Validation of multi-gene biomarkers for clinical outcomes is one of the most important issues for cancer prognosis. An important source of information for virtual validation is the high number of ...available cancer datasets. Nevertheless, assessing the prognostic performance of a gene expression signature along datasets is a difficult task for Biologists and Physicians and also time-consuming for Statisticians and Bioinformaticians. Therefore, to facilitate performance comparisons and validations of survival biomarkers for cancer outcomes, we developed SurvExpress, a cancer-wide gene expression database with clinical outcomes and a web-based tool that provides survival analysis and risk assessment of cancer datasets. The main input of SurvExpress is only the biomarker gene list. We generated a cancer database collecting more than 20,000 samples and 130 datasets with censored clinical information covering tumors over 20 tissues. We implemented a web interface to perform biomarker validation and comparisons in this database, where a multivariate survival analysis can be accomplished in about one minute. We show the utility and simplicity of SurvExpress in two biomarker applications for breast and lung cancer. Compared to other tools, SurvExpress is the largest, most versatile, and quickest free tool available. SurvExpress web can be accessed in http://bioinformatica.mty.itesm.mx/SurvExpress (a tutorial is included). The website was implemented in JSP, JavaScript, MySQL, and R.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Gene fusion represents a class of molecular aberrations in cancer and has been exploited for therapeutic purposes. In this paper we describe TumorFusions, a data portal that catalogues 20 ...731 gene fusions detected in 9966 well characterized cancer samples and 648 normal specimens from The Cancer Genome Atlas (TCGA). The portal spans 33 cancer types in TCGA. Fusion transcripts were identified via a uniform pipeline, including filtering against a list of 3838 transcript fusions detected in a panel of 648 non-neoplastic samples. Fusions were mapped to somatic DNA rearrangements identified using whole genome sequencing data from 561 cancer samples as a means of validation. We observed that 65% of transcript fusions were associated with a chromosomal alteration, which is annotated in the portal. Other features of the portal include links to SNP array-based copy number levels and mutational patterns, exon and transcript level expressions of the partner genes, and a network-based centrality score for prioritizing functional fusions. Our portal aims to be a broadly applicable and user friendly resource for cancer gene annotation and is publicly available at http://www.tumorfusions.org.
Cancer cells survive cellular crisis through telomere maintenance mechanisms. We report telomere lengths in 18,430 samples, including tumors and non-neoplastic samples, across 31 cancer types. ...Telomeres were shorter in tumors than in normal tissues and longer in sarcomas and gliomas than in other cancers. Among 6,835 cancers, 73% expressed telomerase reverse transcriptase (TERT), which was associated with TERT point mutations, rearrangements, DNA amplifications and transcript fusions and predictive of telomerase activity. TERT promoter methylation provided an additional deregulatory TERT expression mechanism. Five percent of cases, characterized by undetectable TERT expression and alterations in ATRX or DAXX, demonstrated elongated telomeres and increased telomeric repeat-containing RNA (TERRA). The remaining 22% of tumors neither expressed TERT nor harbored alterations in ATRX or DAXX. In this group, telomere length positively correlated with TP53 and RB1 mutations. Our analysis integrates TERT abnormalities, telomerase activity and genomic alterations with telomere length in cancer.
Previous methods proposed for the detection of cancer driver mutations have been based on the estimation of background mutation rate, impact on protein function, or network influence. In this paper, ...we instead focus on those factors influencing patient survival. To this end, an approximation of the log-rank test has been systematically applied, even though it assumes a large and similar number of patients in both risk groups, which is violated in cancer genomics. Here, we propose VALORATE, a novel algorithm for the estimation of the null distribution for the log-rank, independent of the number of mutations. VALORATE is based on conditional distributions of the co-occurrences between events and mutations. The results, achieved through simulations, comparisons with other methods, analyses of TCGA and ICGC cancer datasets, and validations, suggest that VALORATE is accurate, fast, and can identify both known and novel gene mutations. Our proposal and results may have important implications in cancer biology, bioinformatics analyses, and ultimately precision medicine.
