Search Results - EGA European Genome-Phenome Archive

Circulating Tumor Cell Heterogeneity in Neuroendocrine Prostate Cancer by Single Cell Copy Number Analysis

Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may arise de novo or develop from pre-existing prostate adenocarcinoma as a mechanism of treatment resistance. Combined loss of tumor suppressors RB1, TP53, PTEN are frequent in NEPC but also present in a subset of prostate adenocarcinomas. Most clinical and preclinical studies support a trans-differentiation process, whereby NEPC arises clonally from a prostate adenocarcinoma precursor during the course of treatment resistance. Here we highlight a case of NEPC with significant intra-patient heterogeneity observed across metastases. We further demonstrate how single-cell genomic analysis of circulating tumor cells combined with phenotypic evaluation of cellular diversity can be considered as a window into tumor heterogeneity in patients with advanced prostate cancer. We performed whole genome sequencing of circulating tumor cells (CTCs) from patients with castration resistant adenocarcinoma (n=4) and neuroendocrine prostate cancer (n=8). CTCs were collected via Epic Sciences platform and single CTC genomic data (n=215) generated via Illumina NextSeq500. 

Study phs002462

Genomic Alterations in Normal Breast Tissues Preceding Breast Cancer Diagnosis (GANPBC)

This study was designed to examine the genomic alterations in histologically normal breast tissues of women who subsequently developed breast cancer and compare it to breast tissues from women who did not. Breast core needle biopsy tissues from 160 healthy women at the Susan G. Komen Tissue Bank were requested for this study and sequenced using whole exome sequencing. The samples included tissues from 79 participants who, during the annual follow-up with Susan G. Komen self-reported a subsequent diagnosis of invasive or non-invasive breast cancer after tissue submission; these cases were classified as pre-diagnosis normal tissues. The remaining 81 samples were from women who had no cancer diagnosis at their last follow-up and were classified as healthy control samples. Among the pre-diagnosis samples, the average time from tissue donation to breast cancer diagnosis was 4.7 years (range: 0-11). For the healthy controls, the average time from tissue donation to the last follow up was 6.1 years (range: 0-14).

Study phs003822

Identification and Characterization of Cancer Mutations in Japanese LungAdenocarcinoma without Sequencing of Normal Tissue Counterparts

We analyzed whole-exome sequencing data from 97 Japanese lung adenocarcinomapatients and identified several putative cancer-related genes and pathways. Particularly, we observed that cancer-related mutation patterns were significantly different between different ethnic groups. As previously reported, mutations in the EGFR gene were characteristic to Japanese, while those in the KRAS gene were more frequent in Caucasians. Furthermore, during the course of this analysis, we found that cancer-specific somatic mutations can be detected without sequencing normal tissue counterparts. 64% of the germline variants could be excluded using a total of 217 external Japanese exome datasets. We also show that a similar approach may beused for other three ethnic groups, although the discriminative power depends on the ethnic group. We demonstrate that the ATM gene and the PAPPA2 gene could be identified as cancer prognosis related genes. By bypassing the sequencing of normaltissue counterparts, this approach provides a useful means of not only reducing the time and cost of sequencing but also analyzing archive samples, for which normal tissue counterparts are not available.

Study JGAS000001

CPC-GENE Prostate Cancer Heterogeneity Study

Herein we describe a molecular portrait of potentially curable, Gleason 7 and intermediate risk prostate cancer based on genome-wide CNV profiles of 96 patients, and subsequent whole-genome sequencing of 28 tumours from 10 patients, using DNA quantities that are achievable in diagnostic biopsies (50 ng). We show that Gleason 7 cancer is highly heterogeneous at the SNV, CNV, and intra-chromosomal translocation levels, and is characterized by a very low number of recurrent SNVs but significant structural variation. We identified a novel recurrent MYCL1 amplification, which was strongly associated with TP53 deletion and prognostic for biochemical recurrence in this cohort. Moreover, we identified clear evidence of divergent tumour evolution in multi focal cancer and, in 2/5 cases evaluated, multiple tumours of independent clonal origin. Taken together, these data represent the first systematic evaluation of the differential genomics of potentially curable prostate cancer, and strongly suggest that a more robust understanding of the relationship between genetic heterogeneity and clinical outcomes is required to effectively develop biomarkers of prognosis based on tumour genomics.

