{"database":"EGA","file_versions":[],"scores":null,"additional":{"omics_type":["Genomics"],"technology_type":["Illumina HiSeq 2000, Illumina MiSeq"],"study_type":["Other"],"full_dataset_link":["https://ega-archive.org/studies/EGAS00001000625"],"host":["EGA"],"description":["EGA study EGAS00001000625"],"dataset_title":["Exome sequencing of tumor samples","Targeted deep sequencing of somatic mutations","Copy number profiling using PlasmaSeq"],"category":["restricted"],"repository":["EGA"],"pubmed_abstract":["<h4>Introduction</h4>The management of metastatic breast cancer needs improvement. As clinical evaluation is not very accurate in determining the progression of disease, the analysis of circulating tumor DNA (ctDNA) has evolved to a promising noninvasive marker of disease evolution. Indeed, ctDNA was reported to represent a highly sensitive biomarker of metastatic cancer disease directly reflecting tumor burden and dynamics. However, at present little is known about the dynamic range of ctDNA in patients with metastatic breast cancer.<h4>Methods</h4>In this study, 74 plasma DNA samples from 58 patients with metastasized breast cancer were analyzed with a microfluidic device to determine the plasma DNA size distribution and copy number changes in the plasma were identified by whole-genome sequencing (plasma-Seq). Furthermore, in an index patient we conducted whole-genome, exome, or targeted deep sequencing of the primary tumor, metastases, and circulating tumor cells (CTCs). Deep sequencing was done to accurately determine the allele fraction (AFs) of mutated DNA fragments.<h4>Results</h4>Although all patients had metastatic disease, plasma analyses demonstrated highly variable AFs of mutant fragments. We analyzed an index patient with more than 100,000 CTCs in detail. We first conducted whole-genome, exome, or targeted deep sequencing of four different regions from the primary tumor and three metastatic lymph node regions, which enabled us to establish the phylogenetic relationships of these lesions, which were consistent with a genetically homogeneous cancer. Subsequent analyses of 551 CTCs confirmed the genetically homogeneous cancer in three serial blood analyses. However, the AFs of ctDNA were only 2% to 3% in each analysis, neither reflecting the tumor burden nor the dynamics of this progressive disease. These results together with high-resolution plasma DNA fragment sizing suggested that differences in phagocytosis and DNA degradation mechanisms likely explain the variable occurrence of mutated DNA fragments in the blood of patients with cancer.<h4>Conclusions</h4>The dynamic range of ctDNA varies substantially in patients with metastatic breast cancer. This has important implications for the use of ctDNA as a predictive and prognostic biomarker."],"pubmed_title":["The dynamic range of circulating tumor DNA in metastatic breast cancer."],"pubmed_authors":["Heidary Maryam M, Auer Martina M, Ulz Peter P, Heitzer Ellen E, Petru Edgar E, Gasch Christin C, Riethdorf Sabine S, Mauermann Oliver O, Lafer Ingrid I, Pristauz Gunda G, Lax Sigurd S, Pantel Klaus K, Geigl Jochen B JB, Speicher Michael R MR"],"name_synonyms":["Tumor DNA, Breast Carcinoma, Human Mammary Neoplasm, primary breast cancer, Carcinoma, malignant tumor of the breast, Breast Carcinomas, cou, \"breast neoplasm\" EXACT [MTH:120], Burden, Tumor Weight, Neoplasms, mammary neoplasm, Mammary Cancers, Human Mammary Neoplasms, Circulating, Cell Free Tumor DNA, Tumor, Tl3, \"breast tumor\" EXACT [NCI2004_11_17:C2910], Tl2, Circulating Tumor, Tumor Weights, Human, Breast Malignant Neoplasm, Load, Breast Malignant Tumor, Lr, \"neoplasm of breast (disorder)\" EXACT [SNOMEDCT_2005_07_31:126926005], Mammary Carcinomas, Breast Tumor, Weight, Cell-Free, Neoplasm, Cell-Free Tumor DNA, Human Mammary Carcinoma, \"mammary tumor\" EXACT [CSP2005:2016-0671], NOS, breast