open access: Genome Biology - Implications for health and disease in the genetic signature of the Ashkenazi Jewish population

Blogger's Note: search results = null for 'ovarian'/'brca'

 The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

Biomedcentral: open access - Biomarker robustness reveals the PDGF network as driving disease outcome in ovarian cancer patients in multiple studies

link:    ABSTRACT and open text PDF
Background:
Ovarian cancer causes more deaths than any other gynecological cancer.
Identifying the molecular mechanisms that drive disease progress in ovarian cancer is a critical step in providing therapeutics, improving diagnostics, and affiliating clinical behavior with disease etiology. Identification of molecular interactions that stratify prognosis is key in
facilitating a clinical-molecular perspective.

Results:  
The Cancer Genome Atlas has recently made available the molecular characteristics of more than 500 patients......

Blogger's Note: see also - The Cancer Genome Atlas completes detailed ovarian cancer analysis  NCI Press Release (2011)

CONCLUSIONS
"..........Over the past few decades, different genes have been used, with greater or lesser success, as biomarkers for prognostics. In the work presented here, by performing genome-wide sequential
analyses across all genes and across all pathways, starting with TCGA and validating in two additional datasets, we saw how the single-gene approach fails to stratify patients robustly into prognostic groups.


"Our results demonstrate that pathway interactions are either associated with improved prognosis by "helping" the pathway counter the tumor, or with poor prognosis by "breaking down" the pathway's normal activity. Through better understanding of the pathway mechanisms and the interactions that undergo changes, we may find targets for new treatments. The fact that the pathway we identified did not correlate with age or tumor diameter and was found in all
three datasets strengthens the hypothesis that this pathway is a core mechanism of the disease."

CAHG Study Highlights Personalized Medicine Gap - PRNewswire

medical news: Sequence of ovarian genome identifies predominant gene mutations, points to possible treatment

"....While high-grade serous ovarian adenocarcinoma is conventionally considered as one type of cancer having uniform features, "we could divide the tumors into four different groups based on gene expression patterns," said Creighton. "They look like four different cancers."
"We were able to define a set of genes that were associated with worse outcomes versus better outcomes in patients," he said. They applied this gene signature to other sets of data collected about ovarian cancer and found that the profile predicted worse or better outcome there as well.
"These data are all public (blogger's note - refers to the Cancer Genome Atlas)," said Creighton. "They are meant for people to use to find specific genes for research. They could influence a lot of future studies."...cont'd

Cancer's Last Stand? The Genome Solution - Wielding Genomes in the Fight Against Cancer - NYTimes.com

"The researchers agreed that there should be global clinical trials of new cancer drugs, and that all patients should have genetic information about their tumors entered into databases that researchers everywhere could study. Dr. Lander said that concerns about genetic privacy had been “fetishized,” and that the potential harm to patients from releasing their genetic information paled next to the harm threatened by their disease."

abstract: Editorial: Whole-Genome Sequencing, April 20, 2011 JAMA

Note: full access requires subscription ($$)

Whole-Genome Sequencing

Since this article does not have an abstract, we have provided the first 150 words of the full text.

KEYWORDS:
• EARLY DIAGNOSIS,
• GENETIC PREDISPOSITION TO DISEASE,
• GENOME, HUMAN,
• LEUKEMIA, MYELOID, ACUTE,
• LEUKEMIA, PROMYELOCYTIC, ACUTE,
• MUTATION,
• NEOPLASMS,
• ONCOGENE PROTEINS, FUSION,
• ONCOGENES,
• SEQUENCE ANALYSIS, DNA,
• TIME FACTORS,
• TP53 GENES,
• TP53 PROTEIN, HUMAN.

The past 60 years have witnessed remarkable progress in genetics and genomics from the description of the DNA double helix by Watson and Crick ¹ to the release of the first draft sequence of the human genome in 2001 ^{2, 3} and the successful completion of the human genome project in 2003. ⁴ From that time, there has been increasing hope and expectation that, as soon as the cost of sequencing the whole genome could become affordable, the promise of personalized medicine would be fulfilled.

No field of medicine has benefited more from advances in genomics and the application of genetic testing than oncology. These advances have had a substantial influence on cancer risk assessment, determination of prognosis, and choice of treatment. Clinical applications of novel genetic tools include sequencing and analysis of germline genomic rearrangements at key cancer genes like BRCA1, BRCA2, and TP53 ⁵; …

NCI Cancer Bulletin: Whole-Genome Sequencing Improves Cancer Diagnoses (including some good links eg Li-Fraumeni Syndrome, BRCA, Editorial)

