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• Identification of High-Risk PHF19 Expressing Cells in Myeloma Single-Cell Multiomics

  The aim of this study is to identify novel subsets of cells that are associated with progression and response to treatment. In this project, we study the tumor fraction from 49 myeloma patients across stages of progression. Samples were collected from 10 smoldering multiple myeloma (SMM), 22 newly diagnosed multiple myeloma (NDMM), and 17 relapsed refractory multiple myeloma (RRMM) patients. These samples were then sorted using magnetic-activated cell sorting (MACS) for CD138+ cells that represent the tumor fraction of each sample. The CD138+ fraction then underwent whole genome sequencing (WGS), where possible, and single-cell multiomics. Single-cell multiomics can now measure scRNA-seq and scATAC-seq simultaneously, which we use in this project. Using single-cell multiomics, we will study subclonal changes in gene expression, chromatin accessibility, and identify novel regulatory relationships within myeloma tumors. Furthermore, we will apply state of the art single-cell and single-cell multiomic techniques to better identify the more high-risk components of myeloma.

  Study phs003220

• Ipilimumab and Decitabine in Treating Patients With Relapsed or Refractory Myelodysplastic Syndrome or Acute Myeloid Leukemia

  The NCI Experimental Therapeutics Clinical Trials Network (ETCTN)/Cancer Therapy Evaluation Program (CTEP) 10026 study (NCT02890329) tested combined ipilimumab and decitabine treatment in two cohorts: Arm A consisted of patients with relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation. Arm B consisted of patients with advanced myelodysplastic syndrome (MDS) or AML that did not previously undergo stem cell transplantation. During the study, peripheral blood and bone marrow samples were obtained from study participants at study entry (screening), following the first lead-in cycle of decitabine monotherapy, during combined treatment with decitabine and ipilimumab, and at the end of treatment.This study tested the combination of the CTLA-4 blocking antibody ipilimumab and the DNA methyltransferase inhibitor decitabine in advanced myeloid disease in the transplant-naive and post-transplant context. The samples were used for bulk and single cell RNA sequencing (scRNA-seq) as well as whole exome sequencing (WES).

  Study phs003015

• Single cell chromatin accessibility allows analysis of the transposable element landscape, revealing shared features of immune tissue-residency

  Tissue adaptation is required for regulatory T (Treg) cells to function within organs. Whether this program shares similarities between different tissue-localized immune populations is poorly understood. Here, we addressed this by analyzing single-cell chromatin accessibility data, including the transposable element (TE) landscape, of CD45+ immune cells from different tissues. We identified features of organ-specific tissue adaptation across different immune cells. Focusing on tissue-Treg cells, we found that the Treg tissue adaptation program was conserved in other tissue-localized immune cells, such as amphiregulin-producing Th17 cells. Accessible TEs can act as regulatory elements but their contribution to tissue adaptation is unclear. TE landscape analysis revealed an enrichment of specific transcription factor binding motifs in TE regions within accessible chromatin peaks. TEs, specifically from the LTR family, were located in enhancer regions and associated with tissue adaptation. These findings broaden our understanding of immune tissue-residency, an important step towards organ-specific immune interventions.

  Study EGAS50000000350

• MutWP6__CRUK_Grand_Challenge_Mutographs_of_Cancer__alkylating_agents

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Within Mutographs, work lead by the Sanger Institute will investigate whether detection of somatic mutations and mutational signatures in circulating white blood cells can be developed into a practical, generic system for surveying and monitoring multiple different endogenous and exogenous exposures, providing an ‘observatory’ on somatic mutational processes in humans. Whole genome sequences are generated at the Wellcome Sanger Institute (Illumina HiSeqX). Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003637

• MutWP6__CRUK_Grand_Challenge_Mutographs_of_Cancer__oncology_agents

  he Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Within Mutographs, work lead by the Sanger Institute will investigate whether detection of somatic mutations and mutational signatures in circulating white blood cells can be developed into a practical, generic system for surveying and monitoring multiple different endogenous and exogenous exposures, providing an ‘observatory’ on somatic mutational processes in humans. Whole genome sequences are generated at the Wellcome Sanger Institute (Illumina HiSeqX). Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001004125

• Single-cell RNA sequencing of human skin tumors (BCC, SCC and Melanoma)

  Cancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. Here, we elucidate the yet unresolved intra-tumoral CAF variety in three skin cancer types at molecular and spatial single-cell resolution in a large cohort. We show that two out of three CAF subtypes contribute to tumor immune surveillance with distinct mechanisms. Matrix CAFs (mCAFs) ensheath tumor nests and synthesize extracellular-matrix to prevent T cell invasion. Immunomodulatory CAFs (iCAFs), which express proinflammatory and immunomodulatory factors, are only detected in high abundance in aggressive tumors. Strikingly, iCAFs but not tumor cells are (apart from immune cells) the exclusive cell type producing chemokines and, thus, play a key role in immune cell recruitment and activation. Mechanistically, we show that cancer cells transform adjacent healthy fibroblasts into cytokine-expressing iCAFs, which subsequently recruit immune cells and modulate the immune response. In conclusion, targeting CAF variants holds promise for improved efficacy of immunotherapy.

