- A high score based on the expression of 23 genes involved in repairing DNA damage after platinum-based chemotherapy for ovarian cancer was associated with improved survival.
- Note that the gene score outperformed clinical factors associated with ovarian cancer outcome and was the only baseline factor that had a significant association with overall survival.
Showing posts with label genome. Show all posts
Showing posts with label genome. Show all posts
Monday, May 14, 2012
PLoS ONE: European American Stratification in Ovarian Cancer Case Control Data: The Utility of Genome-Wide Data for Inferring Ancestry
Blogger's Note: interesting article includes migration of peoples from Europe to North America/s; ovarian cancer and genome
PLoS ONE: European American Stratification in Ovarian Cancer Case Control Data: The Utility of Genome-Wide Data for Inferring Ancestry
Wednesday, May 09, 2012
paywalled: The Predictive Capacity of Personal Genome Sequencing - Science Translational Medicine
[Research Articles] The Predictive Capacity of Personal Genome Sequencing:
New DNA sequencing methods will soon make it possible to identify all germline variants in any individual at a reasonable cost. However, the ability of whole-genome sequencing to predict predisposition to common diseases in the general population is unknown. To estimate this predictive capacity, we use the concept of a "genometype." A specific genometype represents the genomes in the population conferring a specific level of genetic risk for a specified disease. Using this concept, we estimated the maximum capacity of whole-genome sequencing to identify individuals at clinically significant risk for 24 different diseases.
(in research - genome) Integrated Analysis of Gene Expression and Tumor Nuclear Image Profiles Associated with Chemotherapy Response in Serous Ovarian Carcinoma
Integrated Analysis of Gene Expression and Tumor Nuclear Image Profiles Associated with Chemotherapy Response in Serous Ovarian Carcinoma
Background
Small sample sizes used in previous studies result in a lack of overlap between the reported gene signatures for prediction of chemotherapy response. Although morphologic features, especially tumor nuclear morphology, are important for cancer grading, little research has been reported on quantitatively correlating cellular morphology with chemotherapy response, especially in a large data set. In this study, we have used a large population of patients to identify molecular and morphologic signatures associated with chemotherapy response in serous ovarian carcinoma.
Sunday, May 06, 2012
Epigenetic modification and cancer: mark or stamp? (BRCA/fallopian tube....)
Epigenetic modification and cancer: mark or stamp?
Abstract
Hypotheses are built upon data, but
data require hypotheses before they can be understood. The development
of the ‘two-hit’
hypothesis of carcinogenesis was a key event in
cancer genetics because it provided a testable model of how tumours
develop.
In this commentary on ‘Promoter hypermethylation
patterns in Fallopian tube epithelium of BRCA1 and BRCA2 germline mutation carriers’ by Bijron et al. published in the February 2012 issue of Endocrine-Related Cancer, the need for new grammar and some new hypotheses in epigenetics is discussed. Meanwhile, data suggesting an important role
of epigenetic modification in the cause, progression and treatment of cancer continues to accumulate............
Introduction
In hereditary tumours, the first hit
occurs in the germ line, whereas in non-hereditary tumours, the first
hit occurs in the
cell from which the tumour arises. The second
hits are always somatic, and can inactivate the second allele in various
different
ways. The development of the ‘two-hit’
hypothesis of carcinogenesis was a key event in cancer genetics because
it provided
a testable model of how tumours develop (Knudson 1971, 1978). Although there have been extensions and revisions to the basic model (Tomlinson et al. 2001), the essential elements of the basic hypothesis remain intact, 40 years on. In the original ‘test case’ of RB-1 mutations in retinoblastoma, these events were physical alterations in the structure of the chromosome or gene (Cavenee et al. 1983), and the perception was such that physical changes put a ‘stamp’ on the tumour that could be detected by examination of
genomic DNA.............
continue to read full paper
Saturday, May 05, 2012
Tuesday, May 01, 2012
A Comprehensive Analysis of Human Gene Expression Profiles Identifies Stromal Immunoglobulin κ C as a Compatible Prognostic Marker in Human Solid Tumors
A Comprehensive Analysis of Human Gene Expression Profiles Identifies Stromal Immunoglobulin κ C as a Compatible Prognostic Marker in Human Solid Tumors
"No association was observed in ovarian cancer."
