scholarly journals Mobile Element Insertions and Associated Structural Variants in Longitudinal Breast Cancer Samples

2020 ◽  
Author(s):  
Cody J. Steely ◽  
Kristi L. Russell ◽  
Julie E. Feusier ◽  
Yi Qiao ◽  
Gabor Marth ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Progression ◽  
Metastatic Breast ◽  
Mobile Element ◽  
Mobile Elements ◽  
Whole Genome Sequencing Data ◽  
Breast Cancer Patients ◽  
Structural Variants ◽  
Sequencing Data ◽  
Visual Confirmation

AbstractWhile mobile elements are largely inactive in healthy somatic tissues, increased activity has been found in cancer tissues, with significant variation among different cancer types. In addition to insertion events, mobile elements have also been found to mediate many structural variation events in the genome. Here, to better understand the timing and impact of mobile element insertions and mobile element-mediated structural variants in cancer, we examined their activity in longitudinal samples of four metastatic breast cancer patients. With whole-genome sequencing data from multiple timepoints through tumor treatment and progression, we used mobile element detection software followed by visual confirmation of the insertions. From this analysis we identified 11 mobile element insertions or mobile element-mediated structural variants, and found that the majority (nine of the eleven) of these occurred early in tumor progression. Two of the identified insertions were SVA elements, which have not been examined in previous cancer studies. Most of the variants appear to impact intergenic regions; however, we identified a mobile element-mediated translocation in MAP2K4 and a mobile element-mediated deletion in YTHDF2 that likely inactivate reported tumor suppressor genes. MAP2K4 is part of the JNK signaling pathway, influencing cell growth and proliferation. The high variant allele frequency of this translocation and the important function of MAP2K4 indicate that this mobile element-mediated translocation is likely a driver mutation. Overall, using a unique longitudinal dataset, we find that most variants are likely passenger mutations in the four patients we examined, but some variants impact tumor progression.

scholarly journals Mobile element insertions and associated structural variants in longitudinal breast cancer samples

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Cody J. Steely ◽  
Kristi L. Russell ◽  
Julie E. Feusier ◽  
Yi Qiao ◽  
Sean V. Tavtigian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Progression ◽  
Metastatic Breast ◽  
Mobile Element ◽  
Mobile Elements ◽  
Breast Cancer Patients ◽  
Loss Of Function ◽  
Structural Variants ◽  
Intergenic Regions ◽  
Cancer Tissues

AbstractWhile mobile elements are largely inactive in healthy somatic tissues, increased activity has been found in cancer tissues, with significant variation among different cancer types. In addition to insertion events, mobile elements have also been found to mediate many structural variation events in the genome. Here, to better understand the timing and impact of mobile element insertions and associated structural variants in cancer, we examined their activity in longitudinal samples of four metastatic breast cancer patients. We identified 11 mobile element insertions or associated structural variants and found that the majority of these occurred early in tumor progression. Most of the variants impact intergenic regions; however, we identified a translocation interrupting MAP2K4 involving Alu elements and a deletion in YTHDF2 involving mobile elements that likely inactivate reported tumor suppressor genes. The high variant allele fraction of the translocation, the loss of the other copy of MAP2K4, the recurrent loss-of-function mutations found in this gene in other cancers, and the important function of MAP2K4 indicate that this translocation is potentially a driver mutation. Overall, using a unique longitudinal dataset, we find that most variants are likely passenger mutations in the four patients we examined, but some variants impact tumor progression.

scholarly journals Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer

2020 ◽  
Vol 3 (11) ◽  
pp. e202000893
Author(s):  
Meliha Mehmeti-Ajradini ◽  
Caroline Bergenfelz ◽  
Anna-Maria Larsson ◽  
Robert Carlsson ◽  
Kristian Riesbeck ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Immune Cell ◽  
Human Tumor ◽  
Metastatic Breast ◽  
Suppressor Cells ◽  
Breast Cancer Patients ◽  
Maturation Stages

