Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
1,090
result(s) for
"Cooper, Colin"
Sort by:
Major data analysis errors invalidate cancer microbiome findings
We re-analyzed the data from a recent large-scale study that reported strong correlations between DNA signatures of microbial organisms and 33 different cancer types and that created machine-learning predictors with near-perfect accuracy at distinguishing among cancers. We found at least two fundamental flaws in the reported data and in the methods: (i) errors in the genome database and the associated computational methods led to millions of false-positive findings of bacterial reads across all samples, largely because most of the sequences identified as bacteria were instead human; and (ii) errors in the transformation of the raw data created an artificial signature, even for microbes with no reads detected, tagging each tumor type with a distinct signal that the machine-learning programs then used to create an apparently accurate classifier. Each of these problems invalidates the results, leading to the conclusion that the microbiome-based classifiers for identifying cancer presented in the study are entirely wrong. These flaws have subsequently affected more than a dozen additional published studies that used the same data and whose results are likely invalid as well. Recent reports showing that human cancers have a distinctive microbiome have led to a flurry of papers describing microbial signatures of different cancer types. Many of these reports are based on flawed data that, upon re-analysis, completely overturns the original findings. The re-analysis conducted here shows that most of the microbes originally reported as associated with cancer were not present at all in the samples. The original report of a cancer microbiome and more than a dozen follow-up studies are, therefore, likely to be invalid.
Journal Article
A census of amplified and overexpressed human cancer genes
Key Points
Integrated screens of DNA copy number and gene expression in human cancers using microarray platforms have accelerated the rate of discovery of amplified and overexpressed genes. However, the biological importance of most of the genes identified in such studies remains unclear.
Amplification events often include multiple genes, so consideration of the pattern of genetic alteration alone is usually insufficient to identify which gene in an amplicon is being selected for owing to its contribution to oncogenesis. Supplementary datasets are usually required, including physical mapping, determination of overexpression, correlation with clinical outcome, biological investigations of function and, in some cases, efficacy of drugs targeted against the encoded overexpressed proteins.
In this Analysis we propose a weight-of-evidence based classification system for identifying individual genes in amplified regions that are selected for in an amplicon and so contribute to cancer development. The proposed classification scheme takes into account the complex and sometimes distinct datasets that are available for different amplicons in cancer.
Using this classification scheme in a census of the published literature, we have identified 77 genes for which there is evidence of involvement in human cancer development.
The 77 genes were divided into three classes based on the weight of supporting evidence. We consider that for class II (12 genes), and class I (3 genes) the evidence is sufficiently strong for their inclusion in the census of human cancer genes.
Linking newly generated integrated datasets to supporting evidence using the criteria outlined in this Analysis will aid in the future identification of amplified and overexpressed genes that contribute to cancer development.
This article proposes a weight-of-evidence based classification system for identifying individual genes in an amplified region of the genome that contribute to cancer development. The 77 genes identified using this approach have been further subdivided into different gene classes.
Integrated genome-wide screens of DNA copy number and gene expression in human cancers have accelerated the rate of discovery of amplified and overexpressed genes. However, the biological importance of most of the genes identified in such studies remains unclear. In this Analysis, we propose a weight-of-evidence based classification system for identifying individual genes in amplified regions that are selected for during tumour development. In a census of the published literature we have identified 77 genes for which there is good evidence of involvement in the development of human cancer.
Journal Article
Dead man down : revenge is coming
In New York City, a crime lord's right-hand man is seduced by one of his boss's victims, a woman seeking retribution.
DVD
GogB Is an Anti-Inflammatory Effector that Limits Tissue Damage during Salmonella Infection through Interaction with Human FBXO22 and Skp1
Bacterial pathogens often manipulate host immune pathways to establish acute and chronic infection. Many Gram-negative bacteria do this by secreting effector proteins through a type III secretion system that alter the host response to the pathogen. In this study, we determined that the phage-encoded GogB effector protein in Salmonella targets the host SCF E3 type ubiquitin ligase through an interaction with Skp1 and the human F-box only 22 (FBXO22) protein. Domain mapping and functional knockdown studies indicated that GogB-containing bacteria inhibited IκB degradation and NFκB activation in macrophages, which required Skp1 and a eukaryotic-like F-box motif in the C-terminal domain of GogB. GogB-deficient Salmonella were unable to limit NFκB activation, which lead to increased proinflammatory responses in infected mice accompanied by extensive tissue damage and enhanced colonization in the gut during long-term chronic infections. We conclude that GogB is an anti-inflammatory effector that helps regulate inflammation-enhanced colonization by limiting tissue damage during infection.
Journal Article
APOBEC3 mutational signatures are associated with extensive and diverse genomic instability across multiple tumour types
Background
The APOBEC3 (apolipoprotein B mRNA editing enzyme catalytic polypeptide 3) family of cytidine deaminases is responsible for two mutational signatures (SBS2 and SBS13) found in cancer genomes. APOBEC3 enzymes are activated in response to viral infection, and have been associated with increased mutation burden and TP53 mutation. In addition to this, it has been suggested that APOBEC3 activity may be responsible for mutations that do not fall into the classical APOBEC3 signatures (SBS2 and SBS13), through generation of double strand breaks.Previous work has mainly focused on the effects of APOBEC3 within individual tumour types using exome sequencing data. Here, we use whole genome sequencing data from 2451 primary tumours from 39 different tumour types in the Pan-Cancer Analysis of Whole Genomes (PCAWG) data set to investigate the relationship between APOBEC3 and genomic instability (GI).
