Unique evolutionary trajectories of breast cancers with distinct genomic and spatial heterogeneity

AbstractBreast cancers exhibit intratumoral heterogeneity associated with disease progression and therapeutic resistance. To define the sources and the extent of heterogeneity, we performed an in-depth analysis of the genomic architecture of three chemoradiation-naïve breast cancers with well-defined clinical features including variable ER, PR, ERBB2 receptor expression and two distinct pathogenic BRCA2mut genotypes. The latter included a germ line carrier and a patient with a somatic variant. In each case we combined DNA content-based flow cytometry with whole exome sequencing and genome wide copy number variant (CNV) analysis of distinct populations sorted from multiple (4–18) mapped biopsies within the tumors and involved lymph nodes. Interrogating flow-sorted tumor populations from each biopsy provided an objective method to distinguish fixed and variable genomic lesions in each tumor. Notably we show that tumors exploit CNVs to fix mutations and deletions in distinct populations throughout each tumor. The identification of fixed genomic lesions that are shared or unique within each tumor, has broad implications for the study of tumor heterogeneity including the presence of tumor markers and therapeutic targets, and of candidate neoepitopes in breast and other solid tumors that can advance more effective treatment and clinical management of patients with disease.

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Faculty Opinions recommendation of Systematic assessment of copy number variant detection via genome-wide SNP genotyping.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1123296.580444 ◽

2008 ◽

Author(s):

Yasushi Okazaki

Keyword(s):

Copy Number ◽

Copy Number Variant ◽

Snp Genotyping ◽

Systematic Assessment ◽

Genome Wide ◽

Variant Detection ◽

Copy Number Variant Detection

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Genome-Wide Association and Whole Exome Sequencing Studies reveal a Novel Candidate Locus for Restless Legs Syndrome

European Journal of Medical Genetics ◽

10.1016/j.ejmg.2021.104186 ◽

2021 ◽

pp. 104186

Author(s):

Ufuk Ergun ◽

Bahar Say ◽

Sezen Guntekin Ergun ◽

Ferda Emriye Percin ◽

Levent Inan ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Restless Legs Syndrome ◽

Genome Wide Association ◽

Candidate Locus ◽

Restless Legs ◽

Genome Wide ◽

Whole Exome ◽

Sequencing Studies

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Novel idiotypic and antigen-binding characteristics in two anti-dinitrophenyl monoclonal antibodies.

Journal of Experimental Medicine ◽

10.1084/jem.146.1.282 ◽

1977 ◽

Vol 146 (1) ◽

pp. 282-286 ◽

Cited By ~ 6

Author(s):

N H Sigal

Keyword(s):

Monoclonal Antibodies ◽

Germ Line ◽

Hypervariable Region ◽

Weight Basis ◽

Antigen Binding ◽

The Novel ◽

Maximum Frequency ◽

Somatic Variant ◽

Binding Characteristics ◽

Cell Pool

Monoclonal anti-dinitrophenyl antibodies generated in the splenic focus system from B cells of adult BALB/c mice were studied for the presence or absence of murine anti-T15 (M anti-T15) reactivity and for their ability to bind phosphorylcholine (PC). Two foci of the 680 clones analyzed bound PC, and one of these antibodies reacted with M anti-T15 and anti-Fab on a 1:1 weight basis. The discovery of a clonotype reactive with M anti-15 but not with rabbit anti-T15 (R anti-T15) serum, the converse of the R anti-T15+, M anti-T15- clonotype identified in the PC-specific repertoire, points to the novel idiotypic relationships which may be found among homogeneous antibodies binding diverse antigens. The R anti-T15-, M anti-T15+ clonotype may represent a distinct set of hypervariable region sequences inserted into the T15 framework or may be a somatic variant of the T15 germ-line sequence. In addition, the maximum frequency with which this clonotype occurs within the B-cell pool is estimated.

