Integrated whole exome and transcriptome sequencing in cholesterol metabolism in melanoma: systematic review

Background: Melanoma is a highly malignant form of skin cancer that exhibits remarkable metabolic adaptability. Melanoma cells exhibit the capacity to adapt to specific conditions of the tumor microenvironment through the utilization of diverse energy sources, thereby facilitating the growth and advancement of the tumor. One of the notable characteristics of metabolic reprogramming is the heightened rate of lipid synthesis. This review was conducted to illustrate how the integration of whole exom and transcriptome sequencing will enhance the detection of the effect of cholesterol metabolism in melanoma. Methods: The Cochrane database, Embase, PubMed, SCOPUS, Google Scholar, Ovid, and other databases were thoroughly searched for works addressing integrated whole exome and transcriptome sequencing in cholesterol metabolism in melanoma. Skin malignancy, melanoma progression, transcriptome sequencing, whole exome sequencing, transcriptome sequencing by RNA sequencing, and integrated transcriptome and whole exome sequencing were the key phrases employed. This article underwent a phased search for pertinent literature using a staged literature search methodology. Each section's relevant papers were identified and summarized independently. The results have been condensed and narratively given in the pertinent sections of this thorough assessment. Results: DNA-based analysis has proven to be ineffective in identifying numerous mutations that have an impact on splicing or gene expression. RNA-Sequencing, when combined with suitable bioinformatics, offers a reliable method for detecting supplementary mutations that aid in the genetic diagnosis of geno-dermatoses. Therefore, clinical RNA-Sequencing expands the scope of molecular diagnostics for rare genodermatoses, and it has the potential to serve as a dependable initial diagnostic method for expanding mutation databases in individuals with inheritable skin conditions. Conclusion: The integration of patient-specific tumor RNA-sequencing and tumor DNA whole-exome sequencing (WES) would potentially enhance mutation detection capabilities compared to relying solely on DNA-WES.

Interplay between the DNA damage response and the life cycle of DNA tumor viruses.

Approximately 20 % of human cancers are associated with virus infection. DNA tumor viruses can induce tumor formation in host cells by disrupting the cell's DNA replication and repair mechanisms. Specifically, these viruses interfere with the host cell's DNA damage response (DDR), which is a complex network of signaling pathways that is essential for maintaining the integrity of the genome. DNA tumor viruses can disrupt these pathways by expressing oncoproteins that mimic or inhibit various DDR components, thereby promoting genomic instability and tumorigenesis. Recent studies have highlighted the molecular mechanisms by which DNA tumor viruses interact with DDR components, as well as the ways in which these interactions contribute to viral replication and tumorigenesis. Understanding the interplay between DNA tumor viruses and the DDR pathway is critical for developing effective strategies to prevent and treat virally associated cancers. In this review, we discuss the current state of knowledge regarding the mechanisms by which human papillomavirus (HPV), merkel cell polyomavirus (MCPyV), Kaposi's sarcoma-associated herpesvirus (KSHV), and Epstein-Barr virus (EBV) interfere with DDR pathways to facilitate their respective life cycles, and the consequences of such interference on genomic stability and cancer development.

Special Issue "New Frontiers in Small DNA Virus Research".

Scientific progress in understanding, preventing, treating, and managing viral infections and associated diseases exemplifies the extent to which research on small DNA tumor viruses has impacted human health [...].

The landscape of viral associations in human cancers.

Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, for which whole-genome and-for a subset-whole-transcriptome sequencing data from 2,658 cancers across 38 tumor types was aggregated, we systematically investigated potential viral pathogens using a consensus approach that integrated three independent pipelines. Viruses were detected in 382 genome and 68 transcriptome datasets. We found a high prevalence of known tumor-associated viruses such as Epstein-Barr virus (EBV), hepatitis B virus (HBV) and human papilloma virus (HPV; for example, HPV16 or HPV18). The study revealed significant exclusivity of HPV and driver mutations in head-and-neck cancer and the association of HPV with APOBEC mutational signatures, which suggests that impaired antiviral defense is a driving force in cervical, bladder and head-and-neck carcinoma. For HBV, HPV16, HPV18 and adeno-associated virus-2 (AAV2), viral integration was associated with local variations in genomic copy numbers. Integrations at the TERT promoter were associated with high telomerase expression evidently activating this tumor-driving process. High levels of endogenous retrovirus (ERV1) expression were linked to a worse survival outcome in patients with kidney cancer.

