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.

paywalled: Japanese Journal of Clinical Oncology- LAPTM4B Polymorphisms is Associated with Ovarian Cancer Susceptibility and Its Prognosis

LAPTM4B Polymorphisms is Associated with Ovarian Cancer Susceptibility and Its Prognosis:

Objective
Lysosome-associated protein transmembrane 4 beta (LAPTM4B) is an important novel gene associated with the proliferation and differentiation of cells. Recent studies have shown that it was overexpressed in many cancer tissues. This study investigated the association between different LAPTM4B polymorphisms and the susceptibility and prognosis of ovarian cancer.

Methods
A case–control study was performed in 282 patients with ovarian cancer and 365 control subjects. Genomic DNA was extracted from peripheral blood lymphocytes in all participants. LAPTM4B genotypes were determined using polymerase chain reaction.

Results
There was a significantly higher LAPTM4B*2 allele frequency in ovarian cancer cases than controls (P < 0.05). Using the LAPTM4B*1/1 genotype as the reference, we found that the LAPTM4B*1/2 and LAPTM4B*2/2 genotypes were positively associated with ovarian cancer.

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

• 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.

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......

science report: Treating cancer as a chronic disease? (study of clear cell ovarian cancer....)

Treating cancer as a chronic disease?

ScienceDaily (Mar. 29, 2012) — New research from the Technion-Israel Institute of Technology Rappaport Faculty of Medicine and Research Institute and the Rambam Medical Center may lead to the development of new methods for controlling the growth of cancer, and perhaps lead to treatments that will transform cancer from a lethal disease to a chronic, manageable one, similar to AIDS.............

".......For this study, the team took cells from one woman's ovarian clear cell carcinoma and injected them either into or alongside the human stem cell-derived environment. "We noticed very early on, rather strikingly, that the human cancer cells grow more robustly when they are in the teratoma environment compared to any other means in which we grew them, such as in a mouse muscle or under the skin of a mouse," says Skorecki.

The scientists were able to tease out six different kinds of self-renewing cells, based on behavior -- how quickly they grow, how aggressive they are, how they differentiate -- and on their molecular profile. This was a previously unknown finding, that one tumor might have such a diversity of cells with crucial fundamental growth properties. Tzukerman explains that the growth of the cancer cell subpopulations can now be explained by their proximity to the human cell environment.

The researchers cloned and expanded the six distinct cell populations and injected them into the human stem cell teratomas. One key observation is that some cells, which were not self-replicating in any other model, became self-replicating when exposed to the human cells.
Skorecki said that while he wasn't surprised that the human environment affected the growth, he was in fact surprised by the magnitude of the effect: "We've known for years now that cancers are complex organs, but I didn't think the power of the human stem cell environment would be so robust, that it would make such a big difference in how the cells were grown."........

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.

Remembering my sister Rosalind Franklin : The Lancet

Remembering my sister Rosalind Franklin : The Lancet

DNA donor rights affirmed : Nature News & Comment

DNA donor rights affirmed : Nature

NIH committee urges that genome study subjects be told of medically relevant results.

"It is a familiar scenario in genetic research: a subject's DNA is collected for one study, deposited in a database or biobank and then analysed by other researchers for separate studies. But what happens when a later study stumbles on something that could be of significance for the donor, such as an allele for familial hypercholesterolaemia — a treatable genetic disorder that causes progressive atherosclerosis — or some other health-related variation? Do researchers conducting secondary studies and biobanks have a duty to share such revelations with the original research subjects?

They do, when possible, according to a detailed consensus statement from a working group funded by the US National Institutes of Health (NIH) in Bethesda, Maryland, and published this week (S. M. Wolf et al. Gen. Med. http://dx.doi.org/10.1038/gim.2012.23; 2012). The statement's 26 signatories consulted dozens of other researchers and biobank managers over a two-year period. They conclude that biobanks “shoulder significant responsibility” for addressing how to deal with 'incidental findings' — those research results that could have medical consequences for the donors of genetic material.

Genetic testing is increasingly

coming up with 'incidental

findings'.

