Copy number signature analyses in prostate cancer reveal distinct etiologies and clinical outcomes

Genome alteration signatures reflect recurring patterns caused by distinct endogenous or exogenous mutational events during the evolution of cancer. Signatures of single base substitution (SBS) have been extensively studied in different types of cancer, however, signatures of cancer genome copy number alteration (CNA) are still elusive in most cancer types, especially in prostate cancer (PC), which is particularly driven by complex genome alterations. Here, a user-friendly open source bioinformatics tool “sigminer” has been constructed for copy number signature extraction, analysis and visualization. Five copy number signatures are identified from human PC genome with this tool. The underlying driving forces for each signature have been illustrated. Sample clustering based on copy number signature exposure revealed considerable heterogeneity of PC, and copy number signatures show improved PC clinical outcome association when compared with SBS signatures. Copy number signature analyses provide distinct insight into the etiology of PC, and potential biomarkers for PC stratification and prognosis.

Familial primary ovarian insufficiency associated with a SYCE1 point mutation: Defective meiosis elucidated in humanized mice

ObjectiveTo investigate if nonsense mutation SYCE1 c.613C˃T -found in women with familial primary ovarian insufficiency (POI)- is actually responsible for infertility, and to elucidate the involved molecular mechanisms.DesignAs most fundamental mammalian oogenesis events occur during the embryonic phase, thus hindering the study of POI’s etiology/pathogeny in infertile women, we have used CRISPR/Cas9 technology to generate a mouse model line with an equivalent genome alteration (humanized mice).SettingAcademic research laboratories.InterventionsWe present the characterization of the biallelic mutant mice phenotype, compared to wild type and monoallelic littermates.AnimalsStudies were conducted employing the generated humanized mice. All studies were performed for both genders, except otherwise stated.Main outcome measuresreproductive capability by fertility tests; gonadal histological analysis; evaluation of chromosome synapsis and synaptonemal complex (SC) assembly by immunolocalizations; protein studies by Western blotting; transcript quantification by RT-qPCR.ResultsThe studied mutation proved to be the actual cause of the infertile phenotype, both in female and male mice homozygous for the change, confirming infertility of genetic origin with a recessive mode of inheritance. The mechanisms that lead to infertility are related to chromosome synapsis defects; no putative truncated SYCE1 protein was observed, and Syce1 transcript was hardly detected in biallelic mutants.ConclusionsWe present for the first time the generation of humanized mice to study the actual consequences of a SC component mutation found in women with familial POI. By this approach we could confirm the suspected etiology, and shed light on the underlying molecular mechanism.

Lipid Related Genes Altered in NASH Connect Inflammation in Liver Pathogenesis Progression to HCC: A Canonical Pathway

Nonalcoholic steatohepatitis (NASH) is becoming a public health problem worldwide. While the number of research studies on NASH progression rises every year, sometime their findings are controversial. To identify the most important and commonly described findings related to NASH progression, we used an original bioinformatics, integrative, text-mining approach that combines PubMed database querying and available gene expression omnibus dataset. We have identified a signature of 25 genes that are commonly found to be dysregulated during steatosis progression to NASH and cancer. These genes are implicated in lipid metabolism, insulin resistance, inflammation, and cancer. They are functionally connected, forming the basis necessary for steatosis progression to NASH and further progression to hepatocellular carcinoma (HCC). We also show that five of the identified genes have genome alterations present in HCC patients. The patients with these genes associated to genome alteration are associated with a poor prognosis. In conclusion, using an integrative literature- and data-mining approach, we have identified and described a canonical pathway underlying progression of NASH. Other parameters (e.g. polymorphisms) can be added to this pathway that also contribute to the progression of the disease to cancer. This work improved our understanding of the molecular basis of NASH progression and will help to develop new therapeutic approaches.

Replication timing alterations in leukemia affect clinically relevant chromosome domains

Key Points DNA replication timing of >100 pediatric leukemic samples identified BCP-ALL subtype-specific genome alteration signatures. Comparative analyses identified features of specific stages of B-cell differentiation and potential associations with clinical outcome.

