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• HNPCC-Sys: Molecular Characterization of Lynch Syndromes

  Lynch Syndrome (LS) tumors are characterized by constitutional mutations in DNA mismatch-repair genes. Colorectal cancers (CRCs) are the predominant tumor type in patients with LS. Here, we have used whole-genome and transcriptome sequencing of LS- CRC to find similarities and differences of mutation and gene expression characteristics between LS-CRC and sporadic CRC (data provided by TCGA via dbGaP). Furthermore, we were interested in the molecular heterogeneity of LS-CRC. We have performed a molecular characterization of LS-tumors and of matched tumor-distant reference colonic mucosa based on whole-genome DNA- and RNA-sequencing analyses. Our data indicates the existence of two subgroups of LS-CRCs, G1 and G2, where G1 tumors show a higher number of somatic mutations, higher microsatellite slippage and a different mutation spectrum.

  Study phs001407

• HuBMAP: Single-Cell Data from Human Tissues

  The small bowel and colon are organs critical for maintaining homeostasis of the human body by mediating nutritional absorption upon the ingestion of food. Though both organs are extensive in length, there are known differences in function and cellular heterogeneity within different portions of each. Also, a cross section anywhere in the bowel reveals a complex layering of components involved in absorption and secretion, motility of gut contents, circulation, and immunity. We are mapping the complexity of the the small bowel and colon with cell-to-cell resolution in histologic sections, both along their lengths and across multiple individuals. Our molecular data consist of single cell ATAC-seq and RNA-seq. These profiles are spatially mapped to histologic sections using CO-Detection by indEXing (CODEX), a highly multiplexed system of antibody-tagged target epitopes.

  Study phs002272

• Evolution of Resistance in ER+ Breast Cancer

  While the combination of endocrine therapy and CDK4/CDK6 inhibitors has been shown to be effective in the metastatic ER+ breast cancer setting, to test whether it is effective in an earlier stage neoadjuvant setting, the FELINE trial (NCT02712723) was established to test the efficacy of letrozole and ribociclib in a ER-positive, HER2-negative patients in a randomized, placebo-controlled, multicenter trial. Patients were randomized to one of three arms: those in Arm A received letrozole and placebo, Arm B letrozole and intermittent ribociclib, and Arm C letrozole and continuous ribociclib. Samples were collected at screening (Day 0), Cycle 1 (Day 14), and end of trial (Day 180). Samples from 24 patients, where cancer cells were present at Day 0 and one additional time point, were subjected to whole-exome sequencing profiling.

  Study phs002287

• Transcriptomic and Clonal Characterization of T Cells in the Human Central Nervous System

  The cerebrospinal fluid (CSF) is thought to be a main route for immune surveillance in the central nervous system (CNS). Understanding the composition and state of CSF in healthy individuals may provide insight into perturbations present during neuroinflammation. Here, we have used single-cell RNA and TCR sequencing to profile CSF and peripheral blood mononuclear cells (PBMCs) from healthy individuals and patients with relapsing-remitting multiple sclerosis (MS), a chronic autoimmmune disease. In addition, with the goal of understanding how transcriptional artefacts are introduced in transcriptomics experiments, we have performed single-cell and TCR sequencing to profile PBMCs from a healthy individual that were processed with the same enzymatic digestion used for tissues (such as the brain) in the presence or absence of transcription inhibitors. 

  Study phs002222

• Hereditary Cancer Predisposition Syndromes and Uveal Melanoma

  Uveal melanoma (UM) is a subtype of melanoma characterized by the strong contribution of genetic rather than environmental factors in the pathogenesis of the disease, making it an ideal model disease to study the genetic basis of cancer. The long-term goal of our laboratory is to determine the genes and mechanisms responsible for hereditary cancer predisposition associated with UM. BAP1 has been identified as a candidate gene with definitive association with predisposition to UM. However, pathogenic variants in BAP1 are detected in only a small subset of UM patients even those with strong personal and family history of cancer suggesting the existence of other candidate genes. The goal of this project is to identify novel candidate genes contributing to hereditary predisposition to UM in patients with no detectable germline pathogenic variant in BAP1.

