Meta-analysis of cancer triploidy : Rearrangements of genome complements in male human tumors are characterized by XXY karyotypes

Funding Information: Funding: This work has been supported by a grant of the European Regional Development Fund (ERDF) project No. 1.1.1.1/18/A/099 and Alfred Raisner memorial scholarship to N.M.V. Publisher Copyright: © 2019 by the authors.Triploidy in cancer is associated with poor prognosis, but its origins remain unclear. Here, we attempted to differentiate between random chromosomal and whole-genome origins of cancer triploidy. In silico meta-analysis was performed on 15 male malignant and five benign tumor cohorts (2928 karyotypes) extracted from the Mitelman Database, comparing their ploidy and combinations of sex chromosomes. A distinct near-triploid fraction was observed in all malignant tumor types, and was especially high in seminoma. For all tumor types, X-chromosome doubling, predominantly observed as XXY, correlated strongly with the near-triploid state (r ≈ 0.9, p < 0.001), negatively correlated with near-diploidy, and did not correlate with near-tetraploidy. A smaller near-triploid component with a doubled X-chromosome was also present in three of the five benign tumor types, especially notable in colon adenoma. Principal component analysis revealed a non-random correlation structure shaping the X-chromosome disomy distribution across all tumor types. We suggest that doubling of the maternal genome followed by pedogamic fusion with a paternal genome (a possible mimic of the fertilization aberration, 69, XXY digyny) associated with meiotic reprogramming may be responsible for the observed rearrangements of genome complements leading to cancer triploidy. The relatively frequent loss of the Y-chromosome results as a secondary factor from chromosome instability.publishersversionPeer reviewe

Emerging blood-based biomarkers for detection of gastric cancer

Publisher Copyright: © 2015 Baishideng Publishing Group Inc. All rights reserved.Early detection and efficient monitoring of tumor dynamics are prerequisites for reducing disease burden and mortality, and for improving the management of patients with gastric cancer (GC). Blood-based biomarker assays for the detection of early-stage GC could be of great relevance both for population-wide or risk groupbased screening programs, while circulating biomarkers that reflect the genetic make-up and dynamics of the tumor would allow monitoring of treatment efficacy, predict recurrences and assess the genetic heterogeneity of the tumor. Recent research to identify blood-based biomarkers of GC has resulted in the identification of a wide variety of cancer-associated molecules, including various proteins, autoantibodies against tumor associated antigens, cell-free DNA fragments, mRNAs and various non-coding RNAs, circulating tumor cells and cancer-derived extracellular vesicles. Each type of these biomarkers provides different information on the disease status, has different advantages and disadvantages, and distinct clinical usefulness. In the current review, we summarize the recent developments in blood-based GC biomarker discovery, discuss the origin of various types of biomarkers and their clinical usefulness and the technological challenges in the development of biomarker assays for clinical use.publishersversionPeer reviewe

The postmedieval Latvian oral microbiome in the context of modern dental calculus and modern dental plaque microbial profiles

Funding Information: Funding: This work was supported by ERDF grant number 1.1.1.1/16/A/101 (to R.R. and G.G.). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Recent advantages in paleomicrobiology have provided an opportunity to investigate the composition of ancient microbial ecologies. Here, using metagenome analysis, we investigated the microbial profiles of historic dental calculus retrieved from archaeological human remains from postmedieval Latvia dated 16–17th century AD and examined the associations of oral taxa and microbial diversity with specific characteristics. We evaluated the preservation of human oral micro-biome patterns in historic samples and compared the microbial composition of historic dental cal-culus, modern human dental plaque, modern human dental calculus samples and burial soil micro-biota. Overall, the results showed that the majority of microbial DNA in historic dental calculus originated from the oral microbiome with little impact of the burial environment. Good preservation of ancient DNA in historical dental calculus samples has provided reliable insight into the composition of the oral microbiome of postmedieval Latvian individuals. The relative stability of the classifiable oral microbiome composition was observed. Significant differences between the micro-biome profiles of dental calculus and dental plaque samples were identified, suggesting microbial adaptation to a specific human body environment.publishersversionPeer reviewe

Effects of urinary extracellular vesicles from prostate cancer patients on the transcriptomes of cancer-associated and normal fibroblasts