Choosing the right path: membrane trafficking and infectious entry of small DNA tumor viruses.

To infect mammalian cells, all infectious viruses must cross a common set of biophysical membrane barriers to gain access to the cell. The virus capsid proteins attach to a host cell, become endocytosed, and traffic the viral genome to sites of replication. To do this they must interact with the membrane-confined organelles that control endocytosis, endosomal sorting, processing, and degradation of biological molecules. In this review, we highlight some recent advances in our understanding of the mechanisms that small non-enveloped DNA tumor viruses, such as Human Papillomavirus (HPV) and Polyomaviruses (PyV) employ to attain infectious entry. These viruses exploit different pathways to mediate entry, uncoating and subsequent transport to the nucleus via the Trans Golgi Network (TGN) or the Endoplasmic Reticulum (ER). Understanding how the viral capsid proteins interact with cellular membranous organelles sheds light on the novel ways by which viruses can hi-jack endocytic transport pathways and provides unique insights into how the highly complex machinery controlling cargo fate determination is regulated within the cell.

Small size, big impact: how studies of small DNA tumour viruses revolutionized biology.

Intense study of three families of small tumour viruses with double-stranded DNA genomes, carried out over 50 years, has had a profound impact on biology. The polyomaviruses and papillomaviruses have circular DNA genomes of approximately 5000 and approximately 8000 base-pairs, respectively, and thus encode only a handful of proteins. Adenoviruses have a 32 000-base-pair linear DNA genome, still far smaller than the three billion-base-pair human genome. Members of all three virus families can transform cultured cells to tumorigenicity and cause tumours in experimental animals. Several human papillomaviruses (HPV) and at least one polyomavirus are oncogenic in humans. Early analysis of these viruses, particularly the polyomavirus SV40, led to the development of many powerful experimental tools, including restriction mapping, site-directed mutagenesis, gene transfer, genome-wide sequencing and recombinant DNA. These tools have since been refined and used to study cellular genes, revolutionizing our understanding of biology. These tools were also applied to the viruses themselves. Analysis of the virus life cycle and the effect of these viruses on cells yielded important new insights into many aspects of gene expression, DNA replication, cell biology and carcinogenesis. These studies have also led to vaccination strategies to prevent infection and cancer in humans. This article is part of the theme issue 'Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.

DNA Tumor Viruses and Their Contributions to Molecular Biology.

This summer marks the 51st anniversary of the DNA tumor virus meetings. Scientists from around the world will gather in Trieste, Italy, to report their latest results and to agree or disagree on the current concepts that define our understanding of this diverse class of viruses. This article offers a brief history of the impact the study of these viruses has had on molecular and cancer biology and discusses obstacles and opportunities for future progress.

Circular DNA tumor viruses make circular RNAs.