Sunday, April 15, 2012
A snapshot of microarray-generated gene expression signatures associated with ovarian carcinoma
A snapshot of microarray-generated gene expression signatures associated with ovarian carcinoma:
Abstract
It was hypothesized that analysis of global gene expression in ovarian carcinoma can identify dysregulated genes that can serve as molecular markers and provide further insight into carcinogenesis and provide the basis for development of new diagnostic tools as well as new targeted therapy protocols................From these genes, merely three were identified in at least two different studies. This snapshot of available gene expression data not only provides independently described potential diagnostic and therapeutic targets for ovarian carcinoma but also emphasizes the drawbacks of the current state of global gene expression analyses in ovarian cancer.
Saturday, April 14, 2012
Medpage: Medical News: DNA Repair Genes May Predict Ovarian Cancer Survival
Blogger's Note: the original paper and editorial were recently posted, however, the Medpage (Medscape) article is easier to read (eg. plain english)
DNA Repair Genes May Predict Ovarian Cancer Survival - in Oncology/Hematology, Ovarian Cancer from MedPage Today
"A high score based on the expression of 23 genes involved in repairing DNA damage after platinum-based chemotherapy for ovarian cancer was associated with a 5-year survival of 40% versus 17% for women who had a low score, investigators reported......"
Action Points
Monday, April 09, 2012
abstract: Multidrug Resistance-Linked Gene Signature Predicts Overall Survival of Patients With Primary Ovarian Serous Carcinoma
Multidrug Resistance-Linked Gene Signature Predicts Overall Survival of Patients With Primary Ovarian Serous Carcinoma
Abstract
Purpose:
This study assesses the ability
of multidrug resistance (MDR)-associated gene expression patterns to
predict survival
in patients with newly diagnosed carcinoma of the
ovary. The scope of this research differs substantially from that of
previous
reports, as a very large set of genes was evaluated
whose expression has been shown to affect response to chemotherapy.
Experimental Design:
We applied a customized TaqMan
Low Density Array, a highly sensitive and specific assay, to study the
expression profiles of 380 MDR-linked genes in 80
tumor specimens collected at initial surgery to debulk primary serous
carcinoma.
The RNA expression profiles of these drug
resistance genes were correlated with clinical outcomes.
Results:
Leave-one-out cross-validation was used to
estimate the ability of MDR gene expression to predict survival.
Although
gene expression alone does not predict overall
survival (P=0.06), four covariates (age, stage, CA125 level and surgical
debulking)
do (P=0.03).
When gene expression was added to the
covariates, we found an 11-gene signature that provides a major
improvement
in overall survival prediction (log-rank statistic P
less than 0.003). The predictive power of this 11-gene signature was
confirmed by dividing high and low risk patient
groups, as defined by their clinical covariates, into four specific risk
groups
based on expression levels.
Conclusion:
This study reveals an 11-gene signature
that allows a more precise prognosis for patients with serous cancer of
the ovary treated with carboplatin- and
paclitaxel-based therapy. These 11 new targets offer opportunities for
new therapies
to improve clinical outcome in ovarian cancer.