Percent genome alteration and outcomes after radical prostatectomy in African American men.

24 Background: African American (AA) men have a higher incidence of and mortality from prostate cancer (PCa) than European American (EA) men. The potential biological determinants of these racial disparities are unknown. Cancer genome evaluations with available clinical outcome data have been limited to EA cohorts. Here we characterize PCa genomes from a large cohort of AA men and identify the associations between genomic alterations and clinical outcomes. Methods: Cancer genomes from 205 AA men treated with radical prostatectomy (RP) were profiled for known somatic mutations and percent genome alteration (PGA; defined as percentage of tumor genome with copy number variation). Logistic regression and Cox proportional hazard analyses assessed the association of genomic alterations with clinical outcomes in multivariate models. PGA was dichotomized by quartiles in analytical models (≤75th percentile vs. >75th percentile). Results: The median PGA was 3.7% and increased with pathologic grade (p<0.001) and stage (p=0.02). Median follow-up was 5 years. AA men with the highest quartile of PGA had significantly worse biochemical recurrence (BCR)-free survival (10 year: 33.5% vs. 50.2%; p=0.006) and metastasis-free survival (10 year: 47.9% vs. 89.0%; p<0.001) than men with lower quartiles of PGA. PGAwas associated with increased risks of higher grade (OR 2.0, 95% CI 1.1-3.7, p=0.03), higher stage (OR 2.0, 95% CI 1.1-3.8, p=0.03), BCR (univariate: HR 1.9, 95% CI 1.2-3.2, p=0.01), and metastasis (HR 9.6, 95% CI 2.9-31.3, p<0.001). The most common somatic mutations were SPOP (12.5%, 123/184), FOXA1 (9.2%, 17/184), and TP53 (4.4%, 8/184). Only TP53 was associated with increased risks of adverse outcomes: higher stage (OR 5.3, 95% CI 1.5-19.4, p=0.01), BCR (univariate: HR 2.4, 95% CI 1.0-5.9, p=0.06), and metastasis (HR 9.5, 95% CI 2.2-40.6, p=0.002). Conclusions: In AA men, PCa genome profiles reveal unique genomic alterations. Notably, PGA in AA men predicts adverse pathologic and oncologic outcomes after RP and can potentially be considered a prognostic biomarker in this racial group. This research highlights the importance of racial ancestry in cancer genomics studies and precision medicine strategies.

Improving the performance of Transposable Elements detection tools

Summary Transposable Elements (TE) are sequences of DNA that move and transpose within a genome. TEs, as mutation agents, are quite important for their role in both genome alteration diseases and on species evolution. Several tools have been developed to discover and annotate TEs but no single tool achieves good results on all different types of TEs. In this paper we evaluate the performance of several TEs detection and annotation tools and investigate if Machine Learning techniques can be used to improve their overall detection accuracy. The results of an in silico evaluation of TEs detection and annotation tools indicate that their performance can be improved by using machine learning constructed classifiers.

Cost of Having the Largest Mitochondrial Genome: Evolutionary Mechanism of Plant Mitochondrial Genome

The angiosperm mitochondrial genome is the largest and least gene-dense among the eukaryotes, because its intergenic regions are expanded. There seems to be no functional constraint on the size of the intergenic regions; angiosperms maintain the large mitochondrial genome size by a currently unknown mechanism. After a brief description of the angiosperm mitochondrial genome, this review focuses on our current knowledge of the mechanisms that control the maintenance and alteration of the genome. In both processes, the control of homologous recombination is crucial in terms of site and frequency. The copy numbers of various types of mitochondrial DNA molecules may also be controlled, especially during transmission of the mitochondrial genome from one generation to the next. An important characteristic of angiosperm mitochondria is that they contain polypeptides that are translated from open reading frames created as byproducts of genome alteration and that are generally nonfunctional. Such polypeptides have potential to evolve into functional ones responsible for mitochondrially encoded traits such as cytoplasmic male sterility or may be remnants of the former functional polypeptides.