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

Scientists decipher missing piece of first-responder DNA repair machine

Friday, October 2, 2009

Scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory and the Scripps Research Institute have uncovered the role played by the least-understood part of a first-responder molecule that rushes in to bind and repair breaks in DNA strands, a process that helps people avoid cancer.

Last piece of MRN puzzel falls into place

With this final piece of the puzzle in place, scientists can better understand how the repair mechanism fends off cancer in healthy people, and conversely, how it helps cancer cells resist chemotherapy. This could enable researchers to develop more effective therapies with fewer side effects.

The team deciphered the poorly understood component using innovative x-ray imaging techniques at Berkeley Lab’s Advanced Light Source, which generates intense light for scientific research. They found that it extends from the repair machinery like a flexible arm and grabs molecules that are needed to help the machine zip severed DNA strands back together.

Their work is published in the October 2, 2009 issue of the journal Cell.

“This not only reveals how life works at a fundamental level, but also promises to guide the development of cancer treatments,” says John Tainer of Berkeley Lab’s Life Sciences Division and the Scripps Research Institute in La Jolla, CA. Tainer co-led the research with Paul Russell of the Scripps Research Institute.

The first-responder machine, a protein complex called Mre11-Rad50-Nbs1 (or MRN for short), homes in on the gravest kind of breaks in which both strands of a DNA double helix are cut. It then stops the cell from dividing and launches an error-free DNA repair process called homologous recombination, which replaces defective genes. If unrepaired, double strand breaks can lead to the proliferation of cancer cells.

Unfortunately, MRN’s laser-like focus on DNA repair means that it also mends broken DNA in cancerous cells. This sometimes stymies chemotherapy treatments that kill cancer cells by inducing double strand DNA breaks.

Because of its key roles — good and bad — scientists have painstakingly studied MRN since 1995 to learn how it works in healthy people, how its mutations promote diseases such as cancer, and to possibly disable it during cancer treatment.

Despite more than a decade of effort, a critical part was missing: a protein called Nsb1 that is represented by the ‘N’ in MRN.

To determine Nsb1’s function, the team used an Advanced Light Source beamline called SIBYLS, which yields extremely high-resolution images of the crystal structure of a protein via a technique called x-ray crystallography. The beamline is also equipped with small-angle x-ray scattering, which can determine a protein’s overall architecture in solution, a critical step that approximates how a protein appears in its natural state — such as inside a cell.

The scientists trained these two tools on human and yeast Nsb1 proteins. (DNA repair is so essential to life that many of the molecular machines that perform it have changed little throughout evolution). Importantly, the team studied Nbs1 bound to a partner protein that opens DNA during the first steps of double strand break repair. This enabled them to observe Nsb1 at work.

They found that Nbs1 attaches to the MR protein complex precisely where the protein complex converges on the DNA break. Nsb1 also bends in the middle like an elbow to channel molecules to the repair site.

These insights offer the best glimpse yet of how Nsb1 works and how damaged Nsb1 can lead to disease. It also suggests ways to monkey wrench MRN so that it can’t repair DNA during chemotherapy. Perhaps a molecule can be wedged into Nsb1’s elbow joint so it can’t bend, rendering the MRN complex useless.

“These crystal and solution structures have given us an exciting leap forward in our understanding of the Nbs1 and how defects in the protein cause disease,” says Scott Classen of Berkeley Lab’s Physical Biosciences Division.

Adds Tainer, “Understanding how the body responds to DNA breaks is fundamental for cancer interventions and gene therapies. These results open the door to controlling the repair of DNA breaks for cancer therapeutics and gene targeting.”

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DOE/Lawrence Berkeley National Laboratory: http://www.lbl.gov

Thanks to DOE/Lawrence Berkeley National Laboratory for this article.

DNAWellnessinfo.com Resource:  http://www.labspaces.net/99978/Scientists_decipher_missing_piece_of_first_responder_DNA_repair_machine

New Hope For Deadly Childhood Bone Cancer: Surprising Discovery Made By Studying ‘Junk DNA’

ScienceDaily (Sep. 1, 2009) — Researchers at Huntsman Cancer Institute (HCI) at the University of Utah have shed new light on Ewing’s sarcoma, an often deadly bone cancer that typically afflicts children and young adults. Their research shows that patients with poor outcomes have tumors with high levels of a protein known as GSTM4, which may suppress the effects of chemotherapy

The research is published online in the journal Oncogene.

“Doctors and researchers have long known that certain Ewing’s sarcoma patients respond to chemotherapy, but others don’t even though they have the same form of cancer,” says HCI Investigator Stephen Lessnick, M.D., Ph.D. “Our research shows that GSTM4 is found in high levels among those patients where chemotherapy doesn’t seem to work. It’s found in low levels in patients where chemotherapy is having a more positive effect.”

The research could lead to drugs that can suppress GSTM4 in certain patients. It also could lead to a screening test that could reveal which therapies will be most effective for patients. “GSTM4 doesn’t seem to suppress the benefits of all chemotherapy drugs, just certain ones. A GSTM4-based test could help to identify the best therapy for each individual patient,” Lessnick says.

Ewing’s sarcoma is the second most common bone cancer in children and adolescents. The five-year survival rate is considered poor at about 30 percent if the cancer has spread by the time it is diagnosed, and there is an even poorer prognosis for patients who have suffered a relapse.

For this study, researchers focused on an abnormal protein known as EWS-FLI, which is found in most Ewing’s sarcoma tumors. What they discovered is that EWS-FLI causes increased amounts of the GSTM4 gene – and the protein it produces – to be expressed in tumors, a previously unknown effect that led them to make the connection between poor outcomes and high levels of GSTM4. The discovery was made by focusing on repetitive DNA sequences called microsatellites. Microsatellites are sometimes referred to as “junk DNA” because they are not thought to have a normal role in the genome. By examining how EWS-FLI interacts with certain microsatellites, Lessnick and his team were able to identify GSTM4.

Lessnick says the next step in research is to focus on testing and treatments that may lead to better survival rates in patients. “Personalized medicine is the next frontier in the battle against cancer,” he says. “We now know all cancers are not the same. By focusing on how these proteins are expressed in individual tumors, we may soon be able to offer the treatment that will work best for each patient, and that could lead to higher cure rates,” he says.

Lessnick is director of HCI’s Center for Children’s Cancer Research, and is a Jon and Karen Huntsman Presidential Professor in Cancer Research. This research was supported by funds from the Terri Anna Perine Sarcoma Fund, the Liddy Shriver Sarcoma Initiative, the Sunbeam Foundation, the Huntsman Cancer Foundation, and Alex’s Lemonade Stand Foundation.