TGen-Mayo Clinic study discovers role of DNA methylation in multiple myeloma blood cancer

Science Centric | 1 October 2010 11:18 GMT

DNA methylation – a modification of DNA linked to gene regulation – is altered with increasing severity in a blood cancer called multiple myeloma, according to a study by Mayo Clinic and the Translational Genomics Research Institute (TGen).

And at specific points of DNA, ‘global hypomethylation,’ in which many genes lose the modification, may be associated with the step-by-step development of myeloma, according to a scientific paper published this month in the journal Cancer Research.

‘This is the first study to show that hypomethylation occurs early in the development of multiple myeloma and increases through disease progression,’ said Dr Bodour Salhia, a TGen cancer researcher and the paper’s lead author.

DNA methylation suppresses the expression of viral genes and other harmful elements incorporated over time into an individual’s genome. In cancer, hypermethylation at certain genomic locations can turn tumour suppressing genes off, while hypomethylation in some instances may lead to the over-expression of oncogenes, or those genes that give rise to cancer, and is linked to chromosomal instability.

However, there is still much to learn about the consequences of altered methylation.

In this study, researchers examined the methylation status of more than 1,500 CpGs. This is shorthand for C-phosphate-G, or cytosine and guanine – two of the four chemicals that comprise DNA – separated by a phosphate group, which links the two nucleosides together.

Researchers used a high-throughput universal bead array technology to examine CpG methylation at different stages of multiple myeloma, evaluating DNA methylation events associated with the progression of tumours.

They performed DNA methylation profiling analysis for more than 800 genes, including tumour suppressors, oncogenes, and genes involved in cancer-related cellular processes. This process contrasts with previous studies that focused on the analysis of a single gene.

They found only a few genes that were hypermethylated, but importantly found many more hypomethylated genes, even in the earliest stages of multiple myeloma.

‘Our data suggest that the overall degree of methylation may have some prognostic value, and further studies are needed to determine the functional and clinical significance of our findings,’ said Dr John Carpten, Director of TGen’s Integrated Cancer Genomics Division and the paper’s senior author.

Dr Salhia, added, ‘This study represents the most comprehensive examination to date of the role of methylation in multiple myeloma, and is expected to lead to an improved understanding of the biological mechanisms involved in the development of this type of cancer.’

The study of DNA methylation falls under epigenetics – an emerging field in cancer research. Unlike the study of genetics, epigenetics refers to the study of gene activity that does not involve hardwiring alterations in the genetic code. These epigenetic events, which lay atop the genome, are an intricate and heritable mechanism of regulating the expression of genes.

‘Understanding the full spectrum of epigenetic modifications will be key to improving the clinical management of the disease, and studies should continue to find new ways of treating multiple myeloma by targeting the multiple myeloma epigenome. This study also emphasises that hypomethylating strategies may not be the next necessary steps in drug development.’ said Rafael Fonseca, M.D., Deputy Director of Mayo Clinic Cancer Centre in Arizona.

Source: TGen

DNAWellnessnessinfo.com Resource:  http://www.sciencecentric.com/news/10100122-tgen-mayo-clinic-study-discovers-role-dna-methylation-multiple-myeloma-blood-cancer.html

Cancer treatment found among junk DNA

September 27, 2010

AAP

Australian scientists have found a new and potent way to fight cancer among what was once thought of as junk DNA.

The experimental technique, proven to shrink tumours in mice, involves “microRNA”.

Dr Alex Swarbrick said this new class of genes was until recently considered to be junk DNA, the term used to describe the bulk of information contained in the genome that has no apparent purpose.

But far from being junk, he said one specific type of microRNA (microRNA 380) has been found to play a pivotal role in allowing certain types of cancer to grow.

Dr Swarbrick and his research colleagues also found that blocking the action of this microRNA in mice with neuroblastoma cancers caused their tumours to shrink.

“The revolutionary thing about this finding is that it’s the first time anyone has blocked the growth of a primary tumour by the simple delivery of a microRNA inhibitor…,” Dr Swarbrick, from Sydney’s Garvan Institute of Medical Research, said.

“That, of course, makes this microRNA a potential therapeutic target for all cancers that depend on it.”

The discovery points to a new way to combat cancer that could be as simple as a twice-weekly injection of a microRNA inhibitor.

MicroRNA 380 has its cancer-promoting effect on the body by disabling another gene (P53), which is known as the “guardian of the genome” because of its role in suppressing tumour growth.

Dr Swarbrick said the studies in mice showed how their P53 gene was disabled by “overproducing” microRNA 380.

