Identification of pathogenic CDK12 alterations in cell-free DNA (cfDNA) from patients with breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1028-1028
Author(s):  
Mary Love Taylor ◽  
Hiba I. Dada ◽  
Hannah Florian ◽  
Paul Kelly Marcom ◽  
Carey K. Anders ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Kinase Activity ◽  
Three Dimensional ◽  
Missense Mutations ◽  
Breast Cancers ◽  
Genomic Alterations ◽  
Conserved Regions ◽  
Cancer Pathogenesis ◽  
Health Database ◽  
Kinase Expression

1028 Background: Cyclin dependent kinase 12 ( CDK12) has both tumor suppressive and proto-oncogenic potential in metastatic breast cancers (MBC). CDK12 may be an important biomarker and target in MBC. However, a comprehensive genomic analysis of CDK12 alterations from cfDNA in MBC has not been investigated and the genomic impact of CDK12 alterations across the MBC spectrum is unknown. The purpose of this study was to identify the incidence of CDK12 genomic alterations occurring in cfDNA from patients with MBC and elucidate which CDK12 alterations may impact CDK12 kinase activity. Methods: We queried 13,070 MBC samples from the Guardant Health database between April 2019 – November 2020 to identify the incidence of CDK12 alterations detected in cfDNA. We classified each alteration type as: missense mutations, indels, or truncations. Amino acid changes occurring at conserved regions across multiple species were identified. Three-dimensional biochemical in silico analyses with ChimeraX were used to determine which CDK12 alterations may impact CDK12 kinase activity. To gain further biologic insights into CDK12 altered MBC we made associations with CDK12 alterations and co-occurring mutated genes. Results: Nonsynonymous CDK12 alterations from the Guardant Health database were found in 317 samples from a cohort of 13,070 patients indicating an overall incidence of 2.43%. Alterations included: 239 (75.4%) missense mutations; 26 (8.2%) indels; and 52 (16.4%) truncations. We identified 62 alterations within the kinase domain with all occurring at highly conserved regions across species. The most frequent hotspot mutation identified was I76M/T, occurring in 11 unique breast cancers. Three-dimensional analyses indicate that CDK12 alterations within the hinge, HRD, DFG, catalytic spine, and regulatory spine may impact CDK12 kinase activity. The significantly co-occurring mutations from the Guardant Health breast cancer database in samples with CDK12 alterations were ARID1A, APC, RB1, and PTEN. Conclusions: A modest incidence of CDK12 genomic alterations occur in cfDNA from patients with breast cancer. Novel somatic alterations in CDK12 were identified from Guardant Health that were not detected in the public domain. A portion of these occurred at highly conserved regions across species suggesting these specific CDK12 mutations may impact CDK12 kinase expression and be actionable therapeutic targets in breast cancers. Three dimensional analyses of the CDK12 gene further illustrate which specific alterations may induce CDK12 kinase expression or lead to inactivation. Co-occurring mutations reveal a unique genotype associated with CDK12 alterations that may play a biologic role in CDK12-mediated breast cancer pathogenesis. Preclinical studies to determine the prognostic and therapeutic implication of CDK12 alterations in MBC are warranted.

scholarly journals An automated computational biomechanics workflow for improving breast cancer diagnosis and treatment

2019 ◽  
Vol 9 (4) ◽  
pp. 20190034 ◽  
Author(s):  
Thiranja Prasad Babarenda Gamage ◽  
Duane T. K. Malcolm ◽  
Gonzalo Maso Talou ◽  
Anna Mîra ◽  
Anthony Doyle ◽  
...  
Keyword(s):  
Breast Cancer ◽  
State Of The Art ◽  
Three Dimensional ◽  
Breast Cancer Diagnosis ◽  
Automated System ◽  
Machine Learning Techniques ◽  
Breast Cancers ◽  
Computational Biomechanics ◽  
Biomechanical Models ◽  
Treatment Procedures

