scholarly journals Mutational signatures of complex genomic rearrangements in human cancer

2021 ◽  
Author(s):  
Lixing Yang ◽  
Lisui Bao ◽  
Xiaoming Zhong ◽  
Yang Yang
Keyword(s):  
Human Cancer ◽  
Genomic Rearrangements ◽  
Cellular Structures ◽  
Genome Integrity ◽  
Biological Processes ◽  
Extrachromosomal Dna ◽  
Mutational Signatures ◽  
Chromatin Bridge ◽  
Open Questions ◽  
Dna Loss

Complex genomic rearrangements (CGRs) are common in cancer and are known to form via two aberrant cellular structures-micronuclei and chromatin bridge. However, which mechanism is more relevant to CGR formation in cancer cells and whether there are other undiscovered mechanisms remain open questions. Here, we analyze 2,014 CGRs from 2,428 whole-genome sequenced tumors and deconvolute six CGR signatures based on the topology of CGRs. Through rigorous benchmarking, we show that our CGR signatures are highly accurate and biologically meaningful. Three signatures can be attributed to known biological processes-micronuclei- and chromatin-bridge-induced chromothripsis and extrachromosomal DNA. More than half of the CGRs belong to the remaining three newly discovered signatures. A unique signature (we named "hourglass chromothripsis") with highly localized breakpoints and small amount of DNA loss is abundant in prostate cancer. Through genetic association analysis, we find SPOP as a candidate gene causing hourglass chromothripsis and playing important role in maintaining genome integrity. Our study offers valuable insights into the formation of CGRs.

scholarly journals Mutational signatures of complex genomic rearrangements in human cancer

2021 ◽  
Author(s):  
Lixing Yang ◽  
Lisui Bao ◽  
Xiaoming Zhong ◽  
Yang Yang
Keyword(s):  
Human Cancer ◽  
Genomic Rearrangements ◽  
Cellular Structures ◽  
Genome Integrity ◽  
Biological Processes ◽  
Extrachromosomal Dna ◽  
Mutational Signatures ◽  
Chromatin Bridge ◽  
Open Questions ◽  
Dna Loss

Abstract Complex genomic rearrangements (CGRs) are common in cancer and are known to form via two aberrant cellular structures—micronuclei and chromatin bridge. However, which mechanism is more relevant to CGR formation in cancer cells and whether there are other undiscovered mechanisms remain open questions. Here, we analyze 2,014 CGRs from 2,428 whole-genome sequenced tumors and deconvolute six CGR signatures based on the topology of CGRs. Through rigorous benchmarking, we show that our CGR signatures are highly accurate and biologically meaningful. Three signatures can be attributed to known biological processes—micronuclei- and chromatin-bridge-induced chromothripsis and extrachromosomal DNA. More than half of the CGRs belong to the remaining three newly discovered signatures. A unique signature (we named “hourglass chromothripsis”) with highly localized breakpoints and small amount of DNA loss is abundant in prostate cancer. Through genetic association analysis, we find SPOP as a candidate gene causing hourglass chromothripsis and playing important role in maintaining genome integrity. Our study offers valuable insights into the formation of CGRs.

scholarly journals Mutational signatures associated with tobacco smoking in human cancer

Science ◽  
2016 ◽  
Vol 354 (6312) ◽  
pp. 618-622 ◽  
Author(s):  
L. B. Alexandrov ◽  
Y. S. Ju ◽  
K. Haase ◽  
P. Van Loo ◽  
I. Martincorena ◽  
...  
Keyword(s):  
Tobacco Smoking ◽  
Human Cancer ◽  
Mutational Signatures

scholarly journals Dichotomous roles of TGF-β in human cancer

2016 ◽  
Vol 44 (5) ◽  
pp. 1441-1454 ◽  
Author(s):  
Jennifer J. Huang ◽  
Gerard C. Blobe
Keyword(s):  
Signaling Pathway ◽  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Human Cancer ◽  
Transforming Growth Factor Β ◽  
Dependent Manner ◽  
Biological Processes ◽  
Cellular Homeostasis ◽  
Angiogenic Therapy ◽  
Promising Strategy