Study EGAS00001000549

Mitochondrial-Nuclear Mutational Cross-Talk Drives Recurrence of Localized Prostate Cancer

Prostate cancer remains the most prevalent non-skin cancer in men, but has a remarkably quiet mutational profile. Exome sequencing studies have revealed few recurrent somatic single nucleotide variants (SNVs). Whole-genome sequencing studies have not yet identified highly recurrent driver non-coding SNVs (ncSNVs) or genomic rearrangements (Grs). As a result, the underlying events that drive this frequent disease remain unknown. While mitochondrial mutations have been linked to several tumour types, including prostate cancer, their global frequency and impact has remained unknown. To determine if mitochondrial mutations might drive some prostate cancers, we analyzed the mitochondrial genomes of 216 tumours from patients with the most commonly diagnosed form of prostate cancer. We developed a pipeline that conservatively identified only mitochondrial SNVs (mitoSNVs) that differed in the heteroplasmy fraction as compared to their paired-normal by at least 20%. We identified several features of the mitochondrial genome that were correlated with nuclear genomic mutations, as well as features that were significantly associated with biochemical recurrence.

Study EGAS00001001782

Whole Genome Sequencing of Gingivo-buccal Cancer: ICGC-India Project_YR03

As a part of the ICGC, India has undertaken genomic studies on gingivobuccal cancer of the oral cavity, which is the most prevalent form of cancer among men in India. There are various known environmental (life-style) correlates of this cancer, the most important of which are tobacco chewing and HPV infection. Whole genome sequencing of paired DNA samples – isolated from the tumor tissue and from the blood of twenty five patients – have been performed to catalog germline and somatic mutations. Association between each observed genomic alteration and exposure to environmental risk factors is being explored. Detailed clinical characterization of the patients, collection of data on demographic and environmental exposures, and isolation of DNA samples from blood and tumor tissues collected from each patient are being done at the Advanced Centre for Research, Treatment and Education on Cancer, Mumbai. Whole genome sequencing is being performed at the National Institute of Biomedical Genomics, Kalyani. We have completed whole genome sequencing of paired blood and tumor DNA samples using Illumina HiSeq-2000 and 2500.

Study EGAS00001001901

Mapping the breast cancer metastatic cascade onto circulating tumour DNA using genetic and epigenetic clonal tracking

Circulating tumour DNA (ctDNA) allows tracking the evolution of human cancers at high resolution, overcoming many limitations of tissue biopsies. However, exploiting ctDNA to determine how a patient’s cancer is evolving in order to aid clinical decisions remains difficult. This is because ctDNA is a mix of fragmented alleles, and the contribution of different cancer cell subpopulations from distinct lesions to ctDNA remains largely unknown. Profiling of ctDNA almost invariably requires prior knowledge of what genomic alterations to track. Here we leverage on a rapid autopsy programme to demonstrate that unbiased genomic characterisation of several metastatic sites and concomitant ctDNA profiling at whole-genome resolution reveals the extent to which ctDNA is representative of widespread disease. We also present a ctDNA methylation profiling method that allows tracking evolutionary changes in the cancer cell population at single-molecule resolution without prior knowledge. These results have critical implications for the use of liquid biopsies to monitor cancer evolution in humans and potentially guide treatment.