Clinicians face many challenges when diagnosing and treating breast cancer. These challenges include interpreting and co-locating information between different medical imaging modalities that are used to identify tumours and predicting where these tumours move to during different treatment procedures. We have developed a novel automated breast image analysis workflow that integrates state-of-the-art image processing and machine learning techniques, personalized three-dimensional biomechanical modelling and population-based statistical analysis to assist clinicians during breast cancer detection and treatment procedures. This paper summarizes our recent research to address the various technical and implementation challenges associated with creating a fully automated system. The workflow is applied to predict the repositioning of tumours from the prone position, where diagnostic magnetic resonance imaging is performed, to the supine position where treatment procedures are performed. We discuss our recent advances towards addressing challenges in identifying the mechanical properties of the breast and evaluating the accuracy of the biomechanical models. We also describe our progress in implementing a prototype of this workflow in clinical practice. Clinical adoption of these state-of-the-art modelling techniques has significant potential for reducing the number of misdiagnosed breast cancers, while also helping to improve the treatment of patients.

scholarly journals Quantitative Three-Dimensional Assessment of the Pharmacokinetic Parameters of Intra- and Peri-tumoural Tissues on Breast Dynamic Contrast-Enhanced Magnetic Resonance Imaging

2021 ◽  
Author(s):  
A. Niukkanen ◽  
H. Okuma ◽  
M. Sudah ◽  
P. Auvinen ◽  
A. Mannermaa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Magnetic Resonance Imaging ◽  
Three Dimensional ◽  
Pharmacokinetic Parameters ◽  
High Grade ◽  
Breast Cancers ◽  
Resonance Imaging ◽  
Dce Mri ◽  
Dynamic Contrast Enhanced ◽  
Contrast Enhanced

AbstractWe aimed to assess the feasibility of three-dimensional (3D) segmentation and to investigate whether semi-quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters are associated with traditional prognostic factors for breast cancer. In addition, we evaluated whether both intra-tumoural and peri-tumoural DCE parameters can differentiate the breast cancers that are more aggressive from those that are less aggressive. Consecutive patients with newly diagnosed invasive breast cancer and structural breast MRI (3.0 T) were included after informed consent. Fifty-six patients (mean age, 57 years) with mass lesions of > 7 mm in diameter were included. A semi-automatic image post-processing algorithm was developed to measure 3D pharmacokinetic information from the DCE-MRI images. The kinetic parameters were extracted from time-signal curves, and the absolute tissue contrast agent concentrations were calculated with a reference tissue model. Markedly, higher intra-tumoural and peri-tumoural tissue concentrations of contrast agent were found in high-grade tumours (n = 44) compared to low-grade tumours (n = 12) at every time point (P = 0.006–0.040), providing positive predictive values of 90.6–92.6% in the classification of high-grade tumours. The intra-tumoural and peri-tumoural signal enhancement ratios correlated with tumour grade, size, and Ki67 activity. The intra-observer reproducibility was excellent. We developed a model to measure the 3D intensity data of breast cancers. Low- and high-grade tumours differed in their intra-tumoural and peri-tumoural enhancement characteristics. We anticipate that pharmacokinetic parameters will be increasingly used as imaging biomarkers to model and predict tumour behavior, prognoses, and responses to treatment.

Retrospective analysis of phosphorylation status of the estrogen receptor in patients with early stage disease

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21034-21034 ◽  
Author(s):  
R. F. Swaby ◽  
M. Huang ◽  
K. J. Ruth ◽  
E. A. Ross ◽  
Y. Gong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Growth Factor ◽  
Early Breast Cancer ◽  
Nuclear Accumulation ◽  
Type I ◽  
Breast Cancers ◽  
Early Stage Disease ◽  
Akt Activation ◽  
Cancer Pathogenesis