Transforming growth factor-β (TGF-β) mediates numerous biological processes, including embryonic development and the maintenance of cellular homeostasis in a context-dependent manner. Consistent with its central role in maintaining cellular homeostasis, inhibition of TGF-β signaling results in disruption of normal homeostatic processes and subsequent carcinogenesis, defining the TGF-β signaling pathway as a tumor suppressor. However, once carcinogenesis is initiated, the TGF-β signaling pathway promotes cancer progression. This dichotomous function of the TGF-β signaling pathway is mediated through altering effects on both the cancer cells, by inducing apoptosis and inhibiting proliferation, and the tumor microenvironment, by promoting angiogenesis and inhibiting immunosurveillance. Current studies support inhibition of TGF-β signaling either alone, or in conjunction with anti-angiogenic therapy or immunotherapy as a promising strategy for the treatment of human cancers.

scholarly journals Every laboratory with a fluorescence microscope should consider counting molecules

2014 ◽  
Vol 25 (10) ◽  
pp. 1545-1548 ◽  
Author(s):  
Valerie C. Coffman ◽  
Jian-Qiu Wu
Keyword(s):  
Mathematical Modeling ◽  
Fluorescence Microscopy ◽  
Protein Complexes ◽  
The State ◽  
Fluorescence Microscope ◽  
Cellular Structures ◽  
Biological Processes ◽  
Protein Molecules ◽  
Parameter Values

Protein numbers in cells determine rates of biological processes, influence the architecture of cellular structures, reveal the stoichiometries of protein complexes, guide in vitro biochemical reconstitutions, and provide parameter values for mathematical modeling. The purpose of this essay is to increase awareness of methods for counting protein molecules using fluorescence microscopy and encourage more cell biologists to report these numbers. We address the state of the field in terms of utility and accuracy of the numbers reported and point readers to references for details of specific techniques and applications.

scholarly journals FIREVAT: finding reliable variants without artifacts in human cancer samples using etiologically relevant mutational signatures

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Hyunbin Kim ◽  
Andy Jinseok Lee ◽  
Jongkeun Lee ◽  
Hyonho Chun ◽  
Young Seok Ju ◽  
...  
Keyword(s):  
Data Storage ◽  
Human Cancer ◽  
Point Mutations ◽  
Variant Calling ◽  
Human Tumor ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Precision Oncology ◽  
Mutational Signatures ◽  
Accurate Identification

Abstract Background Accurate identification of real somatic variants is a primary part of cancer genome studies and precision oncology. However, artifacts introduced in various steps of sequencing obfuscate confidence in variant calling. Current computational approaches to variant filtering involve intensive interrogation of Binary Alignment Map (BAM) files and require massive computing power, data storage, and manual labor. Recently, mutational signatures associated with sequencing artifacts have been extracted by the Pan-cancer Analysis of Whole Genomes (PCAWG) study. These spectrums can be used to evaluate refinement quality of a given set of somatic mutations. Results Here we introduce a novel variant refinement software, FIREVAT (FInding REliable Variants without ArTifacts), which uses known spectrums of sequencing artifacts extracted from one of the largest publicly available catalogs of human tumor samples. FIREVAT performs a quick and efficient variant refinement that accurately removes artifacts and greatly improves the precision and specificity of somatic calls. We validated FIREVAT refinement performance using orthogonal sequencing datasets totaling 384 tumor samples with respect to ground truth. Our novel method achieved the highest level of performance compared to existing filtering approaches. Application of FIREVAT on additional 308 The Cancer Genome Atlas (TCGA) samples demonstrated that FIREVAT refinement leads to identification of more biologically and clinically relevant mutational signatures as well as enrichment of sequence contexts associated with experimental errors. FIREVAT only requires a Variant Call Format file (VCF) and generates a comprehensive report of the variant refinement processes and outcomes for the user. Conclusions In summary, FIREVAT facilitates a novel refinement strategy using mutational signatures to distinguish artifactual point mutations called in human cancer samples. We anticipate that FIREVAT results will further contribute to precision oncology efforts that rely on accurate identification of variants, especially in the context of analyzing mutational signatures that bear prognostic and therapeutic significance. FIREVAT is freely available at https://github.com/cgab-ncc/FIREVAT