Myeloid-derived suppressor cells (MDSCs) are known to contribute to immune evasion in cancer. However, the function of the human granulocytic (G)-MDSC subset during tumor progression is largely unknown, and there are no established markers for their identification in human tumor specimens. Using gene expression profiling, mass cytometry, and tumor microarrays, we here demonstrate that human G-MDSCs occur as neutrophils at distinct maturation stages, with a disease-specific profile. G-MDSCs derived from patients with metastatic breast cancer and malignant melanoma display a unique immature neutrophil profile, that is more similar to healthy donor neutrophils than to G-MDSCs from sepsis patients. Finally, we show that primary G-MDSCs from metastatic breast cancer patients co-transplanted with breast cancer cells, promote tumor growth, and affect vessel formation, leading to myeloid immune cell exclusion. Our findings reveal a role for human G-MDSC in tumor progression and have clinical implications also for targeted immunotherapy.

scholarly journals TypeTE: a tool to genotype mobile element insertions from whole genome resequencing data

2019 ◽  
Author(s):  
Clement Goubert ◽  
Jainy Thomas ◽  
Lindsay M. Payer ◽  
Jeffrey M. Kidd ◽  
Julie Feusier ◽  
...  
Keyword(s):  
Population Genomics ◽  
Mobile Element ◽  
Whole Genome Sequencing Data ◽  
Human Populations ◽  
Whole Genome ◽  
Structural Variants ◽  
Sequencing Data ◽  
1000 Genomes ◽  
Standard Set ◽  
Whole Genome Resequencing

ABSTRACTAlu retrotransposons account for more than 10% of the human genome, and insertions of these elements create structural variants segregating in human populations. Such polymorphic Alu are powerful markers to understand population structure, and they represent variants that can greatly impact genome function, including gene expression. Accurate genotyping of Alu and other mobile elements has been challenging. Indeed, we found that Alu genotypes previously called for the 1000 Genomes Project are sometimes erroneous, which poses significant problems for phasing these insertions with other variants that comprise the haplotype. To ameliorate this issue, we introduce a new pipeline -- TypeTE -- which genotypes Alu insertions from whole-genome sequencing data. Starting from a list of polymorphic Alus, TypeTE identifies the hallmarks (poly-A tail and target site duplication) and orientation of Alu insertions using local re-assembly to reconstruct presence and absence alleles. Genotype likelihoods are then computed after re-mapping sequencing reads to the reconstructed alleles. Using a ‘gold standard’ set of PCR-based genotyping of >200 loci, we show that TypeTE improves genotype accuracy from 83% to 92% in the 1000 Genomes dataset. TypeTE can be readily adapted to other retrotransposon families and brings a valuable toolbox addition for population genomics.

scholarly journals Validation of HER2 status in whole genome sequencing data of breast cancers with AI-driven, ploidy-corrected approach

2021 ◽  
Author(s):  
Marzena Wojtaszewska ◽  
Rafal Stepien ◽  
Alicja Wozna ◽  
Maciej Piernik ◽  
Maciej Dabrowski ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cancer Diagnostics ◽  
Her2 Status ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Breast Cancer Patients ◽  
Sequencing Data ◽  
Genomic Context

The HER2 protein overexpression is one of the most significant biomarkers for breast cancer diagnostics, prediction, and prognostics. The availability of HER2-inhibitors in routine clinical practice directly translates into a diagnostic need for precise and robust marker identification. At the brink of the genomic era, multigene next-generation sequencing methodologies slowly take over the field of single-biomarker molecular and cytogenetic tests. However, copy number alterations such as amplification of the HER2-coding ERBB2 gene, are certainly harder to validate as an NGS biomarker than simple SNV mutations. They are characterized by several compound genomic factors i.a. structural heterogeneity, dependence on chromosome count and genomic context of ploidy. In our study, we tested the approach of using whole genome sequencing instead of NGS panels to robustly and accurately determine HER2 status in clinical setup. Based on the large dataset of 877 breast cancer patients' genomes with curated clinical data and a machine learning approach for optimization of an unbiased diagnostic classifier, we provide a reliable algorithm of HER2 status assessment.