Epstein-Barr virus (EBV) and Kaposi's sarcoma herpesvirus (KSHV) cause ∼2% of all human cancers. RNase R-resistant RNA sequencing revealed that both gammaherpesviruses encode multiple, uniquely stable, circular RNAs (circRNA). EBV abundantly expressed both exon-only and exon-intron circRNAs from the BamHI A rightward transcript (BART) locus (circBARTs) formed from a spliced BART transcript and excluding the EBV miRNA region. The circBARTs were expressed in all verified EBV latency types, including EBV-positive posttransplant lymphoproliferative disease, Burkitt lymphoma, nasopharyngeal carcinoma, and AIDS-associated lymphoma tissues and cell lines. Only cells infected with the B95-8 EBV strain, with a 12-kb BART locus deletion, were negative for EBV circBARTs. Less abundant levels of EBV circRNAs originating from LMP2- and BHLF1-encoding genes were also identified. The circRNA sequencing of KSHV-infected primary effusion lymphoma cells revealed a KSHV-encoded circRNA from the vIRF4 locus (circvIRF4) that was constitutively expressed. In addition, KSHV polyadenylated nuclear (PAN) RNA locus generated a swarm (>100) of multiply backspliced, low-abundance RNase R-resistant circRNAs originating in both sense and antisense directions consistent with a novel hyperbacksplicing mechanism. In EBV and KSHV coinfected cells, exon-only EBV circBARTs were located more in the cytoplasm, whereas the intron-retaining circBARTs were found in the nuclear fraction. KSHV circvIRF4 and circPANs were detected in both nuclear and cytoplasmic fractions. Among viral circRNAs tested, none were found in polysome fractions from KSHV-EBV coinfected BC1 cells, although low-abundance protein translation from viral circRNAs could not be excluded. The circRNAs are a new class of viral transcripts expressed in gammaherpesvirus-related tumors that might contribute to viral oncogenesis.

DNA Tumor Virus Regulation of Host DNA Methylation and Its Implications for Immune Evasion and Oncogenesis.

Viruses have evolved various mechanisms to evade host immunity and ensure efficient viral replication and persistence. Several DNA tumor viruses modulate host DNA methyltransferases for epigenetic dysregulation of immune-related gene expression in host cells. The host immune responses suppressed by virus-induced aberrant DNA methylation are also frequently involved in antitumor immune responses. Here, we describe viral mechanisms and virus-host interactions by which DNA tumor viruses regulate host DNA methylation to evade antiviral immunity, which may contribute to the generation of an immunosuppressive microenvironment during cancer development. Recent trials of immunotherapies have shown promising results to treat multiple cancers; however, a significant number of non-responders necessitate identifying additional targets for cancer immunotherapies. Thus, understanding immune evasion mechanisms of cancer-causing viruses may provide great insights for reversing immune suppression to prevent and treat associated cancers.

Viral infections and breast cancer - A current perspective.

Sporadic human breast cancer is the most common cancer to afflict women. Since the discovery, decades ago, of the oncogenic mouse mammary tumour virus, there has been significant interest in the potential aetiologic role of infectious agents in sporadic human breast cancer. To address this, many studies have examined the presence of viruses (e.g. papillomaviruses, herpes viruses and retroviruses), endogenous retroviruses and more recently, microbes, as a means of implicating them in the aetiology of human breast cancer. Such studies have generated conflicting experimental and clinical reports of the role of infection in breast cancer. This review evaluates the current evidence for a productive oncogenic viral infection in human breast cancer, with a focus on the integration of sensitive and specific next generation sequencing technologies with pathogen discovery. Collectively, the majority of the recent literature using the more powerful next generation sequencing technologies fail to support an oncogenic viral infection being involved in disease causality in breast cancer. In balance, the weight of the current experimental evidence supports the conclusion that viral infection is unlikely to play a significant role in the aetiology of breast cancer.

[Prevalence of DNA viruses in maxillofacial area of HIV-infected]. / Porazhennost' DNK-virusami cheliustno-litsevoi oblasti bol'nykh s VICh-infektsiei.

DNA viruses have high oncogenic risk viruses; they cause emergence of Kaposi sarcoma, Lymphoma, Squamous cell carcinoma. HIV immunodeficiency promotes increase in frequency of such tumors. Etiotropic therapy of HIV patients considerably reduces prevalence of DNA viruses and a viral malignization.

Oncogenic DNA viruses found in salivary gland tumors.

