scholarly journals Integrating Subclonal Response Heterogeneity to Define Cancer Organoid Therapeutic Sensitivity

2021 ◽  
Author(s):  
Jeremy D Kratz ◽  
Shujah Rehman ◽  
Katherine A Johnson ◽  
Amani A Gillette ◽  
Aishwarya Sunil ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Therapeutic Response ◽  
Cellular Level ◽  
Metabolic Imaging ◽  
Patient Specific ◽  
Molecular Profile ◽  
Organotypic Cultures ◽  
Sequencing Technologies ◽  
Molecular Features ◽  
Formidable Challenge

Tumor heterogeneity is predicted to confer inferior clinical outcomes, however modeling heterogeneity in a manner that still represents the tumor of origin remains a formidable challenge. Sequencing technologies are limited in their ability to identify rare subclonal populations and predict response to the multitude of available treatments for patients. Patient-derived organotypic cultures have significantly improved the modeling of cancer biology by faithfully representing the molecular features of primary malignant tissues. Patient-derived cancer organoid (PCO) cultures contain numerous individual organoids with the potential to recapitulate heterogeneity, though PCOs are most commonly studied in bulk ignoring any diversity in the molecular profile or treatment response. Here we demonstrate the advantage of evaluating individual PCOs in conjunction with cellular level optical metabolic imaging to characterize the largely ignored heterogeneity within these cultures to predict clinical therapeutic response, identify subclonal populations, and determine patient specific mechanisms of resistance.

scholarly journals Degenerative Cervical Myelopathy: Insights into Its Pathobiology and Molecular Mechanisms

2021 ◽  
Vol 10 (6) ◽  
pp. 1214
Author(s):  
Ji Tu ◽  
Jose Vargas Castillo ◽  
Abhirup Das ◽  
Ashish D. Diwan
Keyword(s):  
Cervical Myelopathy ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Imaging Techniques ◽  
Disease Process ◽  
Classification Systems ◽  
Molecular Features ◽  
Formidable Challenge ◽  
Long Term Treatment ◽  
Degenerative Cervical Myelopathy

Degenerative cervical myelopathy (DCM), earlier referred to as cervical spondylotic myelopathy (CSM), is the most common and serious neurological disorder in the elderly population caused by chronic progressive compression or irritation of the spinal cord in the neck. The clinical features of DCM include localised neck pain and functional impairment of motor function in the arms, fingers and hands. If left untreated, this can lead to significant and permanent nerve damage including paralysis and death. Despite recent advancements in understanding the DCM pathology, prognosis remains poor and little is known about the molecular mechanisms underlying its pathogenesis. Moreover, there is scant evidence for the best treatment suitable for DCM patients. Decompressive surgery remains the most effective long-term treatment for this pathology, although the decision of when to perform such a procedure remains challenging. Given the fact that the aged population in the world is continuously increasing, DCM is posing a formidable challenge that needs urgent attention. Here, in this comprehensive review, we discuss the current knowledge of DCM pathology, including epidemiology, diagnosis, natural history, pathophysiology, risk factors, molecular features and treatment options. In addition to describing different scoring and classification systems used by clinicians in diagnosing DCM, we also highlight how advanced imaging techniques are being used to study the disease process. Last but not the least, we discuss several molecular underpinnings of DCM aetiology, including the cells involved and the pathways and molecules that are hallmarks of this disease.

scholarly journals Pancreatic Ductal Adenocarcinoma Arising in Young and Old Patients Displays Similar Molecular Features

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1234
Author(s):  
Jérôme Raffenne ◽  
Fernando A. Martin ◽  
Rémy Nicolle ◽  
Marina Konta ◽  
Yuna Blum ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Responses ◽  
Protein Identification ◽  
Molecular Profile ◽  
Global Methylation ◽  
Old Patients ◽  
Molecular Features ◽  
Age Related ◽  
Clinical Difference ◽  
Dna Repair Gene