Study EGAS00001004014

The subclonal architecture of metastatic breast cancer: Results from a prospective community-based rapid autopsy program 'CASCADE'

Background: Understanding the cancer genome is seen as a key step in improving outcomes for cancer patients. Genomic assays are emerging as a possible avenue to personalised medicine in breast cancer. The majority of work in this area has targeted primary tumours however, and very few studies have performed comprehensive profiling of advanced disease. Evolution of the cancer genome during the natural history of breast cancer is largely unknown, as is the profile of disease at death. We sought to study in detail these aspects of advanced breast cancers that have resulted in lethal disease. Methods and Findings: Three patients with ER-positive, HER2-negative breast cancer and one patient with triple negative breast cancer underwent rapid autopsy as part of an institutional prospective community-based rapid autopsy program. Cases represented a range of management problems in breast cancer, including late relapse after early stage disease; de novo metastatic disease; discordant disease response and disease refractory to treatment. Between 5 and 12 metastatic sites were collected at autopsy together with available primary tumours and longitudinal metastatic biopsies taken during life. Samples underwent paired tumour-normal whole exome sequencing and single nucleotide polymorphism arrays. Subclonal architectures were inferred by jointly analysing all samples from each patient. Mutations were validated using high depth amplicon sequencing.Between cases, there were significant differences in mutational burden, driver mutations, mutational processes and copy number variation. Within each case, we found dramatic heterogeneity in subclonal structure from primary to metastatic disease and between metastatic sites, such that no single lesion captured the breadth of disease. Metastatic cross seeding was found in each case and treatment drove subclonal diversification. Subclones displayed parallel evolution of treatment resistance in some cases, and apparent augmentation of key oncogenic drivers as an alternative resistance mechanism. We also observed the key role of mutational processes in subclonal evolution.Limitations of this study include the potential for bias introduced by joint analysis of formalin fixed archival specimens with fresh specimens, and the difficulties in resolving subclones with whole exome sequencing. Other alterations that could define subclones such as structural variants or epigenetic modifications were not assessed. Conclusions: This study highlights the variety of mechanisms that shape the genome of metastatic breast cancer, and the value of studying advanced disease in detail. Treatment drives significant genomic heterogeneity in breast cancers which has implications for disease monitoring and treatment selection in the personalised medicine paradigm.

Study EGAS00001002153

Enrichment of PTPRT and JAK2 mutations in lung cancer from African Americans and evidence for increased GI and HRD in LUSC

The goal of this study is to compare the somatic mutation landscape between European Americans and African Americans. It includes various histological forms of lung cancer. In LUAD, we find increased prevalence of PTPRT and JAK2 mutations among African Americans. These proteins function in the same pathway and as such, this may be a new actionable target for lung cancer. We have also examined the landscape of copy number profiles in African Americans and European Americans.

Study phs001895

Mutational Landscape of Lethal Castrate Resistant Prostate Cancer

Exome sequencing of matched pairs of tumor / normal genomic DNA was performed from high risk localized prostate cancer or lethal, metastatic, castrate resistant prostate cancer (CRPC). Exome libraries were prepared using Illumina Paired_End Genome DNA Sample Prep Kit and captured using Agilent SureSelect Capture Library or Roche EZ Exome capture library. Sequencing was performed on Illumina GAII and HiSeq 2000 platforms in paired end mde, with 80 base pair reads from the final library fragments. Copy number alterations and somatic mutations were identified.

Study phs000554

Genome-Wide Analysis of Aberrant Position and Sequence of Plasma DNA Fragment Ends in Patients With Cancer

This study investigated fragmentation characteristics in plasma cell-free DNA and evaluated the relevance of such analysis for cancer diagnostics. Specifically, we performed whole genome sequencing (WGS) of healthy individuals and cancer patients, and evaluated genome-wide coverage and sequences surrounding fragment ends. This was a retrospective study of archived plasma samples. The WGS data are available through this submission. Detailed study design and findings were published in Budhraja et al. Science Translational Medicine 2023.

