scholarly journals Targeted sequencing reveals the somatic mutation landscape in a Swedish breast cancer cohort

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Argyri Mathioudaki ◽  
Viktor Ljungström ◽  
Malin Melin ◽  
Maja Louise Arendt ◽  
Jessika Nordin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Somatic Mutation ◽  
Age Of Onset ◽  
Single Nucleotide Variants ◽  
Modifying Genes ◽  
Dna Mismatch ◽  
Targeted Next Generation Sequencing ◽  
Estrogen Receptor Positive ◽  
Underlying Mechanisms ◽  
Swedish Cohort

Abstract Breast cancer (BC) is a genetically heterogeneous disease with high prevalence in Northern Europe. However, there has been no detailed investigation into the Scandinavian somatic landscape. Here, in a homogeneous Swedish cohort, we describe the somatic events underlying BC, leveraging a targeted next-generation sequencing approach. We designed a 20.5 Mb array targeting coding and regulatory regions of genes with a known role in BC (n = 765). The selected genes were either from human BC studies (n = 294) or from within canine mammary tumor associated regions (n = 471). A set of predominantly estrogen receptor positive tumors (ER +  85%) and their normal tissue counterparts (n= 61) were sequenced to ~ 140 × and 85 × mean target coverage, respectively. MuTect2 and VarScan2 were employed to detect single nucleotide variants (SNVs) and copy number aberrations (CNAs), while MutSigCV (SNVs) and GISTIC (CNAs) algorithms estimated the significance of recurrent somatic events. The significantly mutated genes (q ≤ 0.01) were PIK3CA (28% of patients), TP53 (21%) and CDH1 (11%). However, histone modifying genes contained the largest number of variants (KMT2C and ARID1A, together 28%). Mutations in KMT2C were mutually exclusive with PI3KCA mutations (p ≤ 0. 001) and half of these affect the formation of a functional PHD domain. The tumor suppressor CDK10 was deleted in 80% of the cohort while the oncogene MDM4 was amplified. Mutational signature analyses pointed towards APOBEC deaminase activity (COSMIC signature 2) and DNA mismatch repair (COSMIC signature 6). We noticed two significantly distinct patterns related to patient age; TP53 being more mutated in the younger group (29% vs 9% of patients) and CDH23 mutations were absent from the older group. The increased somatic mutation prevalence in the histone modifying genes KMT2C and ARID1A distinguishes the Swedish cohort from previous studies. KMT2C regulates enhancer activation and assists tumor proliferation in a hormone-rich environment, possibly pointing to a role in ER + BC, especially in older cases. Finally, age of onset appears to affect the mutational landscape suggesting that a larger age-diverse population incorporating more molecular subtypes should be studied to elucidate the underlying mechanisms.

scholarly journals Mechanisms of CDK4/6 Inhibitor Resistance in Luminal Breast Cancer

2020 ◽  
Vol 11 ◽  
Author(s):  
Zhen Li ◽  
Wei Zou ◽  
Ji Zhang ◽  
Yunjiao Zhang ◽  
Qi Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Cancer Drug ◽  
Luminal Breast Cancer ◽  
Cancer Drug Resistance ◽  
Estrogen Receptor Positive ◽  
Underlying Mechanisms ◽  
Inhibitor Resistance ◽  
New Generation

As a new-generation CDK inhibitor, a CDK4/6 inhibitor combined with endocrine therapy has been successful in the treatment of advanced estrogen receptor–positive (ER+) breast cancer. Although there has been overall progress in the treatment of cancer, drug resistance is an emerging cause for breast cancer–related death. Overcoming CDK4/6 resistance is an urgent problem. Overactivation of the cyclin-CDK-Rb axis related to uncontrolled cell proliferation is the main cause of CDK4/6 inhibitor resistance; however, the underlying mechanisms need to be clarified further. We review various resistance mechanisms of CDK4/6 inhibitors in luminal breast cancer. The cell signaling pathways involved in therapy resistance are divided into two groups: upstream response mechanisms and downstream bypass mechanisms. Finally, we discuss possible strategies to overcome CDK4/6 inhibitor resistance and identify novel resistance targets for future clinical application.