BACKGROUND: Previous investigations studying the association of DNA viruses with salivary gland tumors (SGTs) have led to conflicting results. The aim of this study was to determine the prevalence of different DNA viruses by using a highly sensitive assay in a multi-center series of over 100 fresh frozen salivary gland samples. METHODS: DNA was isolated from 84 SGTs (80 parotid tumors and 4 submandibular gland tumors) and 28 normal salivary tissue samples from 85 patients in Northeast Italy. Using a highly sensitive type-specific multiplex genotyping assay, we analyzed the samples for the presence of DNA from 62 different viruses including 47 papillomaviruses, 10 polyomaviruses, and 5 herpesviruses. RESULTS: We observed a high prevalence of beta human papillomavirus DNA in malignant tumors. In contrast, polyomavirus DNA was present in benign, malignant, and non-tumor control samples. Most striking was the significant distribution of herpesvirus DNA in the SGT samples, in particular the high prevalence of Epstein-Barr type 1 and type 2 DNA in Warthin's tumor samples. CONCLUSION: Our data provides evidence for the presence of DNA viruses in SGTs. Mechanistic studies are needed to further attribute tumor formation to these viruses.

Take your PIKK: tumour viruses and DNA damage response pathways.

Viruses regulate cellular processes to facilitate viral replication. Manipulation of nuclear proteins and pathways by nuclear replicating viruses often causes cellular genome instability that contributes to transformation. The cellular DNA damage response (DDR) safeguards the host to maintain genome integrity, but DNA tumour viruses can manipulate the DDR to promote viral propagation. In this review, we describe the interactions of DNA tumour viruses with the phosphatidylinositol 3-kinase-like protein kinase (PIKK) pathways, which are central regulatory arms of the DDR. We review how signalling through the ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 related (ATR), and DNA-dependent protein kinases (DNA-PK) influences viral life cycles, and how their manipulation by viral proteins may contribute to tumour formation.This article is part of the themed issue 'Human oncogenic viruses'.

DNA Oncogenic Virus-Induced Oxidative Stress, Genomic Damage, and Aberrant Epigenetic Alterations.

Approximately 20% of human cancers is attributable to DNA oncogenic viruses such as human papillomavirus (HPV), hepatitis B virus (HBV), and Epstein-Barr virus (EBV). Unrepaired DNA damage is the most common and overlapping feature of these DNA oncogenic viruses and a source of genomic instability and tumour development. Sustained DNA damage results from unceasing production of reactive oxygen species and activation of inflammasome cascades that trigger genomic changes and increased propensity of epigenetic alterations. Accumulation of epigenetic alterations may interfere with genome-wide cellular signalling machineries and promote malignant transformation leading to cancer development. Untangling and understanding the underlying mechanisms that promote these detrimental effects remain the major objectives for ongoing research and hope for effective virus-induced cancer therapy. Here, we review current literature with an emphasis on how DNA damage influences HPV, HVB, and EBV replication and epigenetic alterations that are associated with carcinogenesis.

Genotipificación, niveles de expresión y estado físico del virus del papiloma humano en pacientes colombianos con cáncer de células escamosas en la cavidad oral / Genotyping, levels of expression and physical status of human papilloma virus in oropharyngeal squamous cell carcinoma among Colombian patients

Introducción. Uno de los factores de riesgo del carcinoma de células escamosas en la cavidad oral es la infección por el virus del papiloma humano (HPV), cuyas prevalencias dependen de la región geográfica. Objetivo. Identificar los tipos del virus del papiloma humano más frecuentes en el cáncer de la cavidad bucal, sus niveles de expresión y el estado físico del genoma viral. Materiales y métodos. Se seleccionaron 46 pacientes que asistían a los servicios de cirugía de cabeza y cuello en Bogotá, Manizales y Bucaramanga. El examen histopatológico de las muestras incluidas en el estudio demostró la presencia de carcinoma de células escamosas en la cavidad oral en todas ellas. Se extrajo el ADN para genotipificar el virus y determinar el estado físico de su genoma, y el ARN para determinar los transcritos virales mediante reacción en cadena de la polimerasa en tiempo real. Resultados. La prevalencia del virus del papiloma humano en los tumores fue de 21,74% (n=10) y el tipo viral más frecuente fue el HPV-16 (nueve casos). La expresión viral del HPV-16 fue baja (una de 11 copias) y el estado físico predominante fue el mixto (ocho casos), con prevalencia de la disrupción en el sitio de unión de E1 y E2 (2525 a 3720 nucleótidos). Conclusión. En los pacientes con carcinoma de cavidad oral incluidos en este trabajo, la frecuencia del virus del papiloma humano fue relativamente baja (21,7 %) y el tipo viral más frecuente fue el HPV-16, el cual se encontró en forma mixta y con baja expresión de E7 , lo cual puede ser indicativo de un mal pronóstico para el paciente.