Pancreatic ducal adenocarcinoma is classically diagnosed in the 7th decade, but approximately 10% of patients are diagnosed under 55 years (y.o.). While the genomic and transcriptomic landscapes of late-onset tumors (LOT) have been described, little is known about early-onset tumors (EOT). Ageing is known to impact DNA methylation and proteome integrity through carbonylation-related oxidative damages. We therefore aimed to assess the global molecular features of EOT. We compared 176 EOT (≤55 y.o.) and 316 LOT (≥70 y.o.) from three distinct surgical cohorts at the clinical/genomic/epigenomic/transcriptomic level. Furthermore, we assessed oxidative stress responses and oxidative proteome damages using 2D gel electrophoresis followed by mass spectrometry protein identification. There was no consistent clinical difference between EOT and LOT across the three cohorts. The mutational landscape of key driver genes and the global methylation profile were similar in the two groups. LOT did display age-related features such as enriched DNA repair gene signatures and upregulation of oxidative stress defenses together with increased proteome carbonylation. However, these age-related differences were more preeminent in non-tumor tissues while tumor proteome and proteome damages were fairly comparable. In conclusion, this multi-omics comparison showed that EOT harbor a comparable molecular profile to that of LOT.

scholarly journals Novel cancer subtyping method based on patient-specific gene regulatory network

2021 ◽  
Author(s):  
Mai Adachi Nakazawa ◽  
Yoshinori Tamada ◽  
Yoshihisa Tanaka ◽  
Marie Ikeguchi ◽  
Kako Higashihara ◽  
...  
Keyword(s):  
Gene Networks ◽  
Regulatory Networks ◽  
The Cancer Genome Atlas ◽  
Patient Specific ◽  
Specific Gene ◽  
Omics Data ◽  
Cancer Subtypes ◽  
Molecular Systems ◽  
Molecular Features ◽  
Cancer Genome Atlas

The identification of cancer subtypes is important for the understanding of tumor heterogeneity. In recent years, numerous computational methods have been proposed for this problem based on the multi-omics data of patients. It is widely accepted that different cancer subtypes are induced by different molecular regulatory networks. However, only a few incorporate the differences between their molecular systems into the classification processes. In this study, we present a novel method to classify cancer subtypes based on patient-specific molecular systems. Our method quantifies patient-specific gene networks, which are estimated from their transcriptome data. By clustering their quantified networks, our method allows for cancer subtyping, taking into consideration the differences in the molecular systems of patients. Comprehensive analyses of The Cancer Genome Atlas (TCGA) datasets applied to our method confirmed that they were able to identify more clinically meaningful cancer subtypes than the existing subtypes and found that the identified subtypes comprised different molecular features. Our findings show that the proposed method, based on a simple classification using the patient-specific molecular systems, can identify cancer subtypes even with single omics data, which cannot otherwise be captured by existing methods using multi-omics data.

scholarly journals OncoThreads: Visualization of Large Scale Longitudinal Cancer Molecular Data

2021 ◽  
Author(s):  
Theresa A Harbig ◽  
Sabrina Nusrat ◽  
Tali Mazor ◽  
Qianwen Wang ◽  
Alexander Thomson ◽  
...  
Keyword(s):  
Longitudinal Data ◽  
Large Scale ◽  
Cancer Genomics ◽  
Temporal Patterns ◽  
Molecular Data ◽  
Liquid Biopsies ◽  
Sequencing Technologies ◽  
Molecular Features ◽  
Wide Range ◽  
The Impact

Molecular profiling of patient tumors and liquid biopsies over time with next-generation sequencing technologies and new immuno-profile assays are becoming part of standard research and clinical practice. With the wealth of new longitudinal data, there is a critical need for visualizations for cancer researchers to explore and interpret temporal patterns not just in a single patient but across cohorts. To address this need we developed OncoThreads, a tool for the visualization of longitudinal clinical and cancer genomics and other molecular data in patient cohorts. The tool visualizes patient cohorts as temporal heatmaps and Sankey diagrams that support the interactive exploration and ranking of a wide range of clinical and molecular features. This allows analysts to discover temporal patterns in longitudinal data, such as the impact of mutations on response to a treatment, e.g. emergence of resistant clones. We demonstrate the functionality of OncoThreads using a cohort of 23 glioma patients sampled at 2-4 timepoints. OncoThreads is freely available at http://oncothreads.gehlenborglab.org and implemented in Javascript using the cBioPortal web API as a backend.

