scholarly journals Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
David Brown ◽  
Dominiek Smeets ◽  
Borbála Székely ◽  
Denis Larsimont ◽  
A. Marcell Szász ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Copy Number ◽  
Somatic Mutations ◽  
Primary Tumour ◽  
Distant Metastases ◽  
Molecular Techniques ◽  
Metastatic Progression ◽  
Number Of Patients ◽  
Cancer Dissemination

Abstract Several studies using genome-wide molecular techniques have reported various degrees of genetic heterogeneity between primary tumours and their distant metastases. However, it has been difficult to discern patterns of dissemination owing to the limited number of patients and available metastases. Here, we use phylogenetic techniques on data generated using whole-exome sequencing and copy number profiling of primary and multiple-matched metastatic tumours from ten autopsied patients to infer the evolutionary history of breast cancer progression. We observed two modes of disease progression. In some patients, all distant metastases cluster on a branch separate from their primary lesion. Clonal frequency analyses of somatic mutations show that the metastases have a monoclonal origin and descend from a common ‘metastatic precursor’. Alternatively, multiple metastatic lesions are seeded from different clones present within the primary tumour. We further show that a metastasis can be horizontally cross-seeded. These findings provide insights into breast cancer dissemination.

scholarly journals Erratum: Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
David Brown ◽  
Dominiek Smeets ◽  
Borbála Székely ◽  
Denis Larsimont ◽  
A. Marcell Szász ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phylogenetic Analysis ◽  
Copy Number ◽  
Somatic Mutations ◽  
Metastatic Progression ◽  
Copy Number Aberrations

scholarly journals Periodontal inflammation recruits distant metastatic breast cancer cells by increasing myeloid-derived suppressor cells

Oncogene ◽  
2019 ◽  
Vol 39 (7) ◽  
pp. 1543-1556 ◽  
Author(s):  
Ran Cheng ◽  
Sandrine Billet ◽  
Chuanxia Liu ◽  
Subhash Haldar ◽  
Diptiman Choudhury ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Periodontal Diseases ◽  
Metastatic Breast ◽  
Metastatic Progression ◽  
Premetastatic Niche ◽  
Periodontal Inflammation

Abstract Periodontal diseases can lead to chronic inflammation affecting the integrity of the tooth supporting tissues. Recently, a striking association has been made between periodontal diseases and primary cancers in the absence of a mechanistic understanding. Here we address the effect of periodontal inflammation (PI) on tumor progression, metastasis, and possible underlining mechanisms. We show that an experimental model of PI in mice can promote lymph node (LN) micrometastasis, as well as head and neck metastasis of 4T1 breast cancer cells, both in early and late stages of cancer progression. The cervical LNs had a greater tumor burden and infiltration of MDSC and M2 macrophages compared with LNs at other sites. Pyroptosis and the resultant IL-1β production were detected in patients with PI, mirrored in mouse models. Anakinra, IL-1 receptor antagonist, limited metastasis, and MDSC recruitment at early stages of tumor progression, but failed to reverse established metastatic tumors. PI and the resulting production of IL-1β was found to promote CCL5, CXCL12, CCL2, and CXCL5 expression. These chemokines recruit MDSC and macrophages, finally enabling the generation of a premetastatic niche in the inflammatory site. These findings support the idea that periodontal inflammation promotes metastasis of breast cancer by recruiting MDSC in part by pyroptosis-induced IL-1β generation and downstream CCL2, CCL5, and CXCL5 signaling in the early steps of metastasis. These studies define the role for IL-1β in the metastatic progression of breast cancer and highlight the need to control PI, a pervasive inflammatory condition in older patients.

scholarly journals Chromosomal Genotype in Breast Cancer Progression: Comparison of Primary and Secondary Manifestations

2008 ◽  
Vol 30 (1) ◽  
pp. 39-50
Author(s):  
Katrin Friedrich ◽  
Theresa Weber ◽  
Jens Scheithauer ◽  
Wolfdietrich Meyer ◽  
Gunter Haroske ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Cancer Progression ◽  
Lymph Node Metastases ◽  
Distant Metastases ◽  
Comparative Genomic ◽  
Breast Cancers ◽  
Primary Tumors ◽  
Local Recurrences ◽  
Node Metastases