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Whole-exome sequencing associates novel CSMD1 gene mutations with familial Parkinson disease

Neurology Genetics ◽

10.1212/nxg.0000000000000177 ◽

2017 ◽

Vol 3 (5) ◽

pp. e177 ◽

Cited By ~ 12

Author(s):

Javier Ruiz-Martínez ◽

Luis J. Azcona ◽

Alberto Bergareche ◽

Jose F. Martí-Massó ◽

Coro Paisán-Ruiz

Keyword(s):

Parkinson Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genome Wide Association Study ◽

Single Gene ◽

Gene Mutations ◽

Complement Control Protein ◽

Genome Wide ◽

Whole Exome ◽

A Genome

Objective:Despite the enormous advancements made in deciphering the genetic architecture of Parkinson disease (PD), the majority of PD is idiopathic, with single gene mutations explaining only a small proportion of the cases.Methods:In this study, we clinically evaluated 2 unrelated Spanish families diagnosed with PD, in which known PD genes were previously excluded, and performed whole-exome sequencing analyses in affected individuals for disease gene identification.Results:Patients were diagnosed with typical PD without relevant distinctive symptoms. Two different novel mutations were identified in the CSMD1 gene. The CSMD1 gene, which encodes a complement control protein that is known to participate in the complement activation and inflammation in the developing CNS, was previously shown to be associated with the risk of PD in a genome-wide association study.Conclusions:We conclude that the CSMD1 mutations identified in this study might be responsible for the PD phenotype observed in our examined patients. This, along with previous reported studies, may suggest the complement pathway as an important therapeutic target for PD and other neurodegenerative diseases.

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Detection and characterization of copy number variants based on whole-genome sequencing by DNBSEQ platforms

10.1101/786962 ◽

2019 ◽

Author(s):

Junhua Rao ◽

Lihua Peng ◽

Fang Chen ◽

Hui Jiang ◽

Chunyu Geng ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Copy Number ◽

Copy Number Variants ◽

Copy Number Variant ◽

Whole Genome ◽

Genome Wide ◽

Wide Range ◽

Distribution Sensitivity ◽

Cnv Detection

AbstractBackgroundNext-generation sequence (NGS) has rapidly developed in past years which makes whole-genome sequencing (WGS) becoming a more cost- and time-efficient choice in wide range of biological researches. We usually focus on some variant detection via WGS data, such as detection of single nucleotide polymorphism (SNP), insertion and deletion (Indel) and copy number variant (CNV), which playing an important role in many human diseases. However, the feasibility of CNV detection based on WGS by DNBSEQ™ platforms was unclear. We systematically analysed the genome-wide CNV detection power of DNBSEQ™ platforms and Illumina platforms on NA12878 with five commonly used tools, respectively.ResultsDNBSEQ™ platforms showed stable ability to detect slighter more CNVs on genome-wide (average 1.24-fold than Illumina platforms). Then, CNVs based on DNBSEQ™ platforms and Illumina platforms were evaluated with two public benchmarks of NA12878, respectively. DNBSEQ™ and Illumina platforms showed similar sensitivities and precisions on both two benchmarks. Further, the difference between tools for CNV detection was analyzed, and indicated the selection of tool for CNV detection could affected the CNV performance, such as count, distribution, sensitivity and precision.ConclusionThe major contribution of this paper is providing a comprehensive guide for CNV detection based on WGS by DNBSEQ™ platforms for the first time.

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Searching for the missing genetic determinants of hereditary breast cancer risk by whole-exome sequencing of BRCA-negative patients: new candidate genes USP39, SLIT3, CREB3

Problems in oncology ◽

10.37469/0507-3758-2021-67-1-111-116 ◽

2021 ◽

Vol 67 (1) ◽

pp. 111-116

Author(s):

Kirill Zagorodnev ◽

Aleksandr Romanko ◽

Uliy Gorgul ◽

Aleksandr Ivantsov ◽

Anna Sokolenko ◽

...