He said this microRNA served a necessary purpose in embryos when cells needed to divide quickly and it should play no role in a “normal adult’s cells”.

It was not yet known why it could become active and with cancer-causing effects later in life.

“By blocking it, you’re effectively returning cells to normal,” Dr Swarbrick said.

“We still don’t know why it gets switched on again in certain cancers.

“(However) understanding that certain cancers appear to be regulated like this gives us a new avenue to explore in their treatment.”

Dr Swarbrick said the technique could also be applied to treat brain tumours as well as melanoma, which are known to be caused by a disabled P53 gene.

The research was conducted along with Brisbane-based Dr Susan Woods from the Queensland Institute of Medical Research, and a colleague in the US.

The results are reported in the journal Nature Medicine on Monday.

© 2010 AAP

DNAWellnessinfo.com Resource:  http://news.smh.com.au/breaking-news-national/cancer-treatment-found-among-junk-dna-20100927-15sv8.html

Vital cues for cancer prevention through DNA repairing gene

Naveen Kumar, TNN, Mar 6, 2010, 10.23pm IST

VARANASI: Now, the study of DNA repairing gene using single nucleotide polymorphism (SNP) marker would provide vital cue for cancer prevention, especially neck and head that comprises of as many as seven different types of cancer in the facial region. In addition, the study would also enable early prediction of much feared breast cancer in women.

While a team of scientists is studying the genomics in cancer, especially the squamous cell carcinoma in neck, head and breast region under the Hap Map project, the case studies in the last five years have revealed interesting contribution of DNA repairing genes including P53 associated genes, where SNP can be used as a marker for prompt diagnostic purpose.

Senior scientist Central Drug Research Institute Lucknow Dr SK Rath told TOI on Saturday, “The studies have shown that P53 associated genes play a vital role in DNA repair and act as tumour suppressor. It changes the DNA repair scene and plays pivotal role in protection against mutagenic and cytotoxic effects of DNA damage that also prevents cancer.” Similarly, SNP could also provide vital cue for DNA repairing in BRAC 1 and 2 genes that are believed to cause breast cancer in women, he added.

It is to be mentioned here that Dr Rath is a key member of the team that studied genotype of cancerous and non-cancerous cells under the project in the Xth five-year plan. Now, the team is researching on SNP of different people including smokers and non-smokers, drinkers and non-drinkers, where the cause of cancer

could not be ascertained.

Saying that million of SNPs exist in human genome that occur in gene within the regulatory region, Dr Rath emphasised that the method detects the most common type of variation in the genome, as it cater to small alteration, providing better scope for prediction. The SNP markers are preferred for population genomic disease association and are good indicators of squamous cell carcinoma in neck and head region that includes cancers of oral cavity, pharynx, nasopharynx, oropharynx, hypopharynx and tongue, he added.

Stressing that cancers of neck and head region are growing at alarming rate in states like UP, he said the case studies in Lucknow revealed that out of 100 cancer patients, the number of patients with cancer in the neck and head region increased from 30 to 49 (150 per cent increase) in the last five years. Worldwide, it is the fifth most common type of cancer affecting over one million population annually, he concluded.

DNAWellnessinfo.com Resource:  http://timesofindia.indiatimes.com/city/varanasi/-Vital-cues-for-cancer-prevention-through-DNA-repairing-gene/articleshow/5648729.cms

Blood Tests May Reveal Tumor Size

Feb. 22, 2010 – cbsnews.com

(CBS) This article was written by Discover’sAndrew Moseman.

Doctors who are torn over how aggressively to treat a cancer patient, not knowing whether a tumor has fully regressed or is coming back, might someday be able to find out just by testing the patient’s blood. In a study forthcoming his week in Science Translational Medicine, John Hopkins researchers say they have tested a way to spot the “fingerprint” of cancer-the changes to the

Jeffery Schloss of the National Human Genome Research Institute, who wasn’t involved in the study, likened the approach to drawing a map. Sequencing the letters of the genetic code would be akin to plotting every house in a large neighborhood. The Hopkins team was looking only for neighborhoods-in particular, neighborhoods out of place compared with where they would be in normal tissue. The researchers in the study looked at tissue from people with breast or bowel cancer, and found multiple DNA rearrangements in each of the samples of cancerous tissue.

In each patient, the genetic changes in the cancerous cells amount to a unique marker of the patient’s tumor, the researchers say. Using blood samples from two of the colorectal cancer patients, they found the test was sensitive enough to detect this marker or “fingerprint” DNA that had been shed by tumors into the bloodstream.