scholarly journals Iron Dysregulation in Human Cancer: Altered Metabolism, Biomarkers for Diagnosis, Prognosis, Monitoring and Rationale for Therapy

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3524 ◽  
Author(s):  
Pierre Lelièvre ◽  
Lucie Sancey ◽  
Jean-Luc Coll ◽  
Aurélien Deniaud ◽  
Benoit Busser
Keyword(s):  
Iron Homeostasis ◽  
Human Cancer ◽  
Predictive Biomarkers ◽  
Biological Processes ◽  
Clinical Value ◽  
Regulatory Pathways ◽  
Cellular Energy ◽  
Human Therapy ◽  
Cell Death Signaling ◽  
Altered Metabolism

Iron (Fe) is a trace element that plays essential roles in various biological processes such as DNA synthesis and repair, as well as cellular energy production and oxygen transport, and it is currently widely recognized that iron homeostasis is dysregulated in many cancers. Indeed, several iron homeostasis proteins may be responsible for malignant tumor initiation, proliferation, and for the metastatic spread of tumors. A large number of studies demonstrated the potential clinical value of utilizing these deregulated proteins as prognostic and/or predictive biomarkers of malignancy and/or response to anticancer treatments. Additionally, the iron present in cancer cells and the importance of iron in ferroptosis cell death signaling pathways prompted the development of therapeutic strategies against advanced stage or resistant cancers. In this review, we select relevant and promising studies in the field of iron metabolism in cancer research and clinical oncology. Besides this, we discuss some co-existing discrepant findings. We also present and discuss the latest lines of research related to targeting iron, or its regulatory pathways, as potential promising anticancer strategies for human therapy. Iron chelators, such as deferoxamine or iron-oxide-based nanoparticles, which are already tested in clinical trials, alone or in combination with chemotherapy, are also reported.

scholarly journals SIRT6, a Mammalian Deacylase with Multitasking Abilities

2020 ◽  
Vol 100 (1) ◽  
pp. 145-169 ◽  
Author(s):  
Andrew R. Chang ◽  
Christina M. Ferrer ◽  
Raul Mostoslavsky
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Cellular Metabolism ◽  
Multiple Roles ◽  
Biological Processes ◽  
Repair Gene ◽  
Cellular Homeostasis ◽  
Chromatin Dynamics ◽  
Open Questions ◽  
Dna Repair Gene

Mammalian sirtuins have emerged in recent years as critical modulators of multiple biological processes, regulating cellular metabolism, DNA repair, gene expression, and mitochondrial biology. As such, they evolved to play key roles in organismal homeostasis, and defects in these proteins have been linked to a plethora of diseases, including cancer, neurodegeneration, and aging. In this review, we describe the multiple roles of SIRT6, a chromatin deacylase with unique and important functions in maintaining cellular homeostasis. We attempt to provide a framework for such different functions, for the ability of SIRT6 to interconnect chromatin dynamics with metabolism and DNA repair, and the open questions the field will face in the future, particularly in the context of putative therapeutic opportunities.

scholarly journals Nucleosome–nucleosome interactions via histone tails and linker DNA regulate nuclear rigidity