Keyword(s):

Breast Cancer ◽

Exome Sequencing ◽

Candidate Genes ◽

Whole Exome Sequencing ◽

Hereditary Breast Cancer ◽

Germ Line ◽

Genetic Diagnosis ◽

Clinical Signs ◽

Causative Mutation ◽

Whole Exome

The search for the new hereditary mutations and a precise molecular genetic diagnosis that determines the causative mutation in each specific case of hereditary breast cancer (BC) is a clinically important task since it helps to define the personal therapeutic approach and increase the effectiveness of preventive measures. Using whole-exome sequencing (WES) we analyzed the full spectrum of hereditary variations in 49 Russian patients with clinical signs of a hereditary disease which allowed us to compile a list of 229 candidate probably pathogenic germ-line variants. Then, the selected candidate mutations were validated by Sanger sequencing and molecular-epidemiological studies, the predisposing roles of three oncologically relevant mutations (USP39 c.*208G>C, SLIT3 p.Arg154Cys, and CREB3 p.Lys157Glu) were confirmed. Our candidate genes are first mentioned in connection with the hereditary risk of BC. The final proofs of the causative roles of these variants could be obtained through functional tests as well as via the analysis of the mutations segregation in BC families.

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Highly heterogeneous genomic landscape of uterine leiomyomas by whole exome sequencing and genome-wide arrays

Fertility and Sterility ◽

10.1016/j.fertnstert.2016.10.035 ◽

2017 ◽

Vol 107 (2) ◽

pp. 457-466.e9 ◽

Cited By ~ 12

Author(s):

Svetlana A. Yatsenko ◽

Priya Mittal ◽

Michelle A. Wood-Trageser ◽

Mirka W. Jones ◽

Urvashi Surti ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Uterine Leiomyomas ◽

Genome Wide ◽

Whole Exome ◽

Genomic Landscape

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Copy number variant analysis using genome-wide mate-pair sequencing

Genes Chromosomes and Cancer ◽

10.1002/gcc.5 ◽

2018 ◽

Vol 57 (9) ◽

pp. 459-470 ◽

Cited By ~ 24

Author(s):

James B. Smadbeck ◽

Sarah H. Johnson ◽

Stephanie A. Smoley ◽

Athanasios Gaitatzes ◽

Travis M. Drucker ◽

...

Keyword(s):

Copy Number ◽

Copy Number Variant ◽

Genome Wide ◽

Mate Pair ◽

Variant Analysis

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Distinct CoREST complexes act in a cell-type-specific manner

Nucleic Acids Research ◽

10.1093/nar/gkz1050 ◽

2019 ◽

Author(s):

Igor Mačinković ◽

Ina Theofel ◽

Tim Hundertmark ◽

Kristina Kovač ◽

Stephan Awe ◽

...

Keyword(s):

Gene Expression ◽

Germ Line ◽

Protein Complexes ◽

Specific Gene ◽

S2 Cells ◽

Cell Type ◽

Specific Gene Expression ◽

Genome Wide ◽

A Cell ◽

Cell Type Specific

Abstract CoREST has been identified as a subunit of several protein complexes that generate transcriptionally repressive chromatin structures during development. However, a comprehensive analysis of the CoREST interactome has not been carried out. We use proteomic approaches to define the interactomes of two dCoREST isoforms, dCoREST-L and dCoREST-M, in Drosophila. We identify three distinct histone deacetylase complexes built around a common dCoREST/dRPD3 core: A dLSD1/dCoREST complex, the LINT complex and a dG9a/dCoREST complex. The latter two complexes can incorporate both dCoREST isoforms. By contrast, the dLSD1/dCoREST complex exclusively assembles with the dCoREST-L isoform. Genome-wide studies show that the three dCoREST complexes associate with chromatin predominantly at promoters. Transcriptome analyses in S2 cells and testes reveal that different cell lineages utilize distinct dCoREST complexes to maintain cell-type-specific gene expression programmes: In macrophage-like S2 cells, LINT represses germ line-related genes whereas other dCoREST complexes are largely dispensable. By contrast, in testes, the dLSD1/dCoREST complex prevents transcription of germ line-inappropriate genes and is essential for spermatogenesis and fertility, whereas depletion of other dCoREST complexes has no effect. Our study uncovers three distinct dCoREST complexes that function in a lineage-restricted fashion to repress specific sets of genes thereby maintaining cell-type-specific gene expression programmes.

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