tumor, Tumor Load, cancer of the breast, Volume, Low, Malignant Neoplasm of Breast, Carcinomas, BC, Mammary Neoplasms, malignant neoplasm of breast, me75, Human Mammary, Breast Neoplasm, Mammary Neoplasm, Loads, Mammary Carcinoma, Human Mammary Carcinomas, Weights, Cancers, Breast Malignant Neoplasms., \"mammary neoplasm\" RELATED [], D17Mit170, T1, Cancer of the Breast, Cell-Free Tumor, breast cancer, concentration, cancer of breast, Malignant Tumor of Breast, Mammary, Mammary Cancer, Breast Tumors, Breast Cancer, Bra, Breast Malignant Tumors, Cancer of Breast, Tumor Volume, DNA, Breast, mammary cancer, Tumor Loads, cancer, mammary tumor, breast, Tumors, Cancer"],"description_synonyms":["Tumor DNA, malignant tumor of the breast, Biological Markers, Viral Marker, Surrogate Endpoints, determination, Laboratory, Burden, Tumor Weight, Blood, Biochemical, mammary neoplasm, Endpoint, Human Mammary Neoplasms, Circulating, Serum, Tumor, Circulating Tumor, Routine Admission Test, Laboratory Markers, diseases, Roles, \"neoplasm of breast (disorder)\" EXACT [SNOMEDCT_2005_07_31:126926005], Biological, Cell-Free, Concepts, Hospital Admission Test, diseases and disorders, cancer of the breast, Volume, Hospital Admission, Routine Admission Tests, BC, Mammary Neoplasms, malignant neoplasm of breast, Fresh Frozen Plasmas, Fresh Frozen, human disease, Loads, Human Mammary Carcinomas, Weights, allergic reaction, Immune, Markers, cancer of breast, malignant neoplasm, Viral Markers, Role Concepts, Homo sapiens disease, Malignancies, Tumor Volume, mammary cancer, Tumor Loads, Breast Malignant Neoplasms, plasma, Physical Examinations, Tumors, Carcinoma, Frozen Plasma, Viral, \"breast neoplasm\" EXACT [MTH:120], Surrogate Endpoint, metastatic cancer, Test, Biochemical Markers, Cell Free Tumor DNA, Biologic Marker, Plasmas, results, Diagnostic Tests, Preadmission Physical Examinations, Role Concept, Benign, Marker, Weight, Diseases, Role, Cell-Free Tumor DNA, NOS, Malignant Neoplasm of Breast, Carcinomas, End Points, Tests, Admission Tests, Exomes, Benign Neoplasms, Immunologic, whole genome, Laboratory Marker, \"mammary neoplasm\" RELATED [], malignant metastatic neoplasm, Malignant Neoplasms, disease, metastatic, Patient, breast cancer, Biochemical Marker, Breast Tumors, Breast Malignant Tumors, DNA, Physical Examination, other neoplasm, cancer, Routine Diagnostic Tests, Fresh, other disease, primary breast cancer, whole exome, Fresh Frozen Plasma, Clinical Markers, Clinical Marker, Neoplasms, Benign Neoplasm, Preadmission, Mammary Cancers, Malignant, Tumor Weights, Surrogate End Points, Human, Load, Surrogate Markers, Breast Malignant Tumor, sensitive, Breast Tumor, disease or disorder, \"mammary tumor\" EXACT [CSP2005:2016-0671], Hospital Admission Tests, breast tumor, Tumor Load, sensitivity, Routine Diagnostic, Biomarker, Blood Plasma, Human Mammary, Clinical, Diagnostic, Malignancy, Mammary Neoplasm, Biological Marker, Mammary Carcinoma, Cancer of the Breast, Examination, Preadmission Physical Examination, non-neoplastic, Neoplasias, Cell-Free Tumor, Immunologic Markers, Malignant Tumor of Breast, Routine, Clients, Mammary, Mammary Cancer, Blood Plasmas, disorder, liquid, Breast, Immunologic Marker, mammary tumor, Biologic, Cancer, Breast Carcinoma, Human Mammary Neoplasm, Breast Carcinomas, Malignant Neoplasm, metastatic malignant neoplasm, whole blood, malignant, Serum Markers, disorders, End Point, Routine Admission, medical condition, Routine Diagnostic Test, \"breast tumor\" EXACT [NCI2004_11_17:C2910], Hospital, Client, Cell, Immune Marker, metastatic neoplasm, Concept, Breast Malignant Neoplasm, Frozen Plasmas, MT, Preadmission Physical, Mammary Carcinomas, Surrogate End Point, Examinations, chemical analysis, Neoplasm, condition, Human Mammary Carcinoma, Biologic Markers, Plasma, Serum Marker, Breast Neoplasm, primary