Genetics researchers are divided on the matter of incidental findings......"

abstract: Impact of Preanalytic Factors on the Design and Application of Integral Biomarkers

Impact of Preanalytic Factors on the Design and Application of Integral Biomarkers:

Molecular assays have been routinely applied to improve diagnosis for the last 25 years. Assays that guide therapy have a similar history; however, their evolution has lacked the focus on analytic integrity that is required for the molecularly targeted therapies of today. New molecularly targeted agents require assays of greater precision/quantitation to predict the likelihood of response, i.e., to identify patients whose tumors will respond, while at the same time excluding and protecting those patients whose tumors will not respond or in whom treatment will cause unacceptable toxicity. The handling of tissue has followed a fit-for-purpose approach focused on appropriateness for diagnostic needs, which is less rigorous than the demands of new molecular assays that interrogate DNA, RNA, and proteins in a quantitative, multiplex manner. There is a new appreciation of the importance and fragility of tissue specimens as the source of analytes to direct therapy. By applying a total test paradigm and defining and measuring sources of variability in specimens, we can develop a set of specifications that can be incorporated into the clinical-care environment to ensure that a specimen is appropriate for analysis and will return a true result. 

CMAJ: Who should hold the keys to your DNA?

Editor’s note: Third of a multipart series on genetic testing.
Part 1: Separating hype from reality in the era of the affordable genome (www.cmaj.ca/lookup/doi/10.1503/cmaj.109-4143).
Part 2: Popping the genetics bubble (www.cmaj.ca/lookup/doi/10.1503/cmaj.109-4142).
Next: Race and genetics in the doctor’s office



CMAJ: Who should hold the keys to your DNA?

"Opinion is divided over whether doctors or patients should be receiving the results of direct-to-consumer genetic tests........."

"“I think there is a need to think this through and to have some balance. On the one hand, we should respect consumers’ preferences and freedom to choose,” says Peter Neumann, director of the Center for the Evaluation of Value and Risk in Health at the Institute for Clinical Research and Health Policy Studies at Tufts Medical Center in Boston, Massachusetts and lead author on the paper. “We should also inform them about the risks and benefits.”
In some countries, governments have stepped in to ensure that doctors are the ones who must inform consumers about risks and benefits. Laws in France, Germany, Portugal and Switzerland stipulate that genetic tests only be administered by physicians. There are no regulations in Canada and few in the United States, though the US Food and Drug Administration has indicated that it will be stepping up efforts in the area...." 

Bioinformatics and epigenetics - computer-aided cancer diagnosis - medical press

The relatively young research field of epigenetics is the talk of the town. Many scientists expect the research on biochemical modifications beyond the actual DNA strand to lead to huge progress in the understanding of the regulation of gene activity in the years to come. Just how promising the results of epigenetic research are in terms of concrete medical applications is demonstrated by the work of Thomas Lengauer and Christoph Bock from the Max Planck Institute for Informatics in Saarbrücken. With the help of computers, they trawl through the genomes of cancer patients in search for suspect structures, and develop fast and simple new tools for improving cancer diagnosis in hospitals.


"Although Thomas Lengauer regards epigenome analysis as playing a crucial role in the attainment of rapid progress in cancer diagnosis in the near future, he plays down expectations with regard to the development of new drugs. “Many scientists point to the potential of future drugs that can repair defects in the epigenome of diseased cells. I tend to be more cautious in this regard. Such targeted interventions involve significant risks, not least because little or nothing is currently known about the highly-complex gene regulation mechanisms being manipulated here.”"

Genome Research publishes special issue: Cancer Genomics

Genome Research (www.genome.org) publishes online and in print today a special issue entitled, "Cancer Genomics," highlighting insights gained form cutting-edge genomic and epigenomic analyses of cancer.

Included in this special issue are novel biological insights gained from genomic analyses of pancreatic cancer, ovarian cancer, and melanoma, including, functional genomic analyses of breast cancer genes, large scale colorectal and breast cancer epigenomics, advances in methodology identifying driver genes and networks in cancer, in genome-wide cancer association analyses, and using next-generation sequencing technology to detect driver mutations.

Additionally, the issue includes unique perspectives from leaders in the field on the translation of cancer genomics to improved outcomes in medicine. The following sections highlight several of the papers published in the issue:

1. Whole-genome and whole-exome sequencing: Searching for the drivers of cancer
2. Circulating free DNA holds clues to cancer diagnosis and risk of relapse
3. Epigenomic analyses shed new light on breast, colon, and prostate cancers
4. Cutting-edge methods to detect the genes and networks that drive cancer
    

abstract: Balancing repair and tolerance of DNA damage caused by alkylating agents : Nature Reviews Cancer

Blogger's Note: requires subscription ($$$)