  Study phs001943

• Somatic Mutations in Epilepsy: Whole Genome Sequence Analysis of Single Neurons

  Low-coverage whole-genome sequencing was performed on single-cells from resected brain tissues obtained from an individual with hemimegalencephaly (HMG) along with a somatic copy number variant (sCNV) of chromosome 1q in order to characterize the sCNV at the single cell level. Single neuronal nuclei and non-neuronal nuclei were isolated by fluorescence-activated cell sorting (FACS) using NeuN immunoreactivity to identify neurons. 46 neurons and 30 non-neuronal cells, as well as a batch of 10 and a batch of 100 cells from each group, were genome amplified using multiple displacement amplification (MDA) and sequenced on an Illumina HiSeq 2000 sequencer. Thirty-two samples were multiplexed into each HiSeq lane for single-end 50 bp runs, obtaining ~5 million pass-filter reads per sample.

  Study phs002615

• The Oral Microbiome and Head and Neck Cancer

  Oral microbiota may influence head and neck squamous cell carcinoma (HNSCC) development, potentially related to carcinogen metabolism. The human oral cavity hosts a diverse microbiota, including bacteria and fungi. We performed shotgun sequencing and ITS1 sequencing on 236 HNSCC case participants who developed HNSCC during a mean follow-up of 5.1 years and 458 matched controls who remained HNSCC-free. Oral samples were obtained from a prospective nested case-control study within three epidemiological cohorts: the American Cancer Society Cancer Prevention Study II Nutrition Cohort (ACS CPS-II), the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), and the Southern Community Cohort Study (SCCS). Control participants were selected using 2:1 frequency matching based on cohort, age, sex, race and ethnicity, and time since oral sample collection.

  Study phs004018

• Single-Cell Atlas of Human Liver and Blood Immune Cells Across Fatty Liver Disease Stages

  The goal of the study was to investigate immunological correlates of human fatty liver disease progression. We generated a single-cell RNA-seq (scRNA-seq) atlas of immune cells from liver fine needle aspirates (FNAs) and paired peripheral blood mononuclear cells (PBMCs) from a full-spectrum Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)/Metabolic Dysfunction-Associated Steatohepatitis (MASH) human cohort, using the 3' 10X Genomics platform. Using computational analyses to assess changes in cellular frequencies and function, we found heightened immunoregulatory programs with profibrotic potential alongside a shift from antigen-specific to natural killer cytotoxic functions in the liver with MASH progression. Available data include raw single-cell transcriptomic data (FASTQ files) for each sample type (PBMC, FNA) per patient alongside clinical and histological measurements of fatty liver disease.

  Study phs004044

• exploration of biomarkers discriminating squamous cell carcinoma from other lung cancers

  Targeted therapies based on the molecular and histological features of cancer types are becoming standard practice. The most effective regimen in lung cancers is different between squamous cell carcinoma (SCC) and adenocarcinoma (AD). Therefore a precise diagnosis is crucial, but this has been difficult, particularly for poorly differentiated SCC (PDSCC) and AD without a lepidic growth component (non-lepidic AD). Biomarkers enabling a precise diagnosis are therefore urgently needed. To achieve this goal, we initially performed CAGE (Cap Analysis of Gene Expression) to quantify promoter activities on 97 frozen tissues from surgically resected lung cancers (22 SCC and 75 AD). We furhter expanded the transcriptome profiling to cover additional 48 malignant neoplasm of bronchus and lung, including mesothelioma and metastatic lung cancers derived from other tissues.

  Study JGAS000488

• Transcriptomic profiling of circulating regulatory T cells from follicular lymphoma patients before and after Lenalidomide treatment

  Lenalidomide has demonstrated a favorable efficacy profile in follicular lymphoma (FL) in combination with anti-CD20 antibodies. However, in vivo administration of Lenalidomide in FL patients triggers a proliferation of functional regulatory T cells (Tregs), and a high percentage of Tregs before and along the course of treatment with Lenalidomide/anti-CD20 combination is of poor prognosis. In this study, we evaluated the impact of Lenalidomide on circulating Treg in 3 FL patients using single cell RNA sequencing (scRNAseq). For this purpose, we took advantage of the GALEN clinical trial (NCT01582776), where Lenalidomide was initiated one week before starting the anti-CD20 antibody Obinutuzumab, allowing us to compare the transcriptomic profile of immune cells before (D0) and at day 7 (D7) of treatment by Lenalidomide alone.

  Study EGAS50000001048