Cancer types are commonly classified by histopathology and more recently through molecular characteristics such as gene expression, mutations, copy number variations, and epigenetic alterations. ...These molecular characterizations have led to the proposal of prognostic biomarkers for many cancer types. Nevertheless, most of these biomarkers have been proposed for a specific cancer type or even specific subtypes. Although more challenging, it is useful to identify biomarkers that can be applied for multiple types of cancer. Here, we have used a network-based exploration approach to identify a multi-cancer gene expression biomarker highly connected by ESR1, PRKACA, LRP1, JUN and SMAD2 that can be predictive of clinical outcome in 12 types of cancer from The Cancer Genome Atlas (TCGA) repository. The gene signature of this biomarker is highly supported by cancer literature, biological terms, and prognostic power in other cancer types. Additionally, the signature does not seem to be highly associated with specific mutations or copy number alterations. Comparisons with cancer-type specific and other multi-cancer biomarkers in TCGA and other datasets showed that the performance of the proposed multi-cancer biomarker is superior, making the proposed approach and multi-cancer biomarker potentially useful in research and clinical settings.
Purpose
The implications of bowel obstruction occurring secondary to femoral hernia have not been discussed in the literature recently. Thus, we report our experience of treating patients with ...femoral hernias complicated by bowel obstruction versus patients with femoral hernias not complicated by bowel obstruction.
Methods
The subjects of this retrospective study were patients admitted to our hospital for the treatment of femoral hernias between 2016 and 2019. We used the Fisher and Student’s T test to compare the preoperative characteristics, treatment, and outcomes of patients with bowel obstruction versus those without bowel obstruction.
Results
A total of 53 patients (mean age, 66.9 ± 15.1 years) were treated, 18 (33.9%) of whom underwent elective surgery and 35 (66%) of whom required emergency surgery (
p
= 0.001). The mean time between the development of symptoms and hospitalization was 4.5 ± 3.1 days for the patients with bowel obstruction and 1.6 ± 3.2 days for those without bowel obstruction (
p
= 0.001). The length of hospital stay was 11.1 ± 21.1 days for the patients with bowel obstruction and 1 ± 1.8 days for those without bowel obstruction (
p
= 0.028). Overall morbidity and mortality rates were 13.2% and 5.6%, respectively.
Conclusion
Femoral hernias causing bowel obstruction are associated with greater time between the development of symptoms, hospitalization, and with a longer hospital stay.
Sporadic gliomas in companion dogs provide a window on the interaction between tumorigenic mechanisms and host environment. We compared the molecular profiles of canine gliomas with those of human ...pediatric and adult gliomas to characterize evolutionarily conserved mammalian mutational processes in gliomagenesis. Employing whole-genome, exome, transcriptome, and methylation sequencing of 83 canine gliomas, we found alterations shared between canine and human gliomas such as the receptor tyrosine kinases, TP53 and cell-cycle pathways, and IDH1 R132. Canine gliomas showed high similarity with human pediatric gliomas per robust aneuploidy, mutational rates, relative timing of mutations, and DNA-methylation patterns. Our cross-species comparative genomic analysis provides unique insights into glioma etiology and the chronology of glioma-causing somatic alterations.
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•Genomic, epigenomic, and transcriptomic characterization of sporadic glioma in dogs•Somatic alterations in canine glioma converge with human glioma drivers•Canine glioma resemble pediatric human glioma by mutation rate and DNA methylation•Microenvironment similarity between canine and human pediatric and adult glioma
Amin et al. characterize the molecular landscape of canine gliomas and compare it with that of human pediatric and adult gliomas, revealing high similarity between human pediatric and canine gliomas. The cross-species analysis identifies conserved glioma drivers and aneuploidy as a hallmark of high-grade disease.