Friday, April 06, 2012
Cancer's epicentre - The Economist
Cancer's epicentre - The Economist:
Cancer's epicentre
The Economist THE biggest conceptual breakthrough in the war on cancer was the realisation by the 1980s that it is always a genetic disease. Sometimes the genetic flaw is inherited. Sometimes it is the result of exposure to an outside agent such as tobacco smoke or radioactivity. Sometimes it is plain bad luck; a miscopying of a piece of DNA during the normal process of cell division. Turning that breakthrough into medicine, though, is hard. No one has worked out how to repair DNA directly. It is, rather, a question of discovering the biochemical consequences of the genetic damage and trying to deal with those instead. But recently, another pattern has emerged. It is too early to call it a breakthrough as significant as the cancer-is-caused-by-broken-genes finding, but it might be....... |
Tuesday, April 03, 2012
press release: Researchers discover a DNA marker (microRNA-16) that indicates if ovarian cancer treatment will be successful
Researchers discover a DNA marker that indicates if ovarian cancer treatment will be successful
Public release date: 3-Apr-2012
Researchers discover a DNA marker that indicates if ovarian cancer treatment will be successful
CHICAGO, IL – Researchers and doctors at the North Shore-LIJ Health System and the Feinstein Institute for Medical Research have discovered that blood can help determine the best treatment plan for patients with ovarian cancer. More specifically, a genetic marker embedded in deoxyribonucleic acid (DNA), called microRNA, indicates if a patient with ovarian cancer has a benign or cancerous tumor, and that she will benefit from chemotherapy after surgery on the tumor. This data will be presented at the American Association for Cancer Research (AACR) Annual Meeting to be held from Saturday through Wednesday (March 31- April 4) in Chicago, IL.It is estimated that there will be 22,280 new cases and 15,500 deaths this year from ovarian cancer in the United States. Due to lack of adequate screening, the majority of patients with ovarian cancer are diagnosed at stage III (the second-to-last and most devastating stage of cancer), when 70 percent of these patients will die of their disease within 5 years.
"The discovery that microRNAs can help predict the best treatment plan for women with ovarian cancer, who are most likely at stage III of the disease, offers them enormous hope," noted Iuliana Shapira, MD, director of the Cancer Genetics Program at the North Shore-LIJ Health System's Monter Cancer Center. "We can now inform patients at stage III ovarian cancer, if they will have success with chemotherapy following surgery, similar to patients who are at stage 1 disease. This information gives them hope that their disease is curable despite being diagnosed at an 'advanced stage.' It also gives them the strength necessary to undergo chemotherapy, which is a very invasive and toxic therapy necessary to obtain the cure." (Blogger's Note: a 'forward' looking statement; see text in red highlighted below)
Several microRNAs have been found to have links with various types of cancer. The research conducted at the North Shore-LIJ Health System and the Feinstein Institute for Medical Research found that microRNA-195 increased 40 fold during chemotherapy and microRNA-16 increased 80 fold during chemotherapy. These changes may explain why some patients with ovarian cancer have side effects of chemotherapy, why others become cured of cancer as a result of chemotherapy, and why others need ongoing chemotherapy to continue living with the cancer.
"Understanding the changes in microRNA throughout chemotherapy treatment helps us better understand ovarian cancer and how best to treat patients who have this disease," said Annette Lee, PhD, associate investigator at the Feinstein Institute. "The genetic markers we identified allow patients to individualize their own therapy in order to have maximum benefit and minimal side effects. In addition, this knowledge will help researchers develop new treatments for patients with ovarian cancer."
Dr. Shapira adds that, "We applied for a government grant and hope to receive the funds needed to validate these markers allow result in women receiving therapies that are more personalized and match their genetic makeup."
Monday, April 02, 2012
Gene Maps Are No Cure-All - WSJ.com (references ovarian cancer as an example)
Gene Maps Are No Cure-All - WSJ.com
"The new study, published Monday in the journal Science Translational Medicine and presented at a meeting of the American Association for Cancer Research in Chicago, was based on data from thousands of twins in five countries. It found that for 23 of 24 diseases analyzed, most patients would get negative test results, suggesting that their risk of being stricken with these diseases is low.
In reality, the study says, their risk would be only slightly lower than that of the general population. Patients who have been gene-sequenced, particularly without a doctor's counsel, could be lulled into a false sense of security.....