Funding Information: This work was funded by the Latvian Council of Science, Project No. lzp-2018/0269. Publisher Copyright: © 2022, The Author(s).Background: Increasing evidence suggests that cancer-derived extracellular vesicles (EVs) alter the phenotype and functions of fibroblasts and trigger the reprogramming of normal fibroblasts into cancer-associated fibroblasts (CAFs). Here, we for the first time studied the effects of urinary EVs from PC patients and healthy males on the transcriptional landscape of prostate CAFs and normal foreskin fibroblasts. Methods: Patient-derived prostate fibroblast primary cultures PCF-54 and PCF-55 were established from two specimens of PC tissues. EVs were isolated from urine samples of 3 patients with PC and 2 healthy males and used for the treatment of prostate fibroblast primary cultures and normal foreskin fibroblasts. The EV-treated fibroblasts were subjected to RNA sequencing analysis. Results: RNA sequencing analysis showed that the fibroblast cultures differed significantly in their response to urinary EVs. The transcriptional response of foreskin fibroblasts to the urinary EVs isolated from PC patients and healthy controls was very similar and mostly related to the normal functions of fibroblasts. On the contrary, PCF-54 cells responded very differently - EVs from PC patients elicited transcriptional changes related to the regulation of the cell division and chromosome segregation, whereas EVs from healthy males affected mitochondrial respiration. In PCF-55 cells, EVs from both, PC-patients and controls induced the expression of a number of chemokines such as CCL2, CCL13, CXCL1, CXCL8, whereas pathways related to regulation of apoptotic signaling and production of cell adhesion molecules were triggered specifically by EVs from PC patients. Conclusion: This study demonstrates that urinary EVs from PC patients and healthy controls elicit distinct transcriptional responses in prostate CAFs and supports the idea that EVs contribute to the generation of functional heterogeneity of CAFs. Moreover, this study suggests that the changes in the gene expression pattern in EV recipient cells might serve as a novel type of functional cancer biomarkers.publishersversionPeer reviewe

Role of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment Resistance

Funding Information: Funding: This research was funded by the University of Latvia Foundation’s PhD Student Scholarship in the Natural and Life Sciences (awarded to N.M.V.), a grant from the European Regional Development Fund (ERDF) projects No. 1.1.1.2/VIAA/3/19/463 for K.S. and ERDF 099 project No. 1.1.1.1/18/A/099) for D.P. and J.E. Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Here, we review the role of the circadian clock (CC) in the resistance of cancer cells to genotoxic treatments in relation to whole-genome duplication (WGD) and telomere-length regulation. The CC drives the normal cell cycle, tissue differentiation, and reciprocally regulates telomere elongation. However, it is deregulated in embryonic stem cells (ESCs), the early embryo, and cancer. Here, we review the DNA damage response of cancer cells and a similar impact on the cell cycle to that found in ESCs—overcoming G1/S, adapting DNA damage checkpoints, tolerating DNA damage, coupling telomere erosion to accelerated cell senescence, and favouring transition by mitotic slippage into the ploidy cycle (reversible polyploidy). Polyploidy decelerates the CC. We report an intriguing positive correlation between cancer WGD and the deregulation of the CC assessed by bioinformatics on 11 primary cancer datasets (rho = 0.83; p < 0.01). As previously shown, the cancer cells undergoing mitotic slippage cast off telomere fragments with TERT, restore the telomeres by ALT-recombination, and return their depolyploidised offspring to telomerase-dependent regulation. By reversing this polyploidy and the CC “death loop”, the mitotic cycle and Hayflick limit count are thus again renewed. Our review and proposed mechanism support a life-cycle concept of cancer and highlight the perspective of cancer treatment by differentiation.publishersversionPeer reviewe

The Price of Human Evolution : Cancer-Testis Antigens, the Decline in Male Fertility and the Increase in Cancer

Publisher Copyright: © 2023 by the authors.The increasing frequency of general and particularly male cancer coupled with the reduction in male fertility seen worldwide motivated us to seek a potential evolutionary link between these two phenomena, concerning the reproductive transcriptional modules observed in cancer and the expression of cancer-testis antigens (CTA). The phylostratigraphy analysis of the human genome allowed us to link the early evolutionary origin of cancer via the reproductive life cycles of the unicellulars and early multicellulars, potentially driving soma-germ transition, female meiosis, and the parthenogenesis of polyploid giant cancer cells (PGCCs), with the expansion of the CTA multi-families, very late during their evolution. CTA adaptation was aided by retrovirus domestication in the unstable genomes of mammals, for protecting male fertility in stress conditions, particularly that of humans, as compensation for the energy consumption of a large complex brain which also exploited retrotransposition. We found that the early and late evolutionary branches of human cancer are united by the immunity-proto-placental network, which evolved in the Cambrian and shares stress regulators with the finely-tuned sex determination system. We further propose that social stress and endocrine disruption caused by environmental pollution with organic materials, which alter sex determination in male foetuses and further spermatogenesis in adults, bias the development of PGCC-parthenogenetic cancer by default.Peer reviewe

Comprehensive characterization of RNA cargo of extracellular vesicles in breast cancer patients undergoing neoadjuvant chemotherapy