cancer, Surrogate, Endpoints, portion of plasma, patient, Cancers, Biopsies., malignant tumor, Surrogate Marker, Diagnostic Test, Indexes, Breast Cancer, Admission Test, Cancer of Breast, assay, variable, Neoplasia, breast, Immune Markers"],"pubmed_title_synonyms":["Tumor DNA, Breast Carcinoma, Human Mammary Neoplasm, primary breast cancer, Carcinoma, malignant tumor of the breast, Breast Carcinomas, \"breast neoplasm\" EXACT [MTH:120], Neoplasms, mammary neoplasm, Mammary Cancers, Human Mammary Neoplasms, Circulating, Cell Free Tumor DNA, Tumor, \"breast tumor\" EXACT [NCI2004_11_17:C2910], Circulating Tumor, Human, Breast Malignant Neoplasm, Breast Malignant Tumor, \"neoplasm of breast (disorder)\" EXACT [SNOMEDCT_2005_07_31:126926005], Mammary Carcinomas, Breast Tumor, Cell-Free, Neoplasm, Cell-Free Tumor DNA, Human Mammary Carcinoma, \"mammary tumor\" EXACT [CSP2005:2016-0671], NOS, breast tumor, cancer of the breast, Malignant Neoplasm of Breast, Carcinomas, BC, Mammary Neoplasms, malignant neoplasm of breast, Human Mammary, Breast Neoplasm, Mammary Neoplasm, Mammary Carcinoma, Human Mammary Carcinomas, Cancers, Breast Malignant Neoplasms., \"mammary neoplasm\" RELATED [], Cancer of the Breast, Cell-Free Tumor, metastatic, breast cancer, cancer of breast, Malignant Tumor of Breast, Mammary, Mammary Cancer, Breast Tumors, Breast Cancer, Breast Malignant Tumors, Cancer of Breast, DNA, Breast, mammary cancer, cancer, mammary tumor, breast, Tumors, Cancer"],"pubmed_abstract_synonyms":["Tumor DNA, Ghrfr, Global Progressive Disease, Surrogate Endpoints, Laboratory, Ameloblastic fibrosarcoma, Resolution Property, Nanochip Analytical Devices, Serial Number, Tumor, Circulating Tumor, Progressive disease, copy_number, sequencing assay, primary tumour, Biological, Method, analysis, Likely, Importance Rating Score 0, cancer of the breast, Analysis, SEQ, Gene Variation Not Detected, Progression, BC, Fresh Frozen, Neoplastic Cell, thymus nucleic acid, BG, Progressive Disease in Lymph Nodes, Genomes, Fragmented, Tumor Cell, Loads, Weights, Analytical Device, procedures, Evolution, Bulgaria, Supervision, Mutation Abnormality, SERIAL, allergic reaction, Nanochip Analytical, cancer of breast, Familiar, COPYNUM, Identified By, Homo sapiens disease, Tumor Volume, Global Progressive Disease in Blood, Tumor Loads, Breast Malignant Neoplasms, plasma, Tumors, Tumor Embolisms, no evidence of disease, Viral, sequencing_assay, Followed By, RECIST Progressive Disease, Microfluidic Microchip, Difference, Devices, Needs and Demand, lymphatic system, Need, DNA catabolism, Management Occupations, Gene Mutation Detected, MT (more than), Resolution of Pathologic Process, Procedure, copy number, Nanochip Analytical Device, metastatic disease, Benign, Microfluidic Microchips, Representation, Marker, BGR, Tumor Progression, Disease Progression, Weight, About, Gene Variation Negative, Genetic Alteration, Cell-Free Tumor DNA, numerical data, Consistent With, Progressive Disease, Mutant, Microfluidic Device, desoxyribose nucleic acid, Phagocytoses, RELATIONSHIP, Confirmed, DNA degradation, little, Carcinomas, End Points, Cancer Disease Progression, Progressive Disease in Viscera, AFS, Health Services Needs, Benign Neoplasms, Immunologic, Methodological, whole genome, \"mammary neoplasm\" RELATED [], Laboratory Marker, surveillance, Microchip Analytical Device, Malignant Neoplasms, Lab On A Chip Devices, Report, breast cancer, primary tumor, Neither Case nor Control, metastatic tumor, irPD, Breast Tumors, GT, ds DNA, Cells, Breast Malignant Tumors, DNA, cancer, Lugano Lymphoma Response Classification Progressive Disease by CT, Pathology Resolution, Fresh, whole exome, DNS, Fresh Frozen Plasma, (Deoxyribonucleotide)n, RECIL PD, Molecular Marker, Australia-Modified Karnofsky Performance Status 100, Clinical Marker, fractured, Neoplasms, Different, signature