21034 Background: The AKT kinase, when phosphorylated to its activated form (pAKT), mediates many proliferative and survival effects of growth factor receptors such as members of the epidermal growth factor receptor (EGFR) family. Overexpression of AKT in breast neoplasms suggests that AKT activation is involved in breast cancer development and/or progression, and contributes to poor outcome. pAKT is frequently upregulated in Her-2/neu positive breast cancers. Activated AKT is able to phosphorylate in vitro serine 167 (pS167) of estrogen receptor alpha (ERa), resulting in ER-mediated transcriptional activity in the absence of estrogen and possibly contributing to tamoxifen resistance in ERa positive breast cancers. In addition, ERa is phosphorylated at S118 (pS118) by MAPK. Thus, it is possible that pAKT- mediated ERa phosphorylation is implicated in tumorigenesis and resistance to treatment with hormonal therapy in patients with breast cancer. Methods: Utilizing commercially available antibodies, IHC analysis of 125 paraffin-embedded, ERa positive, early breast cancer cases, stratified for stage, were tested for pAKT, PTEN, pS167, and pS118. Staining intensity and number of positive cells were assessed by 4 independent graders. Fisher's exact test was used to determine the significance of associations with a two-sided type I error of 5%. Results: Phosphorylation of AKT occurred in approximately one-half of cases. pS167 was phosphorylated in 66% of pAKT positive cases compared to 35% of pAKT negative cases (p<0.0001). When we analyzed nuclear pAKT staining, this association was more pronounced: 76% of pAKT(+) vs. 37% of pAKT(-) (p<0.0001). 69% of pS118(+) cases were pS167(+) compared to only 15% pS167(+) when pS118 was negative (p<0.0001). In approx. 32% of cases pAKT was present in both the cytoplasm and nucleus. 20% of samples had only cytoplasmic pAKT, while in 4% of cases pAKT was nuclear only, supporting the hypothesis that cytoplasmic phosphorylation of AKT may precede nuclear accumulation. Conclusions: Phosphorylation of pS167ERa is significantly associated with AKT activation (especially in the nucleus) in early breast cancer, supporting the hypothesis that these two events may be causally linked and contribute to breast cancer pathogenesis. No significant financial relationships to disclose.

scholarly journals Nanoliposomal Delivery of MicroRNA-203 Suppresses Migration of Triple-Negative Breast Cancer through Distinct Target Suppression

2021 ◽  
Vol 7 (3) ◽  
pp. 45
Author(s):  
Shuxuan Song ◽  
Kelsey S. Johnson ◽  
Henry Lujan ◽  
Sahar H. Pradhan ◽  
Christie M. Sayes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Mrna Translation ◽  
The United States ◽  
Target Tissue ◽  
Breast Cancers ◽  
Mesenchymal Transition ◽  
Cancer Pathogenesis

Triple-negative breast cancers affect thousands of women in the United States and disproportionately drive mortality from breast cancer. MicroRNAs are small, non-coding RNAs that negatively regulate gene expression post-transcriptionally by inhibiting target mRNA translation or by promoting mRNA degradation. We have identified that miRNA-203, silenced by epithelial–mesenchymal transition (EMT), is a tumor suppressor and can promote differentiation of breast cancer stem cells. In this study, we tested the ability of liposomal delivery of miR-203 to reverse aspects of breast cancer pathogenesis using breast cancer and EMT cell lines. We show that translationally relevant methods for increasing miR-203 abundance within a target tissue affects cellular properties associated with cancer progression. While stable miR-203 expression suppresses LASP1 and survivin, nanoliposomal delivery suppresses BMI1, indicating that suppression of distinct mRNA target profiles can lead to loss of cancer cell migration.

