Intra-tumor heterogeneity is known to contribute to cancer complexity and drug resistance. Understanding the number of distinct subclones and the evolutionary relationships between them is ...scientifically and clinically very important and still a challenging problem.
In this paper, we present BAMSE (BAyesian Model Selection for tumor Evolution), a new probabilistic method for inferring subclonal history and lineage tree reconstruction of heterogeneous tumor samples. BAMSE uses somatic mutation read counts as input and can leverage multiple tumor samples accurately and efficiently. In the first step, possible clusterings of mutations into subclones are scored and a user defined number are selected for further analysis. In the next step, for each of these candidates, a list of trees describing the evolutionary relationships between the subclones is generated. These trees are sorted by their posterior probability. The posterior probability is calculated using a Bayesian model that integrates prior belief about the number of subclones, the composition of the tumor and the process of subclonal evolution. BAMSE also takes the sequencing error into account. We benchmarked BAMSE against state of the art software using simulated datasets.
In this work we developed a flexible and fast software to reconstruct the history of a tumor's subclonal evolution using somatic mutation read counts across multiple samples. BAMSE software is implemented in Python and is available open source under GNU GLPv3 at https://github.com/HoseinT/BAMSE .
Around 75% of breast cancer (BC) patients have tumors expressing the predictive biomarker estrogen receptor α (ER) and are offered endocrine therapy. One-third eventually develop endocrine ...resistance, a majority with retained ER expression. Mutations in the phosphatidylinositol bisphosphate 3-kinase (PI3K) catalytic subunit encoded by PIK3CA is a proposed resistance mechanism and a pharmacological target in the clinical setting. Here we explore the frequency of PIK3CA mutations in endocrine-resistant BC before and during treatment and correlate to clinical features. Patients with ER-positive (ER +), human epidermal growth factor receptor 2 (HER2)-negative primary BC with an ER + relapse within 5 years of ongoing endocrine therapy were retrospectively assessed. Tissue was collected from primary tumors (n = 58), relapse tumors (n = 54), and tumor-free lymph nodes (germline controls, n = 62). Extracted DNA was analyzed through panel sequencing. Somatic mutations were observed in 50% (31/62) of the patients, of which 29% occurred outside hotspot regions. The presence of PIK3CA mutations was significantly associated with nodal involvement and mutations were more frequent in relapse than primary tumors. Our study shows the different PIK3CA mutations in endocrine-resistant BC and their fluctuations during therapy. These results may aid investigations of response prediction, facilitating research deciphering the mechanisms of endocrine resistance.
Early detection of microaneurysms (MAs), the first sign of Diabetic Retinopathy (DR), is an essential first step in automated detection of DR to prevent vision loss and blindness. This study presents ...a novel and different algorithm for automatic detection of MAs in fluorescein angiography (FA) fundus images, based on Radon transform (RT) and multi-overlapping windows. This project addresses a novel method, in detection of retinal land marks and lesions to diagnose the DR. At the first step, optic nerve head (ONH) was detected and masked. In preprocessing stage, top-hat transformation and averaging filter were applied to remove the background. In main processing section, firstly, we divided the whole preprocessed image into sub-images and then segmented and masked the vascular tree by applying RT in each sub-image. After detecting and masking retinal vessels and ONH, MAs were detected and numbered by using RT and appropriated thresholding. The results of the proposed method were evaluated on three different retinal images databases, the Mashhad Database with 120 FA fundus images, Second Local Database from Tehran with 50 FA retinal images and a part of Retinopathy Online Challenge (ROC) database with 22 images. Automated DR detection demonstrated a sensitivity and specificity of 94% and 75% for Mashhad database and 100% and 70% for the Second Local Database respectively.
•Algorithm is not based on morphological functions in order to find microaneurysms.•Algorithm can find microaneurysms for evaluating diabetic retinopathy.•Algorithm is robust to noise because of its linear integral transformation concept.•Identifying the retinal landmarks improves the classification of microaneurysms.
Spatial transcriptomics maps gene expression across tissues, posing the challenge of determining the spatial arrangement of different cell types. However, spatial transcriptomics spots contain ...multiple cells. Therefore, the observed signal comes from mixtures of cells of different types. Here, we propose an innovative probabilistic model, Celloscope, that utilizes established prior knowledge on marker genes for cell type deconvolution from spatial transcriptomics data. Celloscope outperforms other methods on simulated data, successfully indicates known brain structures and spatially distinguishes between inhibitory and excitatory neuron types based in mouse brain tissue, and dissects large heterogeneity of immune infiltrate composition in prostate gland tissue.