scholarly journals Estrogen-regulated feedback loop limits the efficacy of estrogen receptor–targeted breast cancer therapy

2018 ◽  
Vol 115 (31) ◽  
pp. 7869-7878 ◽  
Author(s):  
Tengfei Xiao ◽  
Wei Li ◽  
Xiaoqing Wang ◽  
Han Xu ◽  
Jixin Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Therapy Resistance ◽  
Negative Feedback Loop ◽  
Endocrine Therapy Resistance ◽  
Estrogen Receptor Positive ◽  
Underlying Mechanisms

Endocrine therapy resistance invariably develops in advanced estrogen receptor-positive (ER+) breast cancer, but the underlying mechanisms are largely unknown. We have identified C-terminal SRC kinase (CSK) as a critical node in a previously unappreciated negative feedback loop that limits the efficacy of current ER-targeted therapies. Estrogen directly drives CSK expression in ER+ breast cancer. At low CSK levels, as is the case in patients with ER+ breast cancer resistant to endocrine therapy and with the poorest outcomes, the p21 protein-activated kinase 2 (PAK2) becomes activated and drives estrogen-independent growth. PAK2 overexpression is also associated with endocrine therapy resistance and worse clinical outcome, and the combination of a PAK2 inhibitor with an ER antagonist synergistically suppressed breast tumor growth. Clinical approaches to endocrine therapy-resistant breast cancer must overcome the loss of this estrogen-induced negative feedback loop that normally constrains the growth of ER+ tumors.

Somatic mutation burden in cancer samples determined by targeted next generation sequencing.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 15-15
Author(s):  
Dinesh Cyanam ◽  
Adam Broomer ◽  
David Mandelman ◽  
Ruchi Chaudhary ◽  
Paul D Williams ◽  
...  
Keyword(s):  
Somatic Mutation ◽  
The Cancer Genome Atlas ◽  
Single Nucleotide Variants ◽  
Sequencing Platform ◽  
Targeted Next Generation Sequencing ◽  
Mutation Burden ◽  
Cancer Genome Atlas ◽  
Advance Research ◽  
Ion Torrent Sequencing ◽  
Using Data

15 Background: High somatic mutation burden in tumor tissues is associated with the presentation of neoantigens that promote immune responses particularly in the context of immune checkpoint therapies. Herein, we characterize the ability of targeted cancer research panels to generate estimates of somatic mutation burden. Methods: Somatic mutation data from > 8000 cancer samples obtained from The Cancer Genome Atlas (TCGA) was curated and standardized, and the number of single nucleotide variants (SNVs) in exonic regions of each sample determined. Next, the number of SNVs associated with target regions of two Ion AmpliSeq cancer panels (Oncomine Comprehensive Assay [OCA, 146 genes, 0.35 MB]; Comprehensive Cancer Panel [CCP, 409 genes, 1.7 MB]) was likewise determined and the frequency of mutation counts in the exome and the panel target regions was compared. Mutation counts of samples containing truncating mutations in mismatch repair (MMR) and other DNA repair genes were characterized. A facile workflow with less than 60 minutes of hands-on time was developed to estimate mutation counts for a batch of 8 samples using the Ion Chef for automated library preparation and templating followed by sequencing on the Ion S5. Results: The sensitivity of targeted panels in estimating somatic mutation burden was positively correlated with panel size. The area under the Receiver Operating Characteristic (ROC) curve showed that CCP had > 90% sensitivity and > 95% specificity to differentiate high and low mutation burden based on informatics analysis of TCGA data. As expected, truncating mutations in MMR genes were associated with higher somatic mutation counts in colorectal tumor tissue. Using data generated from OCA and CCP, we characterized a set of filters that provided a good estimate of somatic mutation counts when applied to a tumor-only workflow. Conclusions: A simple workflow was developed on the Ion Torrent sequencing platform to estimate somatic mutation burden in cancer samples. The methods described herein will help advance research in immuo-oncology.