The purpose of this study was to compare the chromosomal genotype between breast cancers with and without secondary manifestations and between primary tumors and their secondary manifestations. Eighty six breast cancers, twenty lymph node metastases, ten distant metastases and ten local recurrences were analyzed by comparative genomic hybridization. Tumors with local recurrences showed significant more frequent losses at 2q32 than the tumors without recurrences. Lymph node positive cases showed significant more frequent losses at 9p21 than node negative cases. Lymph node metastases exhibited significant more frequent losses at 7q11, 14q24.3–q31 and 17q22–q24 than their primary tumors. In cases with distant metastases, losses at 5q23 were more frequent than in those without, but not reaching the significance level. The distant metastases showed significant more frequent losses at 5p15, 12q24 and 17q22–q24 than the primary tumors. These results reveal strong evidence that the potential for progression is determined in the primary tumor and that different ways of the development of local recurrences, lymph node and distant metastases exist. After confirmation of the results by interphase FISH on tissue micro arrays, the detection of these specific chromosomal imbalances may contribute to a more individual prediction of prognosis in breast cancer.

scholarly journals Reconstructing mutational lineages in breast cancer by multi-patient-targeted single cell DNA sequencing

2021 ◽  
Author(s):  
Nicholas Navin ◽  
Jake Leighton ◽  
Min Hu ◽  
Emi Sei ◽  
Funda Meric-Bernstam
Keyword(s):  
Breast Cancer ◽  
Dna Sequencing ◽  
Single Cell ◽  
Copy Number ◽  
Somatic Mutations ◽  
Single Cells ◽  
Tumor Evolution ◽  
Sequencing Method ◽  
Genomic Regions ◽  
Microfluidics Platform

Single cell DNA sequencing (scDNA-seq) methods are powerful tools for profiling mutations in cancer cells, however most genomic regions characterized in single cells are non-informative. To overcome this issue, we developed a Multi-Patient-Targeted (MPT) scDNA-seq sequencing method. MPT involves first performing bulk exome sequencing across a cohort of cancer patients to identify somatic mutations, which are then pooled together to develop a single custom targeted panel for high-throughput scDNA-seq using a microfluidics platform. We applied MPT to profile 330 mutations across 23,500 cells from 5 TNBC patients, which showed that 3 tumors were monoclonal and 2 tumors were polyclonal. From this data, we reconstructed mutational lineages and identified early mutational and copy number events, including early TP53 mutations that occurred in all five patients. Collectively, our data suggests that MPT can overcome technical obstacles for studying tumor evolution using scDNA-seq by profiling information-rich mutation sites.

MOLECULAR DIAGNOSTICS OF BILATERAL BREAST CANCER

2017 ◽  
Vol 63 (3) ◽  
pp. 435-439
Author(s):  
Svetlana Bekhtereva ◽  
Yevgeniy Imyanitov ◽  
Andrey Vazhenin ◽  
Alla Domozhirova ◽  
Sergey Yaytsev
Keyword(s):  
Breast Cancer ◽  
Clinical Practice ◽  
Somatic Mutations ◽  
Malignant Tumors ◽  
Bilateral Breast Cancer ◽  
Genetic Studies ◽  
Number Of Patients ◽  
Genetic Mechanisms ◽  
Prevention Of Breast Cancer

The problem of primary multiplicity of malignant tumors remains actual in oncology due to growing number of patients with polyneoplasia especially of the breast. Modern genetic studies use “genetically enriched” cases of cancer, which include in particular primary-multiple malignant tumors of the breast. Practically every tumor has an individual set of somatic mutations and genetic mechanisms of breast cancer appearance are very different. The multicentre study shows the role of recessive determinants of the predisposition to bilateral breast cancer without a family history. The obtained data could be used in clinical practice as a secondary prevention of breast cancer.

scholarly journals Revealing tumor heterogeneity of breast cancer by utilizing the linkage between somatic and germline mutations

2018 ◽  
Vol 20 (6) ◽  
pp. 2306-2315 ◽  
Author(s):  
Meng Zou ◽  
Rui Jin ◽  
Kin Fai Au
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Tumor Heterogeneity ◽  
Somatic Mutations ◽  
Population Level ◽  
Superior Performance ◽  
Tumor Evolution ◽  
Single Nucleotide Variants ◽  
Long Reads ◽  
Gene Tp53

