Switching off a key DNA repair system in the developing nervous system is linked to smaller brain size as well as problems in brain structures vital to movement, memory and emotion, according to new research led by St. Jude Children’s Research Hospital scientists.

The work, published in the August issue of the journal Nature Neuroscience, also provides the first evidence that cells known as cerebellar interneurons are targeted for DNA damage and are a likely source of neurological problems in humans. The cerebellum coordinates movement and balance. The cerebellar interneurons fine tune motor control.

“These data will be important for understanding the role the DNA damage response plays in preventing neurological disease,” the investigators wrote.

The study also marks the first time researchers have switched off a pathway for repairing damaged single DNA strands in an organ system, in this case the mouse brain and nervous system. While the results suggest certain brain cells are particularly vulnerable, investigators report that with time DNA damage accumulates throughout the nervous system. Some mice in the study eventually develop seizures and difficulty walking.

Peter J. McKinnon, Ph.D., a member of St. Jude Genetics and Tumor Cell Biology, said the work provides a new model for understanding how single-strand DNA damage affects the nervous system and offers a new focus for tracking the origins of neurological disease.

The research also reflects growing scientific interest in damage to single strands of DNA. “A variety of human disease syndromes result from problems in the DNA-repair system,” explained McKinnon, the paper’s senior author.

DNA is the double-stranded molecule found in nearly every cell. In organisms both simple and complex, it serves as the biochemical blueprint for assembling and sustaining life. Diseases like cancer have long been associated with unrepaired damage to both strands of DNA. Single-strand DNA damage is far more common, but was generally considered less catastrophic to the cell.

But the last decade brought evidence linking single-strand DNA damage with human diseases, including ataxia with oculomotor apraxia (AOA1) and spinocerebellar ataxia with axonal neuropathy (SCAN1). Both disorders are inherited and are characterized by progressive difficulty with walking and other movement. AOA1 is among the most common form of certain inherited movement disorders in Japan and Portugal. McKinnon said those reports sparked new interest in single-strand DNA repair.

This study focused on Xrcc1, a protein long recognized as the master regulator of a pathway essential for single-strand DNA repair in the nervous system. The brain is thought to be particularly susceptible to such damage because neurons consume large amounts of oxygen, which can result in excessive production of free radicals and leave them vulnerable to single-strand DNA damage. Because brain cells do not divide, they cannot use the backup repair systems found in other tissues.

Investigators developed a way to switch off Xrcc1 production in the mouse brain and nervous system as development began. The system meant Xrcc1 still worked normally in the rest of the body.

The strategy used mice developed to make a particular enzyme, known as cre recombinase, in just the nervous system. St. Jude researchers then developed a mouse that carried an Xrcc1 gene outfitted with biochemical tags targeting the gene for inactivation by the enzyme. The result was a mouse whose nervous system lacked Xrcc1 and so was unable to efficiently repair the single-strand DNA damage.

The shutdown triggered a dramatic decline of interneurons throughout the cerebellum. In a subgroup of those cells, the damage triggered apoptosis, or programmed cell death. But the findings suggested the greatest loss occurred as the immature cerebellar interneurons, or progenitor cells, were poised to complete differentiation. In those cells, McKinnon said, loss of Xrcc1 activated the p53 pathway and blocked the cells from completing the cell cycle. “The cells appear to undergo permanent arrest,” said McKinnon, noting it is one of the few in vivo examples of the p53 pathway leading to cell cycle arrest rather than apoptosis.

In the hippocampus, which plays a role in memory and emotion, investigators reported abnormal gene expression and neuronal function. Some neurons were eventually replaced by scar tissue in a process known as gliosis. Overall changes in the hippocampus mimicked those found in the brains of adults with the seizure disorder known as temporal lobe epilepsy. In this study, the loss of Xrcc1 also resulted in seizures in mice.

The other authors of this paper were Youngsoo Lee, Sachin Katyal, Yang Li and Helen R. Russell, all of St. Jude; and Sherif F. El-Khamisy and Keith W. Caldecott of the University of Sussex, Brighton, UK.