"For example, one of the diseases studied was ovarian cancer. Dr. Vogelstein noted that of the 156 million or so women in the U.S., about 2.2 million are expected to get ovarian cancer at some point. But even if every woman got a whole-genome scan, the tests would be able to identify only 100,000 of them, Dr. Vogelstein said. "That tells you that 2.1 million women cannot be alerted to the fact that they will get the cancer," he said......
Sunday, April 01, 2012
abstract: Insertion of an SVA element, a non-autonomous retrotransposon, in PMS2 intron 7 as a novel cause of Lynch syndrome.
Insertion of an SVA element, a non-autonomous retrotransposon, in PMS2 intron 7 as a novel cause of Lynch syndrome.:
Hum Mutat. 2012 Mar 27;
Abstract
Heterozygous germline mutations in the mismatch repair gene PMS2 predispose carriers for Lynch syndrome, an autosomal dominant predisposition to cancer. Here, we present a LINE-1-mediated retrotranspositional insertion in PMS2 as a novel mutation type for Lynch syndrome. This insertion, detected with Southern blot analysis in the genomic DNA of the patient, is characterized as a 2.2 kb long 5' truncated SVA_F element. The insertion is not detectable by current diagnostic testing limited to MLPA and direct Sanger sequencing on genomic DNA. The molecular nature of this insertion could only be resolved in RNA from cultured lymphocytes in which nonsense-mediated RNA decay was inhibited. Our report illustrates the technical problems encountered in the detection of this mutation type. Especially large heterozygous insertions will remain unnoticed because of preferential amplification of the smaller wild-type allele in genomic DNA, and are probably underreported in the mutation spectra of autosomal dominant disorders.
Friday, March 30, 2012
open access: PLoS ONE: March 29th Integrated Analyses of microRNAs Demonstrate Their Widespread Influence on Gene Expression in High-Grade Serous Ovarian Carcinoma
PLoS ONE: Integrated Analyses of microRNAs Demonstrate Their Widespread Influence on Gene Expression in High-Grade Serous Ovarian Carcinoma
Background
The Cancer Genome Atlas (TCGA) Network recently comprehensively catalogued the molecular aberrations in 487 high-grade serous ovarian cancers, with much remaining to be elucidated regarding the microRNAs (miRNAs). Here, using TCGA ovarian data, we surveyed the miRNAs, in the context of their predicted gene targets.Conclusions
This study establishes miRNAs as having a widespread impact on gene expression programs in ovarian cancer, further strengthening our understanding of miRNA biology as it applies to human cancer. As with gene transcripts, miRNAs exhibit high diversity reflecting the genomic heterogeneity within a clinically homogeneous disease population. Putative miRNA:mRNA interactions, as identified using integrative analysis, can be validated. TCGA data are a valuable resource for the identification of novel tumor suppressive miRNAs in ovarian as well as other cancers.Sunday, March 25, 2012
open access: Resolving the variable genome and epigenome in human disease - Knight - 2012 - Journal of Internal Medicine - Wiley Online Library
Resolving the variable genome and epigenome in human disease - Knight - 2012 - Journal of Internal Medicine
pdf file
Conclusions
There
is no doubt that recent advances in genomics, currently driven by new
high-throughput sequencing techniques, are taking us to remarkable new
levels in our understanding of the human genome, and the genetic and
epigenetic variation that exists, with important implications for our
understanding of human disease. As this knowledge grows, our
appreciation of the complexity with which we are faced is also
underlined. For common multifactorial traits, GWAs have been very
informative but leave much heritable risk unresolved. Rarer variants may
prove important but in general, more integrated approaches are needed
in which environmental risk factors are considered and combined with
functional genomic analyses. Moreover, we need to derive functional
genomic data in a disease-relevant setting as the consequences of
underlying genetic and epigenetic diversity are increasingly recognized
to be highly context specific.
Current
technologies that can interrogate the whole genome carry with them
significant caveats: these tools are new, and successful application to
important biological problems requires careful experimental design and
consideration of the limitations inherent in such approaches. The data
sets involved are highly complex, and analysis remains extremely
challenging with significant risks of false positive and negative
results until the field matures. High-throughput sequencing is not a
panacea but a critical tool in current genomics.