Abstract The intra-tumor heterogeneity is associated with cancer progression and therapeutic resistance, such as in breast cancer. While the existing methods for studying tumor heterogeneity only analyze variant allele frequency (VAF), the genotype of variant is also informative for inferring subclones, which can be detected by long reads or paired-end reads. We developed GenoClone to integrate VAF with the genotype of variant innovatively, so it showed superior performance of inferring the number of subclones, estimating the fractions of subclones and identifying somatic single-nucleotide variants composition of subclones. When GenoClone was applied to 389 TCGA breast cancer samples, it revealed extensive intra-tumor heterogeneity. We further found that a few somatic mutations were relevant to the late stage of tumor evolution, including the ones at the oncogene PIK3CA and the tumor suppress gene TP53. Moreover, 52 subclones that were identified from 167 samples shared high similarity of somatic mutations, which were clustered into three groups with the sizes of 24, 14 and 14. It is helpful for understanding the development of breast cancer in certain subgroups of people and the drug development for population level. Furthermore, GenoClone also identified the tumor heterogeneity in different aliquots of the same samples. The implementation of GenoClone is available at http://www.healthcare.uiowa.edu/labs/au/GenoClone/.

scholarly journals Bioinformatic analysis reveals GSG2 as a potential target for breast cancer therapy

2019 ◽  
Vol 14 (1) ◽  
pp. 688-698
Author(s):  
Zheng Ye ◽  
Zhaoyu Zhang ◽  
Lijiao Fang ◽  
Daiquan Tian ◽  
Xin Liu
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
Mrna Expression ◽  
Cancer Progression ◽  
Copy Number ◽  
Bioinformatic Analysis ◽  
Copy Number Variations ◽  
Breast Cancer Therapy ◽  
Normal Tissues ◽  
Cancer Tissues

AbstractObjectiveTo explore the potential role of GSG2 in breast cancer progression.MethodsThe mRNA expression, DNA copy number and clinical data used in this study were obtained from the TCGA data portal. The copy number variations (CNVs) thresholds were determined according to the set of discrete copy number calls provided by Genomic Identification of Significant Targets in Cancer (GISTIC).ResultsThe mRNA expression level of GSG2 in 112 breast cancer tissues was much higher than that in adjacent normal tissues. GSG2 was significantly upregulated in stage II compared with stage I, and there was no differential expression of GSG2 between tumors with or without metastasis. Heterozygous deletion occupied 57.1% of CNVs for GSG2 gene in breast cancer samples. Patients with higher GSG2 expression tended to suffer from poorer prognosis.ConclusionOur profiling analysis indicated the overexpression of GSG2 might play an important role in breast cancer development, suggesting that GSG2 could be a new target for breast cancer treatment, making GSG2 inhibitors becoming potential drugs for breast cancer therapy.

scholarly journals SLX4IP and telomere dynamics dictate breast cancer metastasis and therapeutic responsiveness

2020 ◽  
Vol 3 (4) ◽  
pp. e201900427
Author(s):  
Nathaniel J Robinson ◽  
Chevaun D Morrison-Smith ◽  
Alex J Gooding ◽  
Barbara J Schiemann ◽  
Mark W Jackson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Clinical Manifestations ◽  
Metastatic Breast ◽  
Disseminated Tumor Cells ◽  
Telomere Maintenance ◽  
Metastatic Progression ◽  
Metastatic Relapse

Metastasis is the leading cause of breast cancer-related death and poses a substantial clinical burden owing to a paucity of targeted treatment options. The clinical manifestations of metastasis occur years-to-decades after initial diagnosis and treatment because disseminated tumor cells readily evade detection and resist therapy, ultimately giving rise to recurrent disease. Using an unbiased genetic screen, we identified SLX4-interacting protein (SLX4IP) as a regulator of metastatic recurrence and established its relationship in governing telomere maintenance mechanisms (TMMs). Inactivation of SLX4IP suppressed alternative lengthening of telomeres (ALT), coinciding with activation of telomerase. Importantly, TMM selection dramatically influenced metastatic progression and survival of patients with genetically distinct breast cancer subtypes. Notably, pharmacologic and genetic modulation of TMMs elicited telomere-dependent cell death and prevented disease recurrence by disseminated tumor cells. This study illuminates SLX4IP as a potential predictive biomarker for breast cancer progression and metastatic relapse. SLX4IP expression correlates with TMM identity, which also carries prognostic value and informs treatment selection, thereby revealing new inroads into combating metastatic breast cancers.

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