Functional characterization of the cancer clones can shed light on the evolutionary mechanisms driving cancer's proliferation and relapse mechanisms. Single-cell RNA sequencing data provide grounds ...for understanding the functional state of cancer as a whole; however, much research remains to identify and reconstruct clonal relationships toward characterizing the changes in functions of individual clones. We present PhylEx that integrates bulk genomics data with co-occurrences of mutations from single-cell RNA sequencing data to reconstruct high-fidelity clonal trees. We evaluate PhylEx on synthetic and well-characterized high-grade serous ovarian cancer cell line datasets. PhylEx outperforms the state-of-the-art methods both when comparing capacity for clonal tree reconstruction and for identifying clones. We analyze high-grade serous ovarian cancer and breast cancer data to show that PhylEx exploits clonal expression profiles beyond what is possible with expression-based clustering methods and clear the way for accurate inference of clonal trees and robust phylo-phenotypic analysis of cancer.
Copy number variations (CNVs) are common genetic alterations in tumour cells. The delineation of CNVs holds promise for enhancing our comprehension of cancer progression. Moreover, accurate inference ...of CNVs from single-cell sequencing data is essential for unravelling intratumoral heterogeneity. However, existing inference methods face limitations in resolution and sensitivity.
To address these challenges, we present CopyVAE, a deep learning framework based on a variational autoencoder architecture. Through experiments, we demonstrated that CopyVAE can accurately and reliably detect CNVs from data obtained using single-cell RNA sequencing. CopyVAE surpasses existing methods in terms of sensitivity and specificity. We also discussed CopyVAE's potential to advance our understanding of genetic alterations and their impact on disease advancement.
CopyVAE is implemented and freely available under MIT license at https://github.com/kurtsemih/copyVAE.
The spatial distribution of lymphocyte clones within tissues is critical to their development, selection, and expansion. We have developed spatial transcriptomics of variable, diversity, and joining ...(VDJ) sequences (Spatial VDJ), a method that maps B cell and T cell receptor sequences in human tissue sections. Spatial VDJ captures lymphocyte clones that match canonical B and T cell distributions and amplifies clonal sequences confirmed by orthogonal methods. We found spatial congruency between paired receptor chains, developed a computational framework to predict receptor pairs, and linked the expansion of distinct B cell clones to different tumor-associated gene expression programs. Spatial VDJ delineates B cell clonal diversity and lineage trajectories within their anatomical niche. Thus, Spatial VDJ captures lymphocyte spatial clonal architecture across tissues, providing a platform to harness clonal sequences for therapy.
Cell types can be classified according to shared patterns of transcription. Non-genetic variability among individual cells of the same type has been ascribed to stochastic transcriptional bursting ...and transient cell states. Using high-coverage single-cell RNA profiling, we asked whether long-term, heritable differences in gene expression can impart diversity within cells of the same type. Studying clonal human lymphocytes and mouse brain cells, we uncovered a vast diversity of heritable gene expression patterns among different clones of cells of the same type in vivo. We combined chromatin accessibility and RNA profiling on different lymphocyte clones to reveal thousands of regulatory regions exhibiting interclonal variation, which could be directly linked to interclonal variation in gene expression. Our findings identify a source of cellular diversity, which may have important implications for how cellular populations are shaped by selective processes in development, aging, and disease. A record of this paper’s transparent peer review process is included in the supplemental information.
•Many genes exhibit clone-specific patterns of expression within cells of the same type•Genes may exhibit distinct clonal expression patterns that persist for years in vivo•Clone-specific gene expression is determined by variable chromatin accessibility•Clone-specific gene expression is shown in human and mouse cells of different types
Mold et al. show that within a cell type, clonally related cells exhibit heritable differences in gene expression that persist for years in vivo. This form of memory impacts thousands of genes and is found in human and mouse cells of the immune and central nervous system.
Early detection of microaneurysms (MAs), the first sign of Diabetic Retinopathy (DR), is an essential first step in automated detection of DR to prevent vision loss and blindness. This study presents ...a novel and different algorithm for automatic detection of MAs in fluorescein angiography (FA) fundus images, based on Radon transform (RT) and multi-overlapping windows. This project addresses a novel method, in detection of retinal land marks and lesions to diagnose the DR. At the first step, optic nerve head (ONH) was detected and masked. In preprocessing stage, top-hat transformation and averaging filter were applied to remove the background. In main processing section, firstly, we divided the whole preprocessed image into sub-images and then segmented and masked the vascular tree by applying RT in each sub-image. After detecting and masking retinal vessels and ONH, MAs were detected and numbered by using RT and appropriated thresholding. The results of the proposed method were evaluated reported on three different retinal images databases, the Mashhad Database with 120 FA fundus images, Second Local Database from Tehran with 50 FA retinal images and a part of Retinopathy Online Challenge (ROC) database with 22 images. Automated DR detection demonstrated a sensitivity and specificity of 94% and 75% for Mashhad database and 100% and 70% for the Second Local Database respectively.
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