New Genetic Clues to Breast Cancer? - Drugs.com MedNews

SUNDAY Jan. 22, 2012 --
"Researchers have identified three new genomic regions they believe are linked with breast cancer that may help explain why some women develop the disease..........Scientists conducting genome-wide association studies -- research that looks at the association between genetic factors and disease to pinpoint possible causes -- had already identified 22 breast cancer susceptibility loci. Locus is the physical location of a gene or DNA sequence on a chromosome. "The three [newly identified] loci take the number of common susceptibility loci from 22 to 25," said Easton. However, the three new susceptibility loci might explain only about 0.7 percent of the familial risks of breast cancer, bringing the total contribution to about 9 percent, the researchers said.'".......

media: Unleashing the genome in the bottle (Ion Torrent dna testing)

MORE STILL TO LEARN

"Another challenge is that although a person's genome doesn't change, its meaning will. As scientists uncover more DNA variants that protect against disease and variants that make it more likely, a genome sequence that meant one thing in 2012 will have a different meaning in 2013, not to mention 2020.
A DNA variant that was once thought to be dangerous "might turn out to be benign if countered by another," says Greely. "Whose responsibility will it be to tell you that, years later?" DNA testing companies offer subscriptions that give customers regular updates like that."

Read more: http://www.vancouversun.com/health/Unleashing+genome+bottle/5990610/story.html#ixzz1jLlmdIDW

New DNA reader to bring promise | Reuters

open access Frontiers | Epigenomics of Ovarian Cancer and Its Chemoprevention | Frontiers in Epigenomics

.......Due to the atypical syndrome of the early stage of ovarian cancer, it is difficult to diagnose in its early stages. By the time most ovarian cancers are diagnosed, they are already at stage III or IV. The two most significant obstacles to the effective treatment of ovarian cancers are the lack of early diagnostic markers and the development of drug resistance after therapeutic treatment of advanced disease. Ovarian cancer screening with transvaginal ultrasound (TVU) and CA125 was evaluated in the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial, however, it was revealed that the predictive value of both tests was relatively low (Buys et al., 2005). Increasing evidence indicates that epigenetic mechanisms may play a major role in the development of ovarian cancer..........
In this analysis, we will evaluate the current status of epigenomics of ovarian cancer and will include epigenetic mechanisms involved in ovarian cancer development such as DNA methylation, histone modifications, and non-coding microRNA. Development of biomarkers, the epigenetic basis for drug resistance and improved chemotherapy for ovarian cancer will also be assessed. In addition, the potential use of natural compounds as epigenetic modulators in chemotherapy shows promise in moving to the forefront of ovarian cancer treatment strategies........

Exclusive Interview: Eye on DNA Exclusive Interview with Cancer Survivors Sandi Pniauskas and Carolyn Benivegna by Dr. Hsien-Hsien Lei (repost)

Eye on DNA | How will it change your life?

 Eye on DNA Exclusive Interview with Cancer Survivors Sandi Pniauskas and Carolyn Benivegna

by Dr. Hsien-Hsien Lei

abstract: Circulating free DNA and p53 antibodies in plasma of patients with ovarian epithelial cancers (serous/mucinous)

Blogger's Note: the connection between KRAS mutations/mucinous may be due to GI (particularly colorectal cancer eg. common denominator = KRAS mutation/mucinous cell type), see also mucinous article - to be posted subsequent to this item

BACKGROUND:
This study was conducted in order to evaluate the significance of circulating free DNA (CFDNA), blood plasma p53 antibodies (p53-Ab) and mutations of KRAS gene in the prognosis of ovarian epithelial cancers.

PATIENTS AND METHODS:

A total of 126 patients were included in this study. KRAS mutations and CFDNA were detected by means of the PCR-restriction fragment length polymorphism (PCR-RFLP) and enriched by the PCR-RFLP method. Enzyme-linked immunosorbent assay was used to analyze plasma p53-Ab.

RESULTS:

KRAS mutations were detected in 27 (21.4%) of examined tumors. The frequency of KRAS mutations was especially high in mucinous cancers (P < 0.001). CFDNA and p53-Ab were frequently detected in patients with serous cancers in high grade (P < 0.001). The overall survival rate was significantly lower for patients with serous tumors and CFDNA and p53-Ab-positive than negative tumors (P = 0.022 and P < 0.001, respectively). In mucinous ovarian cancer, a worse overall survival was correlated with the KRAS mutations (P = 0.03).

CONCLUSIONS:

The results of the present study suggested that a presence of KRAS mutations in mucinous ovarian cancer and CFDNA and p53-Ab in serous tumors was correlated with the highest risk of cancer progression.

UK: Studying DNA in Patients With Stage I, Stage II, Stage III, or Stage IV Ovarian Epithelial Cancer - Full Text View - ClinicalTrials.gov