Study phs003170

Ontario Familial Colon Cancer Registry Single Nucleotide Polymorphisms and CpG Methylation (OFCCR SNP-CpG)

We profiled the methylation landscape of ~2100 DNA samples (~1100 cases of colorectal cancer and ~1000 controls) from the Ontario Familial Colon Cancer Registry (OFCCR) using the HumanMethylation450 array from Illumina. DNA was extracted from lymphocyte pellets, except for 99 samples for which DNA was extracted from lymphoblastoid cell lines. Samples were genotyped on the Affymetrix Human Mapping 100k and 500k arrays. The aim the study was to evaluate the interplay between genetic variation and methylation, including long-range epigenetic regulation.

Study phs000779

Human Skin Cancer Atlas, Medical University of Vienna Data Access Policy

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.

Dac EGAC50000000154

Uncovering Principles of Adaptive Regulation in Cancer Resistance Through Deep Evolutionary Profiling

A comprehensive understanding of the emergence of therapy resistance in cancer requires new approaches capable of generating and characterizing drug resistant cell lines at scale. Here, we present the EVolution Of Lineages in Vitro (EVOLV) platform, a high-throughput approach for generating diverse libraries of viable, drug-resistant cell lines from a common progenitor. EVOLV enables deeper insights into the genomics of drug resistance as well as into the complex interplay among genomic, transcriptomic, and functional layers during cancer evolution.

Study phs003851

Evaluation of whole genome sequencing utility in identifying driver alterations in cancer genome

This study aimed to assess the effectiveness of whole genome sequencing (WGS) compared to whole exome sequencing (WES) in identifying driver alterations in cancer genomes. Out of 177 cases with no driver alterations detected by WES, WGS identified driver alterations in 68.4% and likely driver alterations in 22.6% of cases. The most common alterations found were oncogene amplifications, tumor suppressor gene deletions, and small variants outside coding regions. WGS proved valuable in uncovering genomic changes associated with cancer development.

Study JGAS000715

Metabolomic and transcriptomic analyses identify metabolic alterations and immune suppression in ovarian cancer

The objective of this study is to identify metabolic alterations and related phenotypes specific to ovarian cancer by performing metabolomic analysis of plasma and tissue samples. In addition, transcriptomic analysis is conducted to investigate the relationship between metabolic status and immune-related gene expression. By integrating metabolomic and transcriptomic data, this study aims to clarify how metabolic reprogramming contributes to tumor progression and immune suppression, particularly the reduction of natural killer (NK) cell activity, in ovarian cancer.

Study JGAS000831

WES of breast cancer patients and controls

This study assessed the variant profiles of 408 samples from 126 breast cancer patients with various survival outcomes, including paired uninvolved mammary gland samples collected at proximal distances from primary lesions. As a reference, control samples from 15 mammoplasty individuals without cancer history were studied. Whole exome sequencing was performed to identify post-zygotic and germline variants present in the studied samples. Variant annotation in known databases, interpretation, and statistical analyses followed to discern the clinical relevance of called variants.

Study EGAS50000000539

analysis of immune infiltration in colorectal cancer metastasis

Metastatic colorectal cancer (mCRC) is the main cause of CRC mortality, with limited treatment options. Although immunotherapy has benefited some cancer patients, mCRC typically lacks the molecular features that respond to this treatment. However, recent studies indicate that the immune microenvironment of mCRC may be modified to enhance the effect of immune checkpoint inhibitors. This study aimed to explore the metastatic immune microenvironment by comparing immune cell populations in colorectal liver (CLM), lung (mLu) and peritoneal (PM) metastases.

Study EGAS50000000652

Sequencing of serial plasma and multiregional tumor samples in a patient with metastatic breast cancer

Circulating tumor DNA analysis can be used to track tumor burden and analyze cancer genomes non-invasively but the extent to which it represents metastatic heterogeneity is unknown. Here, we follow a patient with metastatic ER and HER2 positive breast cancer receiving two lines of targeted therapy over 3 years. We characterize genomic architecture and infer clonal evolution in 8 tumor biopsies and 9 plasma samples collected over 1,193 days of clinical follow-up using exome and targeted amplicon sequencing.