Whole-Genome Sequencing Improves Cancer Diagnoses

Although whole-genome sequencing is not yet ready for routine clinical use, two studies show how the approach could improve the diagnosis and, potentially, the treatment of cancer. The reports, in the April 20 Journal of the American Medical Association, describe how researchers at Washington University School of Medicine in St. Louis and their colleagues used whole-genome sequencing to investigate the cases of two patients.
The first study focused on a 42-year-old woman who died from leukemia that was probably related to previous treatment for breast and ovarian cancers. The woman did not have a known family history of cancer, and tests for mutations in the breast cancer-associated genes BRCA1 and BRCA2 were negative. But a comparison of the genomes of her cancer cells and normal cells revealed a novel mutation in the TP53 gene that altered the function of the encoded protein. TP53 gene mutations have been implicated in a number of cancers, including some early-onset breast and ovarian cancers, as well as Li-Fraumeni syndrome.
The TP53 mutation does not appear to have been inherited from one of the patient’s parents. But because the mutation was seen in both normal and cancer cells, it had to have occurred very early in the patient’s life, possibly at conception. Thus, the mutation could have been present in her germline DNA and been passed on to her children, the researchers noted.
As specified by the study protocol, the researchers contacted the woman’s primary care physician, who then discussed the issue with the patient’s family members and encouraged them to seek genetic counseling. “Even though the patient died, her contribution to this study yielded new knowledge that might one day save the lives of her children,” study co-author Dan Koboldt of the Genome Institute at Washington University wrote in a post about the studies on his blog, MassGenomics.
The second study involved a 39-year-old woman with a form of acute myeloid leukemia (AML). A comparison of DNA from her tumor and normal cells revealed a fusion of two genes in her blood cells that was not detected through routine cytogenetic testing. The presence of this gene fusion is associated with good outcomes after chemotherapy. Consequently, the patient’s doctors recommended chemotherapy rather than stem cell transplantation, the treatment that had been indicated by the standard diagnostic testing results.
At the time of publication, the woman had been in remission for 15 months. The sequencing, analysis, and validation of the fusion gene were completed in just 7 weeks, which was quick enough that doctors could use the information to choose the most effective treatment for the patient, the researchers noted.
“These cases of personalized genomic medicine are just some of the first examples of what will likely be commonplace in the near future,” wrote the authors of an accompanying editorial.
“Clearly, the technology will no longer be the major impediment to widespread clinical use of these tools, and the main challenges will soon move to the clinical implementation and interpretation of genomic data,” the authors added.

press release: Decoding cancer patients' genomes is powerful diagnostic tool (and potential treatments)

Expression of DNA repair genes in ovarian cancer samples: Biological and clinical considerations

Abstract

The purpose of this study was to investigate retrospectively the mRNA expression of genes involved in different DNA repair pathways implicated in processing platinum-induced damage in 171 chemotherapy-naïve ovarian tumours and correlate the expression of the different genes with clinical parameters. The expression of genes involved in DNA repair pathways (PARP1, ERCC1, XPA, XPF, XPG, BRCA1, FANCA, FANCC, FANCD2, FANCF and PolEta), and in DNA damage transduction (Chk1 and Claspin) was measured by RT-PCR in 13 stage I borderline and 77 stage I and 88 III ovarian carcinomas.  


ERCC1, XPA, XPF and XPG genes were significantly less expressed in stage III than in stage I carcinoma; BRCA1, FANCA, FANCC, FANCD2 gene expressions were low in borderline tumours, higher in stage I carcinomas and lower in stage III samples. High levels of ERCC1, XPA, FANCC, XPG and PolEta correlated with an increase in Overall Survival (OS) and Progression Free Survival (PFS), whilst high BRCA1 levels were associated with PFS on univariate analysis.

With multivariate analyses no genes retained an association when adjusted by stage, grade and residual tumour. A tendency towards a better PFS was observed in patients with the highest level of ERCC1 and BRCA1 after platinum-based therapy than those given both platinum and taxol. The expression of DNA repair genes differed in borderline stage I, stage I and stage III ovarian carcinomas. The role of DNA repair genes in predicting the response in ovarian cancer patients seems far from being established.

Progress Being Made in Genome Sequencing - Medscape interview (in research)

Note: the specific references in this article are colorectal cancer but of interest (re: metastases)

The rise of the genome bloggers : Nature News (not amateurs)

“They are not amateurs. They are far from being amateurs.”

abstract: Effect of genome-wide association studies, direct-to-consumer genetic testing, and high-speed sequencing technologies on predictive genetic counselling for cancer risk : The Lancet Oncology

New Whitehead Fellow on the Hunt for Rare Genetic Mutations

New Whitehead Fellow on the Hunt for Rare Genetic Mutations

"As Whitehead Institute’s newest Fellow, Yaniv Erlich comes to Cambridge in search of needles in very large haystacks.In Erlich’s case, the needles are rare genetic variants or mutations occurring in individual human genomes. His quest is born of the growing realization that large-scale genome sequencing projects—genome-wide association studies (GWAS)—are failing to pinpoint genetic causes of common diseases. Indeed, mounting evidence suggests that the common genetic mutations that GWASs have surfaced reveal little about disease manifestation and inheritance risk.
It now appears that rare variants are behind many diseases, prompting the development of the so-called common disease-rare variant hypothesis...."cont'd

