Biology subjects

Huhtinen, K.

Publications and source records attributed to Huhtinen, K..

7 recordsLinked to original sources

bioRxiv2023

Deciphering Cancer Genomes with GenomeSpy: A Grammar-Based Visualization Toolkit

BackgroundVisualization is an indispensable facet of genomic data analysis. Despite the abundance of specialized visualization tools, there remains a distinct need for tailored solutions. However, their implementation typically requires extensive programming expertise from bioinformaticians and software developers, especially when building interactive applications. Toolkits based on visualization grammars offer a more accessible, declarative way to author new visualizations. Nevertheless, current grammar-based solutions fall short in adequately supporting the interactive analysis of large data sets with extensive sample collections, a pivotal task often encountered in cancer research. ResultsWe present GenomeSpy, a grammar-based toolkit for authoring tailored, interactive visualizations for genomic data analysis. Users can implement new visualization designs with little effort by using combinatorial building blocks that are put together with a declarative language. These fully customizable visualizations can be embedded in web pages or end-user-oriented applications. The toolkit also includes a fully customizable but user-friendly application for analyzing sample collections, which may comprise genomic and clinical data. Findings can be bookmarked and shared as links that incorporate provenance information. A distinctive element of GenomeSpys architecture is its effective use of the graphics processing unit (GPU) in all rendering. GPU usage enables a high frame rate and smoothly animated interactions, such as navigation within a genome. We demonstrate the utility of GenomeSpy by characterizing the genomic landscape of 753 ovarian cancer samples from patients in the DECIDER clinical trial. Our results expand the understanding of the genomic architecture in ovarian cancer, particularly the diversity of chromosomal instability. We also show how GenomeSpy enabled the discovery of clinically actionable genomic aberrations. ConclusionsGenomeSpy is a visualization toolkit applicable to a wide range of tasks pertinent to genome analysis. It offers high flexibility and exceptional performance in interactive analysis. The toolkit is open source with an MIT license, implemented in JavaScript, and available at https://genomespy.app/.

bioinformatics↗

bioRxiv2022

L1 retrotransposition is regulated post-transcriptionally In High-Grade Serous Ovarian Cancer

L1 retrotransposons are the only protein-coding active transposable elements in the human genome. Although silenced during normal conditions, they are highly expressed in human epithelial cancers including high-grade serous ovarian cancer (HGSC), where they transcribe to form L1 mRNA and subsequently integrate into the genome by a process called retrotransposition. Despite of high L1 protein expression in the earliest phases of HGSC, these tumors do not accrue many somatic L1 insertions. To understand this unexplained disconnect, we monitored the transcription and retrotransposition activity of two frequently expressed retrotransposition-competent (RC)-L1 (RC-L1) in 64 clinical tumor specimens from 34 HGSC patients and found that despite the presence of RC-L1 mRNA, a third of samples did not acquire somatic L1 insertions. In addition to high inter-patient variability in retrotransposition frequency, there was remarkable intra-patient heterogeneity in L1 insertion patterns between tumor sites, indicating that L1 retrotransposition is highly dynamic in vivo. Comparison of genomic and transcriptomic features of L1-null tumors with L1-high tumors (those with [≥]5 somatic L1 insertions) showed that retrotransposition was favored by increased rate of cell proliferation.

cancer biology↗

bioRxiv2022

Evolutionary states and trajectories characterized by distinct pathways stratify ovarian high-grade serous carcinoma patients

Ovarian high-grade serous carcinoma (HGSC) is typically diagnosed at an advanced stage, with multiple genetically heterogeneous clones existing in the tumors long before therapeutic intervention. Herein we characterized HGSC evolutionary states using whole-genome sequencing data from 214 samples of 55 HGSC patients in the prospective, longitudinal, multiregion DECIDER study. Comparison of the tissues revealed that site-of-origin samples have 70% more unique clones than the metastatic tumors or ascites. By integrating clonal composition and topology of HGSC tumors we discovered three evolutionary states that represent a continuum from genomically highly variable to stable tumors with significant association to treatment response. The states and their evolutionary trajectories were characterized by unique, targetable pathways, which were validated with RNA-seq data. Our study reveals that genomic heterogeneity is unaffected by the current standard-of-care and pinpoints effective treatment targets for each group. All genomics data are available via an interactive visualization platform for rapid exploration.

cancer biology↗

bioRxiv2022

A platform for efficient establishment, expansion and drug response profiling of high-grade serous ovarian cancer organoids

The broad research use of organoids from high-grade serous ovarian carcinoma (HGSC) has been hampered by low culture success rates and limited availability of fresh tumor material. Here we describe a method for generation and long-term expansion of HGSC organoids with efficacy markedly improved over previous reports (55% vs. 23-38%). We established organoids from cryopreserved material, demonstrating the feasibility of using viably biobanked tissue for HGSC organoid derivation. Genomic, histologic and single-cell transcriptomic analyses revealed that organoids recapitulated genetic and phenotypic features of original tumors. Organoid drug responses correlated with clinical treatment outcomes, although in culture conditions-dependent manner and only in organoids maintained in human plasma-like medium (HPLM). Organoids from consenting patients are available to the research community through a public biobank and organoid genomic data explorable through an interactive online tool. Taken together, this resource facilitates the application of HGSC organoids in basic and translational ovarian cancer research.