Application of Nano Measurement in Development of Breast Cancer Perspective & Diagnosis

2014 ◽  
Vol 893 ◽  
pp. 145-148
Author(s):  
Xu Hui Shao
Keyword(s):  
Breast Cancer ◽  
Three Dimensional ◽  
Imaging Systems ◽  
Application Software ◽  
Breast Cancers ◽  
Virtual Image ◽  
Accurate Imaging

According to the principle of accurate imaging systems, the accurate nanomeasurement equipment is designed. On the basis of establishing the model of breast cancers to be processed, the nanomeasurement equipment is assembled in a virtual manner by using the application software Pro/ Engineer provided by three-dimensional CAD. The virtual image of the components of accurate video equipment is implemented either from top to bottom or reversely, providing a basis for simulation and development of this equipment.

scholarly journals Whole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancers

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Xiaotong Li ◽  
Sushant Kumar ◽  
Arif Harmanci ◽  
Shantao Li ◽  
Robert R. Kitchen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Copy Number ◽  
Cancer Genome ◽  
Whole Genome ◽  
Breast Cancers ◽  
Genomic Alterations ◽  
Genomic Features ◽  
Clonal Architecture

Abstract Background Inflammatory breast cancer (IBC) has a highly invasive and metastatic phenotype. However, little is known about its genetic drivers. To address this, we report the largest cohort of whole-genome sequencing (WGS) of IBC cases. Methods We performed WGS of 20 IBC samples and paired normal blood DNA to identify genomic alterations. For comparison, we used 23 matched non-IBC samples from the Cancer Genome Atlas Program (TCGA). We also validated our findings using WGS data from the International Cancer Genome Consortium (ICGC) and the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We examined a wide selection of genomic features to search for differences between IBC and conventional breast cancer. These include (i) somatic and germline single-nucleotide variants (SNVs), in both coding and non-coding regions; (ii) the mutational signature and the clonal architecture derived from these SNVs; (iii) copy number and structural variants (CNVs and SVs); and (iv) non-human sequence in the tumors (i.e., exogenous sequences of bacterial origin). Results Overall, IBC has similar genomic characteristics to non-IBC, including specific alterations, overall mutational load and signature, and tumor heterogeneity. In particular, we observed similar mutation frequencies between IBC and non-IBC, for each gene and most cancer-related pathways. Moreover, we found no exogenous sequences of infectious agents specific to IBC samples. Even though we could not find any strongly statistically distinguishing genomic features between the two groups, we did find some suggestive differences in IBC: (i) The MAST2 gene was more frequently mutated (20% IBC vs. 0% non-IBC). (ii) The TGF β pathway was more frequently disrupted by germline SNVs (50% vs. 13%). (iii) Different copy number profiles were observed in several genomic regions harboring cancer genes. (iv) Complex SVs were more frequent. (v) The clonal architecture was simpler, suggesting more homogenous tumor-evolutionary lineages. Conclusions Whole-genome sequencing of IBC manifests a similar genomic architecture to non-IBC. We found no unique genomic alterations shared in just IBCs; however, subtle genomic differences were observed including germline alterations in TGFβ pathway genes and somatic mutations in the MAST2 kinase that could represent potential therapeutic targets.

scholarly journals HIF-dependent expression of creatine kinase brain isoform (CKB) promotes breast cancer metastasis, and blocking creatine kinase activity with cyclocreatine impairs invasion and improves the efficacy of conventional chemotherapies

2021 ◽  
Author(s):  
Raisa I. Krutilina ◽  
Hilaire C. Playa ◽  
Danielle L. Brooks ◽  
Luciana P. Schwab ◽  
Deanna N. Parke ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Creatine Kinase ◽  
Tumor Cell ◽  
Cell Invasion ◽  
Kinase Activity ◽  
Creatine Kinase Activity ◽  
Breast Cancers ◽  
Invasion And Metastasis