Funding Information: This work was funded by the ERDF project No. 1.1.1.1/18/A/084. Publisher Copyright: Copyright © 2022 Sadovska, Zayakin, Eglītis, Endzeliņš, Radoviča-Spalviņa, Avotiņa, Auders, Keiša, Liepniece-Karele, Leja, Eglītis and Linē.Extracellular vesicles (EVs) are g7aining increased attention as carriers of cancer-derived molecules for liquid biopsies. Here, we studied the dynamics of EV levels in the plasma of breast cancer (BC) patients undergoing neoadjuvant chemotherapy (NAC) and explored the relevance of their RNA cargo for the prediction of patients’ response to the therapy. EVs were isolated from serial blood samples collected at the time of diagnosis, at the end of NAC, and 7 days, 6, and 12 months after the surgery from 32 patients with locally advanced BC, and 30 cancer-free healthy controls (HCs) and quantified by nanoparticle tracking analysis. The pre-treatment levels of EVs in BC patients were higher than in HCs, significantly increased during the NAC and surgery, and decreased to the levels found in HCs 6 months after surgery, thus showing that a substantial fraction of plasma EVs in BC patients are produced due to the disease processes and treatment. RNA sequencing analysis revealed that the changes in the EV levels were associated with the alterations in the proportions of various RNA biotypes in EVs. To search for RNA biomarkers that predict response to the NAC, patients were dichotomized as responders and non-responders based on Miller-Payne grades and differential expression analyses were carried out between responders and non-responders, and HCs. This resulted in the identification of 6 miRNAs, 4 lncRNAs, and 1 snoRNA that had significantly higher levels in EVs from non-responders than responders at the time of diagnosis and throughout the NAC, and significantly lower levels in HCs, thus representing biomarkers for the prediction of response to NAC at the time of diagnosis. In addition, we found 14 RNAs representing piRNA, miRNA, lncRNA, snoRNA, and snRNA biotypes that were induced by NAC in non-responders and 2 snoRNAs and 1 piRNA that were induced by NAC in patients with early disease progression, thus warranting further functional studies on their role in chemoresistance and metastasis.publishersversionPeer reviewe

sRNAflow: A Tool for the Analysis of Small RNA-Seq Data

The analysis of small RNA sequencing data across a range of biofluids is a significant research area, given the diversity of RNA types that hold potential diagnostic, prognostic, and predictive value. The intricate task of segregating the complex mixture of small RNAs from both human and other species, including bacteria, fungi, and viruses, poses one of the most formidable challenges in the analysis of small RNA sequencing data, currently lacking satisfactory solutions. This study introduces sRNAflow, a user-friendly bioinformatic tool with a web interface designed for the analysis of small RNAs obtained from biological fluids. Tailored to the unique requirements of such samples, the proposed pipeline addresses various challenges, including filtering potential RNAs from reagents and environment, classifying small RNA types, managing small RNA annotation overlap, conducting differential expression assays, analysing isomiRs, and presenting an approach to identify the sources of small RNAs within samples. sRNAflow also encompasses an alternative alignment-free analysis of RNA-seq data, featuring clustering and initial RNA source identification using BLAST. This comprehensive approach facilitates meaningful comparisons of results between different analytical methods

Inferring Optimal Kernel Hyperparameters Using Cox Regression for Cancer Outcome Prediction

Modern bioinformatics offers more and more offending challenges that came from highly through-output biomedical and genome data (microarrays) received by immunoscreening of cancer patients and healthy donors. Highly dimensional and much less impressing in sample size data sets experiencing unpredictable and unstable distributions for their covariates make it impossible to use lots of classifiers and regression tools that confirmed their efficiency for more simple and controllable tasks. Improvement of kernel methods for Support Vector Machine (SVM) classification in cancer diagnostics is the main intent of this paper. Unfortunately microarray data causes significant decay in effect of structured risk minimization on examined data. This paper proposes new more effective method for learning SVM kernel on noisy and unpredictable by their nature data sources. As result of this paper we have inferred new method for learning optimal kernel hyperparameters using Cox regression

Antigen Reduction Applied to Support Vector Machine Classification for Melanoma-Related Diagnostics

This paper discusses the application of Support Vector Machines (SVM) to classification of autoantibody profiles with a large number of antigens (attributes) and effectiveness gain produced by the proposed antigen reduction methods. As a result of research effort, a new biologically robust and meaningful method on selecting antigens with high expression level in cancer patients is introduced. The proposed antigen reduction method improves initial full-range SVM model and clearly proves the necessity for more careful attribute selection in classification tasks performed by SVM. The proposed method can also be used for novel biomarker discovery and can give a necessary insight into uncovered connections between already known and newly discovered CT (cancer testis) biomarkers