Used wisely, it is resolving the individual genome and epigenome, at a structural and functional level, and will radically advance our understanding of disease. For Mendelian traits (Wiki) , the impact is already being felt. For common multifactorial diseases, this may take a little longer.
Used wisely, it is resolving the individual genome and epigenome, at a structural and functional level, and will radically advance our understanding of disease. For Mendelian traits (Wiki) , the impact is already being felt. For common multifactorial diseases, this may take a little longer.
open access: Apr 2012 -Role of common genetic variants in ovarian cancer susceptibility and outcome: progress to date from the ovarian cancer association consortium (OCAC) - Journal of Internal Medicine (BRCA, Lynch, high/low penetrance mutations....)
Role of common genetic variants in ovarian cancer susceptibility and outcome: progress to date from the ovarian cancer association consortium (OCAC) - Journal of Internal Medicine
open access pdf file
"In this article, we review the current knowledge of the inherited genetics of epithelial ovarian cancer (EOC) susceptibility and clinical outcome. We focus on recent developments in identifying low-penetrance susceptibility genes and the role of the ovarian cancer association consortium (OCAC) in these discoveries. The OCAC was established to facilitate large-scale replication analyses for reported genetic associations for EOC. Since its inception, the OCAC has conducted both candidate gene and genome-wide association studies (GWAS); the latter has identified six established loci for EOC susceptibility, most of which showed stronger association with the serous histological subtype. Future GWAS and sequencing studies are likely to result in the discovery of additional susceptibility loci and may result in established associations with clinical outcome. Additional rare and uncommon ovarian cancer loci will likely be uncovered from high-throughput next-generation sequencing studies. Applying these novel findings to establish improved preventative and clinical intervention strategies will be one of the major challenges of future work....
Monday, March 19, 2012
Waiting for medicine’s black swans - CMAJ
Waiting for medicine’s black swans
"Over a decade has passed since the medical world quivered
with anticipation at the completion of the Human Genome Project.
For the most part, though, those heady days have been
replaced by the sobering realization that the path from knowledge to
product is riddled with potholes.
Time, tight budgets and delivery complications have emerged as major ruts in the drive toward the pot of therapeutic gold
that was promised for the end of road....."
Thursday, March 15, 2012
abstract: Shared Genetic Basis for Breast Cancer and Breast Density
Shared Genetic Basis for Breast Cancer and Breast Density:
" Together, our results show that PMD and breast cancer have a shared genetic basis that is mediated through a large number of common variants."
Percent mammographic breast density (PMD) is a strong heritable risk factor for breast cancer. However, the pathways through which this risk is mediated are still unclear. To explore whether PMD and breast cancer have a shared genetic basis, we identified genetic variants most strongly associated with PMD in a published meta-analysis of five genome-wide association studies (GWAS) and used these to construct risk scores for 3,628 breast cancer cases and 5,190 controls from the UK2 GWAS of breast cancer.
Thursday, February 23, 2012
Whole genome sequencing in health services
Whole genome sequencing in health services:
The rapid development of fast, affordable whole genome sequencing (WGS) technologies is set to bring major changes to clinical and public health practice. The potential benefits within the next few years are significant: improved diagnosis and management of inherited diseases and cancer, and more personalised use of treatments and therapies.
The potential benefits of the new technologies are significant: improved diagnosis and management of inherited diseases and cancer, and more personalised use of treatments and therapies. However,successful delivery of a more efficient and effective system of healthcare using genomics requires:
- Creation of new biomedical informatics expertise within the NHS and building databases that will drive better understanding of which genomic variants affect health.
- Use of targeted forms of genome analysis that minimise unexpected (incidental) findings and telling patients only about medically important information that arises.
- Better understanding of genomic data interpretation among health professionals
The full report is available as a free electronic download at Next steps in the sequence.
Whole genome sequencing overview is also available.
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