molecule, CDISC Relationship Class, Mammary Cancers, Analytical, Determine, Neoplasm Circulating Cell, Tumor Weights, Human, sequenceNumber, BULGARIA, Load, Breast Malignant Tumor, Immune-Related Response Criteria Progressive Disease, Biopolymer Sequencing, Deoxyribonucleic Acid, Breast Tumor, sensitive, disease or disorder, mutation, Progressive Neoplastic Disease, breast tumor, Higher, Technique, Microchip, Gene Variant Positive, Health Services, Clinical, Pathologic Process Resolution, disease progression, occurrence, Mammary Neoplasm, Mammary Carcinoma, prevalence, Target, Double Stranded, Deoxyribonucleic acid, Population, Analytical Devices, Sequencing, Global Progressive Disease in Viscera, Solution, Study, Neoplasias, Progressive Disease in Skin, Malignant Tumor of Breast, Microfluidic Lab-On-A-Chips, Gene Variation Detected, Dynamic Range, Resolve, Not Mutated, Approximately, (Deoxyribonucleotide)m, report, CLINICAL EVALUATION, Biologic, Cancer, Circulating Tumor Cells, Breast Carcinoma, Human Mammary Neoplasm, Probably, ctdDNA, use, Breast Carcinomas, Malignant Neoplasm, metastatic malignant neoplasm, whole blood, Immune Markers., DNAn+1, Neoplasm Circulating Cells, Serum Markers, disorders, split, \"breast tumor\" EXACT [NCI2004_11_17:C2910], Cell, Immune Marker, Frozen Plasmas, Genetic Change, Tumor Embolism, MT, Progressive chronic Graft vs Host Disease, Confirmatory, Surrogate End Point, chemical analysis, Neoplasm, hemorrhaged, Human Mammary Carcinoma, condition, supply and distribution, Mutation, outbreaks, nodus lymphaticus, Biologic Markers, Skin Progressive Disease, Represent, Destination, torn, Lab-On-A-Chip Device, Copy Number, Tumor Cells, Embolisms, primary cancer, Homogeneous, progression, Surrogate, Endpoints, Accuracy, Directly, Target Population, Lugano Lymphoma Response Classification Progressive Disease by PET, Likeliness, Microfluidic Lab-On-A-Chip, Cancers, Ameloblastic Fibrosarcoma, One Hundred, malignant tumor, Lymph Node Progressive Disease, High, LAB_SEQ_METHOD, Differential, Lansky Performance Status 100, Desoxyribonukleinsaeure, 100, Cancer of Breast, epidemics, PD, Representative, Neoplasia, breast, Immune Markers, Microfluidic Devices, Clinical Evaluation, malignant tumor of the breast, Biological Markers, Viral Marker, Needs, Node, Approximate, determination, Burden, Tumor Weight, supply, Blood, Direct, Biochemical, Greater Than, mammary neoplasm, Endpoint, Human Mammary Neoplasms, molecular marker, Circulating, FRAGMENT, Serum, Highly, Global Progressive Disease in Skin, Laboratory Markers, Techniques, diseases, \"neoplasm of breast (disorder)\" EXACT [SNOMEDCT_2005_07_31:126926005], RECIL Progressive Disease, Cell-Free Circulating Tumor DNA, Lab-On-A-Chip, Cell-Free, Managing, diseases and disorders, Volume, Biomarkers, Lymph, Mammary Neoplasms, malignant neoplasm of breast, Fresh Frozen Plasmas, Targeting, human disease, Target Populations, Copy Number Reported, Gene Mutation Negative, Progressive Disease in Blood, Determination, Signature Molecule, Human Mammary Carcinomas, Microchips, irPD (Immune-Related Response Criteria), Immune, Markers, Methodological Studies, Neoplasm Circulating, malignant neoplasm, Progressive cGVHD, Subsequent, Viral Markers, Embolism, Health Services Need, Analyzed, Allele, Double-Stranded DNA, Malignancies, deoxyribonucleic acids, DNAn, mammary cancer, Consistent, Circulating Neoplastic Cells, Importance Score 0, Clinical Assessment, Managed, Carcinoma, Circulating Neoplastic, Frozen Plasma, \"breast neoplasm\" EXACT [MTH:120], Determined, Surrogate Endpoint, metastatic cancer, statistics and numerical data, no complaints, frequency, Identifier, Reported, Importance 0, Biochemical Markers, lit, Republic of Bulgaria, Cell Free Tumor DNA, Double-Stranded, Biologic Marker, Plasmas, fragmented, results, (Deoxyribonucleotide)n+m, PD-Progressive