  Study EGAS50000000365

• Base-excision repair pathway shapes 5-methylcytosine deamination signatures in pan-cancer genomes

  Transition of cytosine to thymine in CpG dinucleotides is the most frequent type of mutation in cancer. This increased mutability is commonly attributed to spontaneous deamination of 5-methylcytosine (5mC), which is normally repaired by the base-excision repair (BER) pathway. However, the contribution of 5mC deamination in the increasing diversity of cancer mutational signatures remains poorly explored. Here, we integrate mutational signatures analysis in a large series of tumor whole genomes with lineage-specific epigenomic data to draw a detailed view on 5mC deamination in cancer. We uncover tumor type-specific patterns of 5mC deamination signatures in CpG and non-CpG contexts. We demonstrate that the BER glycosylase MBD4 preferentially binds to open chromatin domains, which correlates with lower mutational burden in these domains. We validate our findings by modelling BER deficiencies in isogenic cell models. Overall, we establish MBD4 as the main actor responsible for 5mC deamination repair in humans.

  Study EGAS50000000536

• Integrative Molecular Characterization of Breast Cancer

  Version 1: We have performed integrative analyses of breast cancer tumors, including whole exome sequencing (WES) of tumor and normal pairs, whole transcriptome sequencing, and single-cell RNA sequencing (scRNA-seq) or single-nucleus RNA sequencing (snRNA-seq), to determine molecular correlates of response to novel and immune therapies. We have focused on dissecting the role of anticancer immunity in response to these therapies and understanding biological mechanisms underlying therapeutic resistance. The goal of this work is to advance a precision medicine approach to breast cancer treatment by identifying molecular biomarkers to improve therapy selection and novel therapeutic targets to overcome resistance. Version 2: We performed bulk whole exome sequencing (WES) of fresh frozen tissue from primary hormone receptor-positive breast cancer. Additionally, where available, we performed bulk whole transcriptome sequencing for the same individuals (tumor only). Additionally, we performed single cell sequencing on fresh frozen tissue from primary hormone receptor-positive breast cancer.

  Study phs002419

• Plasma mutation profile of precursor lesions and colorectal cancer using the Oncomine Colon cfDNA Assay

  Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. Early detection of precursor lesions or early-stage cancer could hamper cancer development or improve survival rates. Liquid biopsy, which detects tumor biomarkers, such as mutations, in blood, is a promising avenue for cancer screening. To assess the presence of genetic variants in plasma cell-free tumor DNA from patients with precursor lesions and colorectal cancer using the commercial Oncomine Colon cfDNA Assay. Cell-free DNA (cfDNA) samples from the blood plasma of 52 Brazilian patients were analyzed. Eight patients did not have any significant lesions (five normal colonoscopies and three hyperplastic polyps), 24 exhibited precursor lesions (13 nonadvanced adenomas, ten advanced adenomas, and one sessile serrated lesion), and 20 patients with cancer (CRC). The mutation profile of 14 CRC-associated genes were determined by next-generation sequencing (NGS) using the Oncomine Colon cfDNA Assay in the Ion Torrent PGM/S5 sequencer.

  Study EGAS50000000471

• MP2PRT: Genomic and Molecular Characterization of Biomarkers Associated with Tumor Angiogenesis, DNA Repair, and Immunologic Tolerance using Samples from the NRG Oncology Phase 3 Randomized Trial, GOG-0240 (NCT00803062)

  The Molecular Profiling to Predict Response to Treatment (MP2PRT) program is part of the NCI's Cancer Moonshot Initiative. The aim of this program is the retrospective characterization and analysis of biospecimens collected from completed NCI-sponsored trials of the National Clinical Trials Network and the NCI Community Oncology Research Program. This study is one of the selected studies under this program. For this study, genomic characterization (WGS, WXS, Total RNAseq, miRNAseq) has been performed on cervical tumor tissue from patients with advanced disease (persistent, recurrent, and metastatic) and matching germline samples. It is hypothesized that the characterization of these tissues using next generation sequencing will lead to the identification of relevant novel genetic aberrations within the immunologic, DNA repair, and tumor angiogenesis domains that dichotomize the study population into exceptional responders and non-responders to systemic therapy, with a spectrum of response manifesting between the two extremes.

  Study phs002293