The study’s approach could be invaluable for tracking the progress of a tumor. When a cancer is operated on or treated with radio – or chemotherapy, the levels of the fingerprint should fall, and vanish altogether if the tumor has been eradicated. Indeed, in one of their patients, the study authors saw the cancer biomarker drop after surgery but then rise again, suggesting to them that the cancer wasn’t fully eradicated.

Because the technique requires sequencing a person’s whole genome, it’s not coming to a hospital near you in the immediate future, says study author Bert Vogelstein: “This is really personalized medicine. This is not something off the shelf…. This is something that has to be designed for each individual patient”. But with the cost of genome sequencing rapidly coming down in price, this kind of approach might not be too far away, and doctors could use it to catch a recurring cancer before it’s large enough to be visible to other methods, like CT scans.


By Andrew Moseman
Reprinted with permission from Discover

DNAWellnessinfo.com Resource: http://www.cbsnews.com/stories/2010/02/22/tech/main6232081.shtml

Breast cancer is not a single disease, scientists discover

Cancer Researchers Focus On DNA Damage

POSTED: 3:08 pm PST December 16, 2009

Understanding DNA Repair and Cancer

ScienceDaily (Dec. 3, 2009) — A protein that plays a key role in copying DNA also plays a vital role in repairing breaks in it, UC Davis scientists have found. The work is helping researchers understand how cancer cells can resist radiation and chemotherapy, as well as how cells become cancerous in the first place.

The protein, known as proliferating cell nuclear antigen, forms a ring that fits around the DNA double helix. This cuff-like ring helps to keep in place DNA polymerase, the enzyme that makes a copy of the DNA strand when cells divide into two new cells.

The new study, published Nov. 25 in the journal Molecular Cell, shows that PCNA performs a similar function during DNA recombination — when pairs of chromosomes line up and exchange strands of DNA. Recombination occurs when cells divide to form eggs and sperm, and also when cells try to repair breaks that cross both strands of DNA.

“This is a new trick from an old horse,” said Wolf-Dietrich Heyer, professor of microbiology at UC Davis and leader of the molecular oncology program at the UC Davis Cancer Center.

The system developed by Heyer and colleagues for their experiments, using defined DNA substrates and purified proteins in a test tube, can be used to investigate the behavior of other molecules involved in copying and repairing DNA as well, he said.

Heyer’s lab works primarily with yeast. While yeast don’t get cancer, Heyer notes that their DNA recombination and repair machinery is essentially the same as in humans. This problem was solved by evolution a long time ago, he said.

Radiation therapy and cancer drugs both cause breaks in cancer cells’ DNA. Create enough breaks, and the malignant cell dies — but at the same time, the cell’s repair machinery is at work patching and sealing the gaps.

Understanding how DNA recombination and repair work could open up ways to make tumors more vulnerable to treatment, or to predict how well patients will fare with a specific treatment. The research could also reveal genes that predispose some people to cancer. For example, the “breast cancer gene,” BRCA-2, is involved in DNA repair.

“We now know a lot about the molecules involved in DNA repair; we’re beginning to think about how they can be used in the clinic,” Heyer said.

Co-authors of the study were UC Davis graduate student Xuan Li, now a postdoctoral fellow at Harvard Medical School; and research lab supervisor Carrie Stith and Professor Peter Burgers, both of the Department of Biochemistry and Molecular Biophysics at Washington University School of Medicine in St. Louis. The work was funded by the National Institutes of Health.

DNAWellnessinfo.com Resource:  http://www.sciencedaily.com/releases/2009/12/091203171716.htm

Loss Of Tumor-suppressor And DNA-maintenance Proteins Causes Tissue Demise

ScienceDaily (Oct. 15, 2009) — A study published in the October issue of Nature Genetics demonstrates that loss of the tumor-suppressor protein p53, coupled with elimination of the DNA-maintenance protein ATR, severely disrupts tissue maintenance in mice. As a result, tissues deteriorate rapidly, which is generally fatal in these animals. In addition, the study provides supportive evidence for the use of inhibitors of ATR in cancer therapy.

Hair follicle regeneration by undamaged cells (red, left panel) is delayed by the presence of damaged cells (arrows, right panel). Damaged cells are maintained because of the absence of p53 (right panel). (Credit: Yaroslava Ruzankina, PhD; David Schoppy; Eric Brown, PhD, University of Pennsylvania School of Medicine)

Essentially, says senior author Eric Brown, PhD, Assistant Professor of Cancer Biology at the University of Pennsylvania School of Medicine, the findings highlight the fact that day-to-day maintenance required to keep proliferative tissues like skin and intestines functional is about more than just regeneration, a stem cell-based process that forms the basis of tissue renewal. It’s also about housekeeping, the clearing away of damaged cells.