Disease, Neither Case or Control Status, Circulating Tumor DNA, Diseases, NOS, Microfluidic Lab On A Chip, Conflict, Malignant Neoplasm of Breast, Karnofsky Performance Status 100, Confirmation, Circulating Tumor Cell, Populations, progressive disease, Representational, Mutated, Nucleic Acid Sequencing, Prognostic, cracked, Exomes, Relationships, Methodological Study, malignant metastatic neoplasm, morbidity, Gene Mutant Negative, disease, metastatic, Patient, Biochemical Marker, Circulating Neoplastic Cell, Nodes, Neither, Gene Mutation Positive, Lab-On-A-Chips, Embolic, Nanochip, Sequence Analysis, IMWG Progressive Disease, primary breast cancer, other disease, Allelomorphs, Important, Procedures, 100: Normal, Clinical Markers, Fragment, Importance, Benign Neoplasm, Improvement, Viscera Progressive Disease, Malignant, Deoxyribonucleic acids, Surrogate End Points, Surrogate Markers, SEQUENCING, Microfluidic, utilization, DNA breakdown, Gene Variant Negative, Studies, \"mammary tumor\" EXACT [CSP2005:2016-0671], Tumor Load, Next, sensitivity, Biomarker, study, irRC Progressive Disease, Blood Plasma, Human Mammary, PROGRESSIVE DISEASE, ANALYSIS, Malignancy, Embolic Tumor Cells, distribution, Embolic Tumor, ctDNA, Biological Marker, noninvasive, Circulating Tumor-Derived DNA, Cancer of the Breast, non-neoplastic, Allelomorph, Administration, Cell-Free Tumor, Immunologic Markers, Following, Mammary, Mammary Cancer, Clients, Blood Plasmas, Gene Mutant Positive, Physiologic Resolution, disorder, biological marker, Gene Mutation Not Detected, Known, Global Progressive Disease in Lymph Nodes, Breast, Homogeneity, mammary tumor, Immunologic Marker, incidence, Microchip Analytical Devices, Molecular Biology, Identifying Person, malignant, More Than, Performance Status 100, Targeted, End Point, medical condition, Resolved, Ameloblastic sarcoma, Client, metastatic neoplasm, Breast Malignant Neoplasm, Microchip Analytical, Device, Circulating Cells, Mammary Carcinomas, biomarker, marker, techniques, ds-DNA, Resolution, Plasma, Blood Progressive Disease, Breast Neoplasm, Serum Marker, Lymph Node, primary neoplasia, Sequence Number, portion of plasma, Embolic Tumor Cell, patient, Noninvasive, Surrogate Marker, endemics, NUCLEIC ACID SEQUENCING, Accurate, Gene Variation Positive, Lymph node, Oversight, Cancer Progression, Management, Indexes, Breast Cancer, metastatic tumour, lymph gland, assay, variable, methodology, serialNumberText"],"additional_accession":[]},"is_claimable":false,"name":"Divergence between high metastatic tumor burden and  low circulating tumor DNA concentration in metastasized breast cancer","description":"Circulating tumor DNA (ctDNA) was reported to represent a highly sensitive biomarker of metastatic cancer disease directly reflecting tumor burden and dynamics. Here we investigated the role of ctDNA in patients with metastatic breast cancer. In an index patient with more than 100,000 circulating tumor cells (CTCs) in serial blood analyses, whole genome, exome, or targeted deep sequencing of the primary tumor, metastases, and 551 CTCs were consistent with a genetically homogeneous cancer. However, the allele fractions (AFs) of ctDNA were only 2-3% in each analysis, which did neither reflect the tumor burden nor the dynamics of this progressive disease by far. Indeed, plasma analyses of 71 further patients demonstrated highly variable AFs of mutant fragments, which frequently did not correspond to the tumor burden. These results provide insights into mechanisms involved in CTC and ctDNA release into the circulation and have important implications for diagnostic tests based on liquid biopsies.","dates":{"updated":"2017-07-26 15:39:25"},"accession":"EGAS00001000625","cross_references":{"TAXONOMY":["9606"],"pubmed":["25107527"],"EGA":["EGAD00001000762","EGAD00001000763","EGAD00001000761","EGAC00001000072"]}}