Results and conclusions
We found that the number of classical APOBEC3 signature mutations correlates with increased mutation burden across different tumour types. In addition, the number of APOBEC3 mutations is a significant predictor for six different measures of GI. Two GI measures (INDELs attributed to INDEL signatures ID6 and ID8) strongly suggest the occurrence and error prone repair of double strand breaks, and the relationship between APOBEC3 mutations and GI remains when SNVs attributed to kataegis are excluded.We provide evidence that supports a model of cancer genome evolution in which APOBEC3 acts as a causative factor in the development of diverse and widespread genomic instability through the generation of double strand breaks. This has important implications for treatment approaches for cancers that carry APOBEC3 mutations, and challenges the view that APOBECs only act opportunistically at sites of single stranded DNA.
Journal Article
Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue
Colin Cooper and colleagues report genome-wide sequences of multiple samples of multifocal cancer and morphologically normal tissue from the prostates of three men. They found high levels of mutations in morphologically normal tissue distant from the cancer, consistent with field effects.
Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct
ERG
fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different
ERG
lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.
Journal Article
ETS gene fusions in prostate cancer
The discovery of recurrent ETS gene fusions in prostate cancer has improved our understanding of prostate carcinogenesis and suggests novel targets for therapy. Here, Clark and Cooper discuss the variety of ETS gene fusions and their role in prostate cancer development, and outline the prognostic and therapeutic implications of this knowledge.
Chromosomal rearrangements that result in high level expression of ETS gene family members are common events in human prostate cancer. Most frequently, the androgen-activated gene
TMPRSS2
is found fused to the
ERG
gene. Fusions involving
ETV1
,
ETV4
and
ETV5
occur less frequently but exhibit greater variability in fusion structure with 12 unique 5′ fusion partners identified so far. ETS gene rearrangement seems to be a key event in driving prostate neoplastic development: the rearrangement occurs as an early event and continues to be expressed in metastatic and castration-resistant disease. However, ETS alterations seem insufficient on their own to induce cancer formation. No consistent associations are seen between the presence of ETS alteration and clinical outcome, with the possible exception that duplication of rearranged
ERG
, reflecting aneuploidy, is associated with poor outcome. Thus, factors other than
ERG
gene status may be the major determinants of poor clinical outcome. Expression signatures of prostate cancers containing the
TMPRSS2–ERG
fusion suggest involvement of β-estradiol signaling, and reveal higher levels of expression of
HDAC1
and ion channel genes when compared to cancers that lack the rearrangement. These observations suggest new therapeutic possibilities for patients harboring ETS gene fusions.
Key Points
Fusions involving
ERG
,
ETV1
,
ETV4
, and
ETV5
, are frequent events in human prostate cancer and result in high levels of ETS gene expression
In the most common fusion,
ERG
becomes fused to 5′-
TMPRSS2
gene sequences; by contrast,
ETV1
,
ETV4
and
ETV5
have multiple 5′-fusion partners
Most, although not all, 5′-fusion partners are androgen-activated genes
Encoded full length and N-terminal-truncated proteins believed to be responsible for inducing cell transformation retain the Ets DNA-binding domain
ETS gene translocations represent an early event in prostate cancer but seem to be insufficient on their own to induce cancer formation
Prostate cancers harboring the
TMPRSS2–ERG
fusion exhibit an expression signature matching that of β-estradiol signaling; overexpression of
HDAC1
and ion channels in these cancers suggests new therapeutic approaches
Journal Article
Core shell lipid-polymer hybrid nanoparticles with combined docetaxel and molecular targeted therapy for the treatment of metastatic prostate cancer
Many prostate cancers relapse after initial chemotherapy treatment. Combining molecular and chemotherapy together with encapsulation of drugs in nanocarriers provides effective drug delivery and toxicity reduction. We developed core shell lipid-polymer hybrid nanoparticles (CSLPHNPs) with poly (lactic-co-glycolic acid) (PLGA) core and lipid layer containing docetaxel and clinically used inhibitor of sphingosine kinase 1 (SK1) FTY720 (fingolimod). We show for the first time that FTY720 (both free and in CSLPHNPs) re-sensitizes castrate resistant prostate cancer cells and tumors to docetaxel, allowing a four-fold reduction in effective dose. Our CSLPHNPs showed high serum stability and a long shelf life. CSLPHNPs demonstrated a steady uptake by tumor cells, sustained intracellular drug release and
in vitro
efficacy superior to free therapies. In a mouse model of human prostate cancer, CSLPHNPs showed excellent tumor targeting and significantly lower side effects compared to free drugs, importantly, reversing lymphopenia induced by FTY720. Overall, we demonstrate that nanoparticle encapsulation can improve targeting, provide low off-target toxicity and most importantly reduce FTY720-induced lymphopenia, suggesting its potential use in clinical cancer treatment.
Journal Article