Whereas loss of ATR causes DNA damage, the job of p53 is to monitor cells for such damage and either stimulate the early demise of such cells or prevent their replication, the housekeeping part of the equation. The findings indicate that as messy as things can become in the absence of a DNA maintenance protein like ATR, failing to remove resulting damaged cells by also deleting p53, is worse. “Because the persistence of damaged cells in the absence of p53 prevents appropriate tissue renewal, these and other studies have underscored the importance not only of maintaining competent stem cells, but also of eliminating what gets in the way of regeneration,” explains Brown.

“An analogy to our findings is what happens to trees during the changing seasons,” says Brown. “In springtime, leaves are new and undamaged. But as the summer wears on, the effects of various influences – insects, drought, and disease – cause them to lose the pristine qualities they once had. However, the subsequent fall of these leaves presents a unique opportunity for regeneration later on, a chance to rejuvenate from anew without pre-existing obstacles. Similarly, by suppressing the accumulation of damaged cells in tissues, p53 permits more efficient tissue renewal when ATR is deleted.”

Cells without ATR that remain uncleared may be block tissue regeneration either by effectively refusing to relinquish space to undamaged cells, or by secreting signals that halt regeneration until they have been removed.

These results came as something of a surprise, says Brown. Previous studies pairing DNA-repair mutations with p53 mutations always led to a partial rescue of the DNA repair mutation “We think this happens because p53 loss helps cells with just a little DNA damage to continue to contribute to the tissue” says Brown. So at a minimum, the team expected nothing to happen.

“But we got the opposite result: Absence of p53 did not rescue the tissue degeneration caused by ATR loss, it made it much worse. This result suggested that allowing mutant cells without ATR to persist is more harmful to tissues than eliminating them in the first place.” Brown speculates that could be because the ATR mutation produces much more damage than most other DNA-repair defects.

According to Brown, their findings and those of other laboratories also reinforce the potential of a new therapeutic for cancer. That’s because, among their other discoveries, the team noticed that cells missing both ATR and p53 have more DNA damage than those missing either gene alone. As a large fraction of human cancers have p53 mutations, he says, “p53-deficient tumors might be especially susceptible to ATR inhibition.” Indeed, clinical trials already are underway involving an ATR partner protein called Chk1. “Our study provides supportive evidence for the potential use of ATR/Chk1 inhibitors in cancer therapy,” says Brown

The report was supported by the National Institute on Aging and the Abramson Family Cancer Research Institute.

Laboratory members Yaroslava Ruzankina, PhD and MD/PhD student David Schoppy are lead authors of this study. Amma Asare, Carolyn Clark, and Robert Vonderheide, all from Penn, are co-authors.

Canadian researchers decode DNA of breast cancer tumor

Triangle Business Journal – by James Gallagher Triangle Business Journal – 10/7/09

Gene Discovery May Advance Head and Neck Cancer Therapy

Expanded list of genetic links might improve diagnosis, treatment, researchers say

MONDAY, Oct. 5 (HealthDay News) — In a finding that could have a major impact on the diagnosis and treatment of one of the most deadly types of cancer, U.S. researchers have identified 231 potential new genes associated with head and neck cancer

Previously, only 33 genes were known to be linked to head and neck cancer, which includes cancers of the mouth, nose, sinuses, salivary glands, throat and lymph nodes in the neck.

“These new genes should advance selection of head- and neck-specific gene targets, opening the door to promising new molecular strategies for the early detection and treatment of head and neck cancer. It also may offer the opportunity to help monitor disease progression and a patient’s response to treatment,” study lead author Maria J. Worsham, director of research in the oncology department at Henry Ford Hospital, Detroit, said in a news release.

She and her colleagues examined DNA in five head and neck cancer tumor samples for 1,043 possible cancer-related genes. Of the 231 potential new genes associated with head and neck cancer, 50 percent were present in three or more of the DNA samples and 20 percent were present in all five samples.

The study was scheduled to be presented Oct. 4 at the annual meeting of the American Academy of Otolaryngology–Head and Neck Surgery Foundation in San Diego.

Head and neck cancer causes 2.1 percent of all cancer deaths in the United States. About 39,000 Americans develop head and neck cancer a year, according to the U.S. National Cancer Institute. Tobacco use is linked to 85 percent of head and neck cancers, according to the Cancer Institute.

More information

The American Society of Clinical Oncology has more about head and neck cancer.

DNAWellnessinfo.com Resource:  http://health.usnews.com/articles/health/healthday/2009/10/05/gene-discovery-may-advance-head-and-neck-cancer.html