cancer biology↗

bioRxiv2021

Ovarian cancers with low CIP2A tumor expression constitute an APR-246 sensitive disease subtype

Identification of ovarian cancer (OvCa) patient subpopulations with increased sensitivity to targeted therapies could offer significant clinical benefit. We report that 22% of the high grade OvCa tumors at diagnosis express CIP2A oncoprotein at low levels. CIP2Alow OvCa tumors have significantly lower likelihood of disease relapse after standard chemotherapy, but yet a portion of relapsed tumors retain their CIP2Alow phenotype. We further discover that reactive oxygen species (ROS) inducing compound APR-246 (PRIMA-1Met/Eprenetapopt), currently in clinical development, preferentially kill CIP2Alow OvCa cells across multiple chemotherapy resistant cell lines. Consistent with CIP2Alow OvCa subtype in humans, CIP2A is dispensable for development of MISIIR-TAg-driven mouse OvCa tumors. Nevertheless, CIP2A deficient OvCa tumor cells from MISIIR-TAg mice displayed APR-246 hypersensitivity both in vitro and in vivo. Mechanistically, the lack of CIP2A expression hypersensitizes the OvCa cells to APR-246 by inhibition of NF-kB activity. Accordingly, combination of APR-246 and Nf-kB inhibitor compounds strongly synergized in killing of CIP2A positive OvCa cells. Collectively, we discover low CIP2A expression as a vulnerability for APR-246 in OvCa. The results warrant consideration of clinical testing of APR-246 for CIP2Alow OvCa tumor subtype patients, and reveal CIP2A as a candidate APR-246 combination therapy target.

cancer biology↗

bioRxiv2020

Analysis of single-cell RNA-seq data from ovarian cancer samples before and after chemotherapy links stress-related transcriptional profile withchemotherapy resistance

Chemotherapy resistance is the greatest contributor to cancer mortality and the most urgent unmet challenge in oncology. In order to reveal transcriptomics changes due to platinum-based chemotherapy we analyzed single-cell RNA-seq data from fresh tissue samples taken at the time of diagnosis and after neoadjuvant chemotherapy from 11 high-grade serous ovarian cancer (HGSOC) patients. With a novel clustering method accounting for patient-specific variability and technical confounders, we identified 12 clusters. Of these, a stress-related transcriptional profile was enriched during chemotherapy and associated significantly to poor progression-free survival (PFS) and disease-free interval (DFI) in deconvoluted bulk RNA-seq data analysis of treatment-naive samples in TCGA cohort. Pan-cancer cell line analysis suggests that patients with high stress-related transcriptional profile may benefit from MEK1/2 inhibitors instead of platinum. Further, high proportion of stromal components and high interaction score between tumor and stromal suggest the tumor cells with high-stress profile actively interact with and potentially recruit stromal cells to their microenvironment already prior to chemotherapy, potentially facilitating protection from chemotherapeutic treatments. In summary, we have identified a stress-related transcriptional profile, which is present at the time of diagnosis, enriched during platinum treatment, independent predictor for poor PFS and DFI, and, based on in vitro data, targetable with MEK1/2 inhibitors. Translational relevanceWe discovered a stress-related transcriptional profile that is significantly enriched in fresh tissue samples after chemotherapy and is significantly associated with poor progression-free survival in an independent patient cohort. The survival association is independent of age, tumor purity or BRCAness. Therefore, this chemotherapy resistance associated profile is intrinsic and could thus be targeted already in treatment-naive patients. The translation potential of the stress-related transcriptomics profile was further supported by pan-cancer cell line analysis that showed that cell lines with high stress-related transcriptional profile are not affected by platinum, corroborating our results, whereas they were more sensitive to MEK1/2 inhibitors. Taken together, the stress-related transcriptional profile, quantifiable with a set of 35 marker genes, provides a basis for improved prediction of platinum response as well as novel avenues to treat this patient group more effectively.

bioinformatics↗

bioRxiv2019

PRISM: Recovering cell type specific expression profilesfrom composite RNA-seq data

A major challenge in analyzing cancer patient transcriptomes is that the tumors are inherently heterogeneous and evolving. We analyzed 214 bulk RNA samples of a longitudinal, prospective ovarian cancer cohort and found that the sample composition changes systematically due to chemotherapy and between the anatomical sites, preventing direct comparison of treatment-naive and treated samples. To overcome this, we developed PRISM, a latent statistical framework to simultaneously extract the sample composition and cell type specific whole-transcriptome profiles adapted to each individual sample. Our results indicate that the PRISM-derived composition-free transcriptomic profiles and signatures derived from them predict the patient response better than the composite raw bulk data. We validated our findings in independent ovarian cancer and melanoma cohorts, and verified that PRISM accurately estimates the composition and cell type specific expression through whole-genome sequencing and RNA in situ hybridization experiments. PRISM is freely available with full source code and documentation.

bioinformatics↗