2017 ◽  
Vol 28 (11) ◽  
pp. 1580-1589 ◽  
Author(s):  
Yuta Shimamoto ◽  
Sachiko Tamura ◽  
Hiroshi Masumoto ◽  
Kazuhiro Maeshima
Keyword(s):  
Molecular Mechanisms ◽  
Mechanical Response ◽  
Nuclear Architecture ◽  
Living Cells ◽  
Genome Integrity ◽  
Biological Processes ◽  
Cell Nuclei ◽  
Histone Tails ◽  
Insight Into

Cells, as well as the nuclei inside them, experience significant mechanical stress in diverse biological processes, including contraction, migration, and adhesion. The structural stability of nuclei must therefore be maintained in order to protect genome integrity. Despite extensive knowledge on nuclear architecture and components, however, the underlying physical and molecular mechanisms remain largely unknown. We address this by subjecting isolated human cell nuclei to microneedle-based quantitative micromanipulation with a series of biochemical perturbations of the chromatin. We find that the mechanical rigidity of nuclei depends on the continuity of the nucleosomal fiber and interactions between nucleosomes. Disrupting these chromatin features by varying cation concentration, acetylating histone tails, or digesting linker DNA results in loss of nuclear rigidity. In contrast, the levels of key chromatin assembly factors, including cohesin, condensin II, and CTCF, and a major nuclear envelope protein, lamin, are unaffected. Together with in situ evidence using living cells and a simple mechanical model, our findings reveal a chromatin-based regulation of the nuclear mechanical response and provide insight into the significance of local and global chromatin structures, such as those associated with interdigitated or melted nucleosomal fibers.

scholarly journals Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Stephanie Berger ◽  
Erik Procko ◽  
Daciana Margineantu ◽  
Erinna F Lee ◽  
Betty W Shen ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Human Cancer ◽  
High Specificity ◽  
Specific Protein ◽  
Biological Processes ◽  
Protein Protein Interactions ◽  
Human Cancer Cell Lines ◽  
Bcl2 Family ◽  
Bcl2 Protein

Many cancers overexpress one or more of the six human pro-survival BCL2 family proteins to evade apoptosis. To determine which BCL2 protein or proteins block apoptosis in different cancers, we computationally designed three-helix bundle protein inhibitors specific for each BCL2 pro-survival protein. Following in vitro optimization, each inhibitor binds its target with high picomolar to low nanomolar affinity and at least 300-fold specificity. Expression of the designed inhibitors in human cancer cell lines revealed unique dependencies on BCL2 proteins for survival which could not be inferred from other BCL2 profiling methods. Our results show that designed inhibitors can be generated for each member of a closely-knit protein family to probe the importance of specific protein-protein interactions in complex biological processes.

scholarly journals Small but Heavy Role: MicroRNAs in Hepatocellular Carcinoma Progression

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Erbao Chen ◽  
Xiaojing Xu ◽  
Ruiqi Liu ◽  
Tianshu Liu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Primary Liver Cancer ◽  
Tumor Development ◽  
Biological Processes ◽  
Regulate Gene Expression ◽  
Small Noncoding Rnas ◽  
Pathological Mechanism ◽  
Cellular Target

Hepatocellular carcinoma (HCC), which accounts for 85–90% of primary liver cancer, is the fifth most common malignant tumor and the third leading cause of cancer-related deaths worldwide, but the pathological mechanism of HCC is still not fully elucidated. miRNAs are evolutionarily endogenous small noncoding RNAs that negatively regulate gene expression via posttranscriptional inhibition or target mRNA degradation in several diseases, especially human cancer. Therefore, discovering the roles of miRNAs is appealing to scientific researchers. Emerging evidence has shown that the aberrant expressions of numerous miRNAs are involved in many HCC biological processes. In hepatocarcinogenesis, miRNAs with dysregulated expression can exert their function as oncogenes or tumor suppressors depending on their cellular target during the cell cycle, and in tumor development, differentiation, apoptosis, angiogenesis, metastasis, and progression of the tumor microenvironment. In this review, we summarize current findings on miRNAs and assess their functions to explore the molecular mechanisms of tumor progression in HCC.

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