AbstractThe oxygen-responsive Hypoxia Inducible Factor (HIF)-1 promotes several steps of the metastatic cascade. A hypoxic gene signature is enriched in triple negative breast cancers (TNBCs), which correlates with poor patient survival. Since inhibiting the HIF transcription factors with small molecules is challenging, we sought to identify genes downstream of HIF-1 that could be targeted to block invasion and metastasis. Creatine kinase brain isoform (CKB) was identified as a highly differentially expressed gene in a screen of HIF-1 wild type and knockout mammary tumor cells derived from a transgenic model of metastatic breast cancer. CKB is a cytosolic enzyme that reversibly catalyzes the phosphorylation of creatine, generating phosphocreatine (PCr) in the forward reaction, and regenerating ATP in the reverse reaction. Creatine kinase activity is inhibited by the creatine analog cyclocreatine (cCr). Loss and gain of function genetic approaches were used in combination with cCr therapy to define the contribution of CKB expression or creatine kinase activity to cell proliferation, migration, invasion, and metastasis in ER-negative breast cancers. Although tumor cell-intrinsic CKB was not essential for breast tumor cell proliferation or cell migration in vitro, CKB was necessary for cell invasion in vitro and strongly promoted tumor growth and metastasis in vivo. Similarly, cyclocreatine therapy repressed cell migration, cell invasion, formation of invadopodia, and lung metastasis. Moreover, in common TNBC cell line models, the addition of cCr to conventional agents, paclitaxel (Taxol) or doxorubicin, was either additive or synergistic to repress tumor cell growth.

scholarly journals Deep whole genome sequencing identifies recurrent genomic alterations in commonly-used breast cancer cell lines and patient derived xenograft models

2021 ◽  
Author(s):  
Niantao Deng ◽  
Andre Minoche ◽  
Kate Harvey ◽  
Andrei Goga ◽  
Alex Swarbrick
Keyword(s):  
Breast Cancer ◽  
Whole Genome Sequencing ◽  
Cell Lines ◽  
Cancer Cell ◽  
Genome Sequencing ◽  
Cancer Cell Lines ◽  
Whole Genome ◽  
Breast Cancers ◽  
Genomic Alterations ◽  
Pdx Models

Abstract BackgroundBreast cancer cell lines (BCCLs) and patient-derived xenografts (PDX) are the most frequently used models in breast cancer research. Despite their widespread usage, genome sequencing of these models is incomplete, with previous studies only focusing on targeted gene panels, whole exome or shallow whole genome sequencing. Deep whole genome sequencing is the most sensitive and accurate method to detect single nucleotide variants and indels, gene copy number and structural events such as gene fusions. ResultsHere we describe deep whole genome sequencing (WGS) of commonly used BCCL and PDX models using the Illumina X10 platform with an average ~ 60x coverage. We identify novel genomic alterations, including point mutations and genomic rearrangements at base-pair resolution, compared to previously available sequencing data. Through integrative analysis with publicly available functional screening data, we annotate new genomic features likely to be of biological significance. CSMD1 , previously identified as a tumor suppressor gene in various cancer types, including head and neck, lung and breast cancers, has been identified with deletion in 50% of our PDX models, suggesting an important role in aggressive breast cancers. ConclusionsOur WGS data provides a comprehensive genome sequencing resource of these models.

Genomic Drivers in Breast Cancers

2016 ◽  
Vol 12 (01) ◽  
pp. 28
Author(s):  
Luis Teixeira ◽  
Françoise Rothé ◽  
Christos Sotiriou ◽  
◽  
◽  
...  
Keyword(s):  
Breast Cancer ◽  
Next Generation Sequencing ◽  
Precision Medicine ◽  
Liquid Biopsy ◽  
Targeted Drugs ◽  
Breast Cancers ◽  
Genomic Alterations ◽  
Sequencing Technologies ◽  
Circulating Tumour Dna ◽  
Generation Sequencing

Significant advances in next-generation sequencing technologies have allowed the identification of genomic alterations in breast cancer. These alterations offer the opportunity to conduct studies with targeted drugs. However, there are still several scientific challenges to be addressed before precision medicine is widely used in the clinic. Nonetheless, different solutions are developed to overcome these obstacles such as the improvement of bioinformatics tools and the use of “liquid biopsy” to assess circulating tumour DNA.