scholarly journals TypeTE: a tool to genotype mobile element insertions from whole genome resequencing data

2020 ◽  
Vol 48 (6) ◽  
pp. e36-e36 ◽  
Author(s):  
Clément Goubert ◽  
Jainy Thomas ◽  
Lindsay M Payer ◽  
Jeffrey M Kidd ◽  
Julie Feusier ◽  
...  
Keyword(s):  
Population Genomics ◽  
Mobile Element ◽  
Whole Genome Sequencing Data ◽  
Human Populations ◽  
Whole Genome ◽  
Structural Variants ◽  
Sequencing Data ◽  
1000 Genomes ◽  
Alu Insertions ◽  
Whole Genome Resequencing

Abstract Alu retrotransposons account for more than 10% of the human genome, and insertions of these elements create structural variants segregating in human populations. Such polymorphic Alus are powerful markers to understand population structure, and they represent variants that can greatly impact genome function, including gene expression. Accurate genotyping of Alus and other mobile elements has been challenging. Indeed, we found that Alu genotypes previously called for the 1000 Genomes Project are sometimes erroneous, which poses significant problems for phasing these insertions with other variants that comprise the haplotype. To ameliorate this issue, we introduce a new pipeline – TypeTE – which genotypes Alu insertions from whole-genome sequencing data. Starting from a list of polymorphic Alus, TypeTE identifies the hallmarks (poly-A tail and target site duplication) and orientation of Alu insertions using local re-assembly to reconstruct presence and absence alleles. Genotype likelihoods are then computed after re-mapping sequencing reads to the reconstructed alleles. Using a high-quality set of PCR-based genotyping of >200 loci, we show that TypeTE improves genotype accuracy from 83% to 92% in the 1000 Genomes dataset. TypeTE can be readily adapted to other retrotransposon families and brings a valuable toolbox addition for population genomics.

scholarly journals Impact of Physical Activity on Oxidative Stress Markers in Patients with Metastatic Breast Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Lidia Delrieu ◽  
Marina Touillaud ◽  
Olivia Pérol ◽  
Magali Morelle ◽  
Agnès Martin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Physical Activity ◽  
Enzyme Activity ◽  
Metastatic Breast Cancer ◽  
Tumor Progression ◽  
Plasma Concentrations ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Oxidative Stress Biomarkers

Purpose. Regular physical activity (PA) can affect oxidative stress, known to be involved in carcinogenesis. The objective of this study was to evaluate the associations between a six-month PA intervention and oxidative stress biomarkers, PA, and clinical outcomes in patients with metastatic breast cancer. Methods. Forty-nine newly diagnosed patients with metastatic breast cancer were recruited for a single-arm, unsupervised, and personalized six-month walking intervention with activity tracker. PA level and PA fitness, plasma concentrations of DNA oxidation (8OhdG), lipid peroxidation (MDA), and protein oxidation (AOPP), plasma activities of superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase, plasma and leucocyte activities of myeloperoxidase (MPO) and NADPH oxidase (NOX), and clinical markers of tumor progression (RECIST criteria) were measured at baseline and after the six-month intervention. Results. GPX activity (+17%) and MDA (+9%) significantly increased between baseline and the end of the intervention. Changes in PA level and fitness were significantly positively correlated with changes in plasma GPX and significantly negatively with changes in NOX in the leucocytes. Plasma MDA was significantly higher (+20%) whereas plasma AOPP was lower (-46%) for patients with tumor progression or that died during the six months as compared to patients without progression. Conclusion. A six-month PA intervention may be potentially beneficial in metastatic breast cancer patients for enhancing antioxidant enzyme activity and decreasing prooxidant enzyme activity. Moreover, AOPP and MDA could also be favorable and unfavorable biomarkers, respectively, since they are associated with disease progression and fitness level in this population. This trial is registered with NCT number: NCT03148886.

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