 in advanced cancers, and 0.80 in early stage and challenging settings for ctDNA detection. We generalized this method to whole-exome and whole-genome sequencing, showing that the INVAR may be applied without requiring personalized sequencing panels, so long as a tumor mutation list is available. As tumor sequencing becomes increasingly performed, such methods for personalized cancer monitoring may enhance the sensitivity of cancer liquid biopsies.

  Study EGAS00001004446

• WGS of human colorectal cancer organoid exposed to genotoxic pks+ E. coli

  Organoid cultures were exposed to two different E.Coli strains and a dye control with three biological duplicates. Their original culture was harvested as a control. In total 10 organoid cultures were whole-genome sequenced using the Novaseq6000 platforms. The data is deposited as .bam format.

  Dataset EGAD00001005416