Study EGAS00001001466

A Comparative Analysis of Algorithms for Somatic SNV Detection in Cancer

Four recently published algorithms for the detection of somatic SNV sites in matched cancer-normal sequencing datasets are VarScan, SomaticSniper, JointSNVMix and Strelka. In this analysis, we apply these four SNV calling algorithms to cancer- normal Illumina exome sequencing of a chronic myeloid leukaemia (CML) patient. The candidate SNV sites returned by each algorithm are filtered to remove likely false positives, then characterised and compared to investigate the strengths and weaknesses of each SNV calling algorithm.

Study EGAS00001000927

Mutations conferring differential treatment response in breast cancer

Poor prognosis primary breast cancer patients usually receive cytotoxic chemotherapy as a component of treatment, but despite this aggressive therapy recurrences remain common. Improved understanding of chemoresistance pathways would allow better stratification of chemotherapy using predictive markers, and may allow therapeutic inhibition of resistance mechanisms in order to chemosensitise tumours. We aimed to identify molecular pathways that define chemoresponse using the novel approach of examining the selection exerted by neoadjuvant chemotherapy on sub-clonal somatic mutational profiles of cancer cells.

Study EGAS00001003626

The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival

Tumor infiltration by T cells is paramount for effective anti-cancer immune responses. We hypothesized that the T cell receptor (TCR) repertoire of tumor infiltrating T lymphocytes (TIL/Tc) could determine disease course at different stages in cancer progression. We show that the diversity of the TIL/Tc TCR at baseline is prognostic in various cancers, whereas in metastatic melanoma TIL/Tc TCR clonality at baseline is predictive for activity and efficacy of PD1 blockade immunotherapy.

Study EGAS00001005201

Defining structural variation associated with breast cancer susceptibility by long-read genome sequencing

Germline structural variants (SVs) are challenging to identify by conventional genetic testing assays. Long-read sequencing has improved the global characterization of SVs, but its sensitivity at genetic loci associated with high- and moderate-penetrance cancer susceptibility has not been reported. This study used long-read genome sequencing performed on the Oxford Nanopore Technologies' PromethION to resolve variants underlying breast cancer susceptibility in sixteen individuals with pathogenic germline SVs in BRCA1, BRCA2, CHEK2 or PALB2.

Study EGAS00001005872

Deep whole genome sequencing identifies recurrent genomic alterations in breast cancer cell lines and patient derived xenograft models

Breast cancer cell lines (BCCLs) and patient-derived xenografts (PDX) are the most frequently used models in breast cancer research. Despite their widespread usage, genome sequencing of these models is incomplete, with previous studies only focusing on targeted gene panels, whole exome or shallow whole genome sequencing. Here we describe deep whole genome sequencing (WGS) of commonly used BCCL and PDX models using the Illumina X10 platform with an average ~ 60x coverage.

Study EGAS00001006285

Whole Genome Sequencing Data of High Grade Serous Ovarian Cancer

Longitudinal whole genome sequencing data to study chemoresponse in ovarian cancer. These samples belong to an ongoing sample collection and the data already includes hundreds of samples from over 200 patients. Samples are from primary and metastatic tissues and ascites. All patients have been treated with platinum-taxane based chemotherapy and majority of them are diagnosed with high-grade serous ovarian cancer.

Study EGAS00001006775

Yale Policy for head and neck cancer and HPV clinical trials

Yale Policy for human controlled access data associated with head and neck cancer and HPV clinical trials

Dac EGAC50000000403

Identification_and_functional_validation_of_driver_mutations_in_colorectal_cancer

Targeted exome sequencing of human colorectal cancers for the identification of novel cancer drivers.

Study EGAS00001000044