Introduction: One of the risk factors for squamous cell oropharyngeal carcinoma is infection with the human papilloma virus (HPV), with prevalences that vary depending on the geographical region. Objective: To identify the most frequent HPV viral types in oropharyngeal cancer, the levels of expression and the physical condition of the viral genome. Materials and methods: Forty-six patients were included in the study from among those attending head and neck surgical services in the cities of Bogotá, Manizales and Bucaramanga. In the histopathological report all study samples were characterized as oropharyngeal squamous cell carcinoma. DNA extraction was subsequently performed for HPV genotyping and to determine the physical state of the viral genome, as well as RNA to determine viral transcripts using real-time PCR. Results: HPV prevalence in tumors was 21.74% (n=10) and the most common viral type was HPV-16 (nine cases). Viral expression for HPV-16 was low (one of 11 copies) and the predominant physical state of the virus was mixed (eight cases), with disruption observed at the E1 - E2 binding site (2525 - 3720 nucleotides). Conclusion: The prevalence of HPV associated with oropharyngeal carcinoma among the Colombian study population was 21.7%, which is relatively low. The most frequent viral type was HPV-16, found in a mixed form and with low expression of E7 , possibly indicating a poor prognosis for these patients.

DNA Tumor Viruses and Cell Metabolism.

Viruses play an important role in cancerogenesis. It is estimated that approximately 20% of all cancers are linked to infectious agents. The viral genes modulate the physiological machinery of infected cells that lead to cell transformation and development of cancer. One of the important adoptive responses by the cancer cells is their metabolic change to cope up with continuous requirement of cell survival and proliferation. In this review we will focus on how DNA viruses alter the glucose metabolism of transformed cells. Tumor DNA viruses enhance "aerobic" glycolysis upon virus-induced cell transformation, supporting rapid cell proliferation and showing the Warburg effect. Moreover, viral proteins enhance glucose uptake and controls tumor microenvironment, promoting metastasizing of the tumor cells.

DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway.

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) detects intracellular DNA and signals through the adapter protein STING to initiate the antiviral response to DNA viruses. Whether DNA viruses can prevent activation of the cGAS-STING pathway remains largely unknown. Here, we identify the oncogenes of the DNA tumor viruses, including E7 from human papillomavirus (HPV) and E1A from adenovirus, as potent and specific inhibitors of the cGAS-STING pathway. We show that the LXCXE motif of these oncoproteins, which is essential for blockade of the retinoblastoma tumor suppressor, is also important for antagonizing DNA sensing. E1A and E7 bind to STING, and silencing of these oncogenes in human tumor cells restores the cGAS-STING pathway. Our findings reveal a host-virus conflict that may have shaped the evolution of viral oncogenes.

No significant viral transcription detected in whole breast cancer transcriptomes.

BACKGROUND: Studies evaluating the presence of viral sequences in breast cancer (BC), including various strains of human papillomavirus and human herpes virus, have yielded conflicting results. Most were based on RT-PCR and in situ hybridization. METHODS: In this report we searched for expressed viral sequences in 58 BC transcriptomes using five distinct in silico methods. In addition, we complemented our RNA sequencing results with exome sequencing, PCR and immunohistochemistry (IHC) analyses. A control sample was used to test our in silico methods. RESULTS: All of the computational methods correctly detected viral sequences in the control sample. We identified a small number of viral sequences belonging to human herpesvirus 4 and 6 and Merkel cell polyomavirus. The extremely low expression levels-two orders of magnitude lower than in a typical hepatitis B virus infection in hepatocellular carcinoma-did not suggest active infections. The presence of viral elements was confirmed in sample-matched exome sequences, but could not be confirmed by PCR or IHC. CONCLUSIONS: Our results show that no viral sequences are expressed in significant amounts in the BC investigated. The presence of non-transcribed viral DNA cannot be excluded.