Largest Study Matching Genomes To Potential Anticancer Treatments Releases Initial Results blog - Libby's H*O*P*E*

Libby's Hope Blog
see section: Ovarian Cancer Sample Gene Mutation Prevalence

BioMed Central Blog : Correspondence: Sequencing of a tumor and its metastases

Note: Correspondence (in full), still early days in research but progress noted 

"In an article just published in Genome Biology, Steven Jones and colleagues at the British Columbia Cancer Agency have used next generation sequencing to monitor the development of a tumor as it metastasized and used the genomic information to inform treatment.

Cancers are known to accumulate mutations as they progress, and there are several mutations characteristic of metastases. However, even the most well-characterised of tumor types show genetic heterogeneity, and there are few data available for rare tumor types. The recent advent of next generation sequencing technology, allowing rapid and inexpensive genome sequencing, has made it possible to explore the genomic landscape of tumors in more detail.

In this study, a man presented with an unusual cancer of the tongue. He received surgery and radiotherapy, but was subsequently found to have metastases in the lungs. The patient was initially treated with the EGFR inhibitor erlotinib, but the lung metastases continued to grow. Sequencing of the metastases uncovered amplification of the RET oncogene, which explained the resistance to erlotinib, and also suggested the use of the RET inhibitor sunitinib. This drug reduced the size of the lung lesions for a few months, before they started to grow again. A skin metastasis was also detected, and sequencing uncovered seven new mutations that were present in neither the lung metastases nor the original tongue tumor. It appeared that the tumor had upregulated the AKT signalling pathway to compensate for the inhibition of the RET pathway.

This eloquent study demonstrates nicely both how tumors respond to treatment with compensatory changes and also how genomics can be used to guide medical treatment.

No Gene For That? | The Daily Scan | GenomeWeb (personality)

abstract: DNA copy numbers profiles in affinity-purified ovarian clear cell carcinoma (research/pathology)

Note: in research

CONCLUSIONS: This study provides the first high resolution, genome-wide view of DNA copy number alterations in ovarian CCC. The findings provide a genomic landscape for future studies aimed at elucidating the pathogenesis and developing new target-based therapies for CCCs.


Abstract

PURPOSE: Advanced ovarian clear cell carcinoma (CCC) is one of the most aggressive ovarian malignancies, in part because it tends to be resistant to platinum-based chemotherapy. At present, little is known about the molecular genetic alterations in CCCs except that there are frequent activating mutations in PIK3CA. The purpose of this study is to comprehensively define the genomic changes in CCC based on DNA copy number alterations.

EXPERIMENTAL DESIGN: We performed 250K high-density single nucleotide polymorphism array analysis in 12 affinity-purified CCCs and 10 CCC cell lines. Discrete regions of amplification and deletion were also analyzed in additional 21 affinity-purified CCCs using quantitative real-time PCR.

RESULTS: The level of chromosomal instability in CCC as defined by the extent of DNA copy number changes is similar to those previously reported in low-grade ovarian serous carcinoma but much less than those in high-grade serous carcinoma. The most remarkable region with DNA copy number gain is at chr20, which harbors a potential oncogene, ZNF217. This discrete amplicon is observed in 36% of CCCs but rarely detected in serous carcinomas regardless of grade. In addition, homozygous deletions are detected at the CDKN2A/2B and LZTS1 loci. Interestingly, the DNA copy number changes observed in fresh CCC tissues are rarely detected in the established CCC cell lines.

CONCLUSIONS: This study provides the first high resolution, genome-wide view of DNA copy number alterations in ovarian CCC. The findings provide a genomic landscape for future studies aimed at elucidating the pathogenesis and developing new target-based therapies for CCCs.

How to read a genome-wide association study « Genomes Unzipped

interactive map: human genome/dna - the 'A T,C and G's' of the human genome (BBC) plus video

Note: #3 'junk dna' - there is still much to be learned in those 'junk dna'
 (maybe not 'junk' after all)
 
Introduction All the biological instructions needed to make a human being can be written in just four letters. But the book of those instructions is over three billion letters long. Here, BBC News Online shows how you go from A, T, G and C to a whole person.

also: short video on 'junk dna'

Guest Blog: A genome story: 10th anniversary commentary by Francis Collins

".....Already, in its pilot phase, this NIH-supported project has produced comprehensive molecular classification systems for ovarian cancer and glioblastoma, which is the most common form of brain cancer. This information may help doctors do a better job of matching individual patients with the therapies that are most likely to work well for them. What's more, the findings may lead to new therapies directed at the molecular changes underlying various subtypes of cancer.

Some of this is already happening today...."