Evaluation of pathologic and genomic characteristics in male breast cancer (MBC) patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1098-1098
Author(s):  
Damien Mikael Hansra ◽  
Eugene R Ahn ◽  
John Edward McKnight ◽  
Haritha Pabbathi ◽  
Cynthia Lynch ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Primary Tumor ◽  
Ductal Carcinoma ◽  
Genomic Alteration ◽  
Breast Cancers ◽  
Genomic Profile ◽  
Adult Males ◽  
Genomic Alterations ◽  
Primary Tumor Site ◽  
Metastatic Site

1098 Background: MBC is a rare entity comprising less than 1% of breast cancers [Siegel RL 2017]. Due to the low incidence of MBC, information about the genomic landscape of MBC is lacking. Here we describe detailed pathologic and genomic characteristics of MBC patients. Methods: IRB approval was obtained for a retrospective analysis of archived pathology on patients treated at Cancer Treatment Centers of America. Comprehensive genomic profiling of tumors was derived from Foundation One next generation sequencing. Clinical information was derived from retrospective chart review. Inclusions: adult males with breast cancer with stage IV metastatic disease. Exclusions: Females, stage 0-IIIC disease, missing genomic and pathology information. Results of clinical, pathology and genomic data were summarized. Results: 10 patients met study criteria. Median age: 56 yrs., range 39-61 yrs. Race: 5/10 (50%) Caucasian, 5/10 (50%) African American. Number of prior treatment regimens: mean = 2.6 (range 0-6). Intrinsic subgroup: hormone receptor (HR)+/ HER2- 7/10 (70%), HR+/ HER2+ 2/10 (20%), HR-/ HER2+ 1/10 (10%), triple negative breast cancer (TNBC) 0/10 (0%). Tumor histology: invasive ductal carcinoma 10/10 (100%). Histology grade: poorly differentiated (diff.) 4/10 (40%), moderate diff. 4/10 (40%), well diff. 1/10 (10%), unknown 1/10 (10%). Biopsy site: primary tumor 4/10 (40%), metastatic site 4/10 (40%), liquid biopsy 1/10 (10%). Most frequent genomic alterations: PIK3CA 5/9 (56%), CCND1 4/9 (44%), ZNF703 3/9 (33%), FGF4 3/10 (33%), GATA3 3/9 (33%) FGF 19 3/9 (33%), FGF3 3/9 (33%) Alterations in FGF seen 14/38 (36.8%) of total genomic alterations. Most frequent alterations by primary tumor: ZNF703 3/4 (75%), FGF3 2/4 (50%), FGFR1 2/4 (50%), CCND1 2/4 (50%), FGF19 2/4 (50%), FGF4 2/4 (50%); by metastatic site: PIK3CA 4/5 (80%), GATA 3 2/5 (40%), CCND1 2/5 (40%), FGF3 1/5 (20%), FGF19 1/5 (20%), FGF4 1/5 (20%). Genomic alteration by histologic subgroup; HR+ HER2- PIK3CA 3/6 (50%), CCND1 3/6 (50%), FGF4 3/6 (50%), ZNF703 3/6 (50%), FGF19 3/6 (50%), FGF3 3/6 (50%); HR+/ HER2+: PIK3CA 2/2 (100%), CCND1 1/2 (50%), GATA3 1/2 (50%), MLL3 1/2 (50%); TNBC: BRCA2 1/1 (100%), BARD1 1/1 (100%). Microsatellite status was stable in 6/6 (100%) of patients. Conclusions: MBC patients display a heterogeneous variety of complex genomic alterations. Mutations in FGF genes were most commonly observed. Other common alterations seen in this series include PIK3CA, CCND1, ZNF703, and GATA3. Furthermore, the genomic profile of primary tumor site differed from the genomic profile of the metastatic site.

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