We previously found that therapeutic targetable fusions are detected across various cancers. To identify therapeutic targetable fusion in uterine cervical cancer, for which no effective gene targeted ...therapy has yet been clinically applied, we analyzed RNA sequencing data from 306 cervical cancer samples. We detected 445 high confidence fusion transcripts and identified four samples that harbored FGFR3-TACC3 fusion as an attractive therapeutic target. The frequency of FGFR3-TACC3-fusion-positive cervical cancer is also 1.9% (2/103) in an independent cohort. Continuous expression of the FGFR3-TACC3 fusion transcript and protein induced anchorage-independent growth in the cervical epithelial cell line established from the ectocervix (Ect1/E6E7) but not in that from endocervix (End1/E6E7). Injection of FGFR3-TACC3 fusion-transfected-Ect1/E6E7 cells subcutaneously into NOG mice generated squamous cell carcinoma xenograft tumors, suggesting the association between FGFR3-TACC3 fusion and squamous cell carcinogenesis. Transfection of a FGFR3-TACC3 fusion transcript into four cervical cancer cell lines (SiHa, ME180, HeLa, and Ca Ski) induced activation of the MAPK pathway and enhancement of cell proliferation. Transcriptome analysis of the FGFR3-TACC3 fusion-transfected cell lines revealed that an IL8-triggered inflammatory response was increased, via activation of FGFR3-MAPK signaling. Continuous expression of FGFR3-TACC3 fusion led to activation of the PI3K-AKT pathway only in the two cell lines that harbored PIK3CA mutations. Sensitivity to the FGFR inhibitor, BGJ398, was found to depend on PIK3CA mutation status. Dual inhibition of both FGFR and AKT showed an obvious synergistic effect in cell lines that harbor mutant PIK3CA. Additionally, TACC3 inhibitor, KHS101, suppressed FGFR3-TACC3 fusion protein expression and showed antitumor effect against FGFR3-TACC3 fusion-transfected cell lines. FGFR3-TACC3 fusion-positive cancer has frequent genetic alterations of the PI3K/AKT pathway and selection of appropriate treatment based on PI3K/AKT pathway status should be required.
The prevalence of breast cancer in young women (YWBC) has increased alarmingly. Significant efforts are being made to elucidate the biological mechanisms concerning the development, prognosis, and ...pathological response in early-onset breast cancer (BC) patients. Dysfunctional DNA repair proteins are implied in BC predisposition, progression, and therapy response, underscoring the need for further analyses on DNA repair genes. Public databases of large patient datasets such as METABRIC, TCGA, COSMIC, and cancer cell lines allow the identification of variants in DNA repair genes and possible precision drug candidates. This study aimed at identifying variants and drug candidates that may benefit Latin American (LA) YWBC. We analyzed pathogenic variants in 90 genes involved in DNA repair in public BC datasets from METABRIC, TCGA, COSMIC, CCLE, and COSMIC Cell Lines Project. Results showed that reported DNA repair germline variants in the LA dataset are underrepresented in large databases, in contrast to other populations. Additionally, only six gene repair variants in women under 50 years old from the study population were reported in BC cell lines. Therefore, there is a need for new approaches to study DNA repair variants reported in young women from LA.
Androgenetic alopecia is a highly prevalent condition mainly affecting men. This complex trait is related to aging and genetics; however, multiple other factors, for example, lifestyle, are also ...involved. Despite its prevalence, the underlying biology of androgenetic alopecia remains elusive, and thus advances in its treatment have been hindered. Herein, we review the functional anatomy of hair follicles and the cell signaling events that play a role in follicle cycling. We also discuss the pathology of androgenetic alopecia and the known molecular mechanisms underlying this condition. Additionally, we describe studies comparing the transcriptional differences in hair follicles between balding and non-balding scalp regions. Given the genetic contribution, we also discuss the most significant risk variants found to be associated with androgenetic alopecia. A more comprehensive understanding of this pathology may be generated through using multi-omics approaches.
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