Exploring PLAC1 Structure and Underlying Mechanisms to Design a Derivative Vaccine Against Breast Cancer Progression; In-Silico Study

2020 ◽  
Vol 17 (5) ◽  
pp. 379-391
Author(s):  
Farzaneh Afzali ◽  
Parisa Ghahremanifard ◽  
Mohammad Mehdi Ranjbar ◽  
Mahdieh Salimi
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
In Silico ◽  
Tertiary Structure ◽  
Specific Antigen ◽  
Docking Simulation ◽  
Post Translational Modification ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Underlying Mechanisms

Background: The tolerogenic homeostasis in Breast Cancer (BC) can be surpassed by rationally designed immune-encouraging constructs against tumor-specific antigens through immunoinformatics approach. Objective: Availability of high throughput data providing the underlying concept of diseases and awarded computational simulations, lead to screening the potential medications and strategies in less time and cost. Despite the extensive effects of Placenta Specific 1 (PLAC1) in BC progression, immune tolerance, invasion, cell cycle regulation, and being a tumor-specific antigen the fundamental mechanisms and regulatory factors were not fully explored. It is also worth to design an immune response inducing construct to surpass the hurdles of traditional anti-cancer treatments. Methods and Result: The study was initiated by predicting and modelling the PLAC1 secondary and tertiary structures and then engineering the fusion pattern of PLAC1 derived immunodominant predicted CD8+ and B-cell epitopes to form a multi-epitope immunogenic construct. The construct was analyzed considering the physiochemical characterization, safety, antigenicity, post-translational modification, solubility, and intrinsically disordered regions. After modelling its tertiary structure, proteinprotein docking simulation was carried out to ensure the attachment of construct with Toll-Like Receptor 4 (TLR4) as an immune receptor. To guarantee the highest expression of the designed construct in E. coli k12 as an expressional host, the codon optimization and in-silico cloning were performed. The PLAC1 related miRNAs in BC were excavated and validated through TCGA BC miRNA-sequencing and databases; the common pathways then were introduced as other probable mechanisms of PLAC1 activity. Conclusion: Regarding the obtained in-silico results, the designed anti-PLAC1 multi-epitope construct can probably trigger humoral and cellular immune responses and inflammatory cascades, therefore may have the potential of halting BC progression and invasion engaging predicted pathways.

scholarly journals Toronto Workshop on Late Recurrence in Estrogen Receptor–Positive Breast Cancer: Part 1: Late Recurrence: Current Understanding, Clinical Considerations

2019 ◽  
Vol 3 (4) ◽  
Author(s):  
Ryan J O Dowling ◽  
Kevin Kalinsky ◽  
Daniel F Hayes ◽  
Francois-Clement Bidard ◽  
David W Cescon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
International Workshop ◽  
Recurrence Risk ◽  
Late Recurrence ◽  
Current Understanding ◽  
Breast Cancer Patients ◽  
Related Factors ◽  
Estrogen Receptor Positive ◽  
Positive Breast Cancer

Abstract Disease recurrence (locoregional, distant) exerts a significant clinical impact on the survival of estrogen receptor–positive breast cancer patients. Many of these recurrences occur late, more than 5 years after original diagnosis, and represent a major obstacle to the effective treatment of this disease. Indeed, methods to identify patients at risk of late recurrence and therapeutic strategies designed to avert or treat these recurrences are lacking. Therefore, an international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. In this article, the major issues surrounding late recurrence are defined and current approaches that may be applicable to this challenge are discussed. Specifically, diagnostic tests with potential utility in late-recurrence prediction are described as well as a variety of patient-related factors that may influence recurrence risk. Clinical and therapeutic approaches are also reviewed, with a focus on patient surveillance and the implementation of extended endocrine therapy in the context of late-recurrence prevention. Understanding and treating late recurrence in estrogen receptor–positive breast cancer is a major unmet clinical need. A concerted effort of basic and clinical research is required to confront late recurrence and improve disease management and patient survival.

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