PATH-41. POLYMORPHOUS LOW-GRADE NEUROEPITHELIAL TUMOR OF THE YOUNG WITH FGFR3-TACC3 FUSION MIMICKING HIGH-GRADE GLIOMA: CASE REPORT AND SERIES OF HIGH-GRADE CORRELATES

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi124-vi124
Author(s):  
Danielle Golub ◽  
Peter C Pan ◽  
Benjamin Liechty ◽  
Cheyanne Slocum ◽  
Tejus Bale ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
High Grade Glioma ◽  
Proliferation Index ◽  
Molecular Profile ◽  
Low Grade ◽  
High Grade ◽  
Molecular Features ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

Abstract BACKGROUND Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently-described entity that can occasionally histologically and molecularly mimic high-grade glioma. The histologic and molecular features that predict aggressive behavior in FGFR3-TACC3 altered tumors are unclear. CASES We present a rare case of an indolent neuroepithelial neoplasm in a 59-year-old female with imaging initially suggestive of high-grade glioma and analyze common molecular features between this case and a series of high-grade gliomas. After total resection, pathology of the case patient revealed predominantly low-grade cytomorphology, abundant microcalcifications, unusual neovascularization, and a low proliferation index. The lesion was diffusely CD34 immunoreactive and harbored both an FGFR3-TACC3 fusion and a TERT promoter mutation. Based on the overall histologic and molecular profile, a diagnosis of PLNTY was favored. The patient was thereafter observed without adjuvant therapy with no evidence of progression at 15-month follow-up. In contrast, a series of eight adult patients with glioblastomas harboring FGFR3-TACC3 fusions and correspondingly aggressive clinical courses are also presented. Common molecular findings included IDH-wildtype status, absence of 1p19q codeletion, and CDKN2A loss. TERT promoter mutations and lack of MGMT promoter methylation were also frequently observed. These patients demonstrated a median 15-month overall survival and a 6-month progression-free survival. CONCLUSIONS PLNTY is a rare low-grade entity that can display characteristics of high-grade glioma, particularly in adults. The potential for a unique entity mimicking PLNTY which may act as a precursor lesion for a more malignant phenotype should be considered in cases with FGFR3-TACC3 fusions and other high-grade features.

Molecular Profile and Clinical Variables in Brca1-Positive Breast Cancers. A Population-Based Study

2005 ◽  
Vol 91 (6) ◽  
pp. 505-512 ◽  
Author(s):  
Antonino Musolino ◽  
Maria Michiara ◽  
Maria A. Bella ◽  
Nadia Naldi ◽  
Paola Zanelli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Direct Sequencing ◽  
Population Based ◽  
Molecular Profile ◽  
Breast Cancers ◽  
Population Based Study ◽  
Free Survival ◽  
Molecular Features ◽  
Inherited Susceptibility ◽  
Brca1 Mutations

Purpose To evaluate the clinical features of breast cancer patients with genetic susceptibility to this disease and to investigate the contribution of BRCA1 germline mutations to the phenotype of these tumors. Patients and Methods We reviewed the clinical and pathological records of 102 women with suspected inherited susceptibility to breast cancer consecutively seen at the Genetic Oncology Service of Parma, Italy. Sixty-two patients with a high probability of harboring a germline, cancer-predisposing mutation were tested for BRCA1 mutations. Exon 11 was screened using the protein truncation test and detected mutations were confirmed by direct sequencing (DS). All other exons were analyzed by DS. Results Among the 62 patients with a completed mutation analysis, 48 (77.4%) had wild-type BRCA1, six (9.6%) had variants of unclear significance, eight (13%) had deleterious mutations. BRCA1-associated breast cancers (BABC) were significantly less likely to be diagnosed at stage I than breast cancers in women without mutations (12.5% vs 51%; P = 0.045), more likely to have a high proliferation rate (100% vs 24%, P<0.001), and more likely to be histological grade 3 (100% vs 14%, P<0.001), estrogen and progesterone receptor negative (87.5% vs 13%, P<0.001; 75% vs 23%, P = 0.004), and p53 positive (87.5% vs 30%, P = 0.023). All tumors with BRCA1 mutations were HER-2/neu negative compared with 57% of the non-BRCA1 tumors ( P = 0.04). There were no significant differences between BABC and non-BABC in 20-year relapse-free survival, 20-year event-free survival, and 20-year overall survival. Conclusion In this population-based study, BABC seems to present with adverse molecular features when compared with non-BABC, although the prognosis appears to be similar.

MicroRNAs as Therapeutic Agents: The Future of the Battle Against Cancer

2019 ◽  
Vol 18 (30) ◽  
pp. 2544-2554 ◽  
Author(s):  
Sumit Biswas
Keyword(s):  
Drug Resistance ◽  
Cancer Biology ◽  
Therapeutic Agents ◽  
Nucleotide Level ◽  
Target Mrnas ◽  
Sequencing Technologies ◽  
Tumour Suppressors ◽  
The Future ◽  
New Strategies

Since their discovery in the 1990’s, the study of a class of non-coding, single-stranded RNAs, christened the microRNAs has opened up new vistas in the field of cancer biology. MicroRNAs bind to their target mRNAs to act as either oncogenes or tumour suppressors. With the near-complete elucidation of the biogenesis pathway, and the advent of rapid sequencing technologies, microRNAs have slowly cemented their place as essential biomarkers for delineating the progression, metastasis, relapse or drug resistance of cancer. Being crucial players in the cancer pathway, there has been considerable urgency in designing molecules - both at the nucleotide and non-nucleotide level to counter the effects of their binding. A number of different approaches have yielded quite a body of compounds which have been found to be effective in the treatment of various tumours across many different organs. In this study, the focus is on the review of the timeline of discovery and characterization of microRNAs, underlining their importance in different cancers, shedding light on the discovery of anti-microRNA compounds and illustrating their uses in deriving new strategies to combat cancer.

scholarly journals Acute Myeloid Leukemia Stem Cells: The Challenges of Phenotypic Heterogeneity

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3742
Author(s):  
Marlon Arnone ◽  
Martina Konantz ◽  
Pauline Hanns ◽  
Anna M. Paczulla Stanger ◽  
Sarah Bertels ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Current Knowledge ◽  
Phenotypic Variability ◽  
Cellular Level ◽  
Patient Specific ◽  
Heterogeneous Landscape ◽  
Cells Of Origin ◽  
Acute Myeloid

Patients suffering from acute myeloid leukemia (AML) show highly heterogeneous clinical outcomes. Next to variabilities in patient-specific parameters influencing treatment decisions and outcome, this is due to differences in AML biology. In fact, different genetic drivers may transform variable cells of origin and co-exist with additional genetic lesions (e.g., as observed in clonal hematopoiesis) in a variety of leukemic (sub)clones. Moreover, AML cells are hierarchically organized and contain subpopulations of more immature cells called leukemic stem cells (LSC), which on the cellular level constitute the driver of the disease and may evolve during therapy. This genetic and hierarchical complexity results in a pronounced phenotypic variability, which is observed among AML cells of different patients as well as among the leukemic blasts of individual patients, at diagnosis and during the course of the disease. Here, we review the current knowledge on the heterogeneous landscape of AML surface markers with particular focus on those identifying LSC, and discuss why identification and targeting of this important cellular subpopulation in AML remains challenging.

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