The work was supported in part by the National Institutes of Health and ALSAC.

Source:
Summer Freeman

St. Jude Children’s Research Hospital

HOUSTON, July 28 — The inability to detect small ovarian tumors emphasizes the need for cancer-specific biomarkers that can detect more tumors at a curable stage, researchers suggested after analyzing statistical models of cancer growth, progression, and detection.

To achieve even 50% sensitivity, a biomarker assay would have to detect serous tumors that are 1/200th as large as the clinically apparent tumors typically used to evaluate candidate biomarkers, investigators reported online in PLoS Medicine.

However, the study also showed that the window of opportunity for detecting curable, serous ovarian cancer is surprisingly long.

“These cancers spend on average more than four years as in situ, stage I, or stage II cancers, and approximately one year as stage III or IV cancers before they become clinically apparent,” said Patrick O. Brown, MD, PhD, of Stanford University, and Chana Palmer, PhD, of the Canary Foundation in San Jose, Calif.

• Explain to patients that early detection of ovarian cancer will require tests that can detect small tumors.
• The findings of this study are based on a review of literature and statistical modeling.

“For most of the occult period, serous cancers are less than one centimeter in diameter and not visible on gross examination of the ovaries and Fallopian tubes. The median diameter of a serous ovarian cancer when it progresses to an advanced stage . . . is about three centimeters.”

“It is likely that some combination of new biomarkers and new approaches will be needed to meet the challenge of early detection,” they added.

When detected early, ovarian cancer has a favorable outlook, including a five-year survival of 70% to 80%. However, most tumors are detected in advanced stages, when patients have become symptomatic. Five-year survival for stage IV ovarian cancer is 15% or less.

The challenge of early detection is further complicated by the fact that “we know surprisingly little about the target for early detection of serous ovarian cancer,” the authors said. “What do lethal serous ovarian cancers look like during the ‘window of opportunity’ . . .?”

“By defining the what, when, and where of preclinical ovarian cancer, we can begin to rationally design an effective early detection strategy,” they added.

Data from studies of prophylactic bilateral salpingo-oophorectomy have provided some insights into the early natural history of ovarian cancer. Using data from published reports of the prophylactic surgery, the authors developed a model for the preclinical natural history of ovarian cancer and then evaluated its implications for early detection.

The analysis was limited to women with BRCA1 mutations, which can increase the lifetime risk of ovarian cancer to 40% for some women.

The review and analysis yielded five principal insights regarding early ovarian cancer:

• The prolonged period that serous ovarian tumors spend in situ and early-stage disease
• The small size (<1 cm) of serous tumors during most of the early-stage period
• Stage III-IV ovarian cancers have a median diameter of about 3 cm
• To achieve 50% sensitivity for detecting tumors before stage III, an annual screen would have to detect tumors no larger than 1.3 cm in diameter; and no larger than 0.4 cm for 80% sensitivity
• To reduce serous ovarian cancer mortality by 50%, an annual screen would have to detect tumors no larger than 0.5 cm in diameter

Most candidate biomarkers are tested against larger, symptomatic, advanced-stage ovarian tumors, the authors noted.

The study was funded by the Canary Foundation and the Howard Hughes Medical Institute. The authors reported no disclosures.

Primary source: PLoS Medicine

Source reference:

2009; DOI: 10.1371/journal.pmed.1000114.

HOUSTON, July 28 — Men have a low risk of dying from prostate cancer 15 years after radical prostatectomy, suggesting that at least some did not require surgery, a large multicenter review suggests.

• Explain to patients that the study showed that most men who undergo surgery for prostate cancer are unlikely to die of prostate cancer.
• The findings were based on a retrospective review of medical records.

The 15-year prostate cancer-specific mortality was 12% after radical prostatectomy, including 5% in men with low-risk features.

The favorable prognosis might reflect the effectiveness of radical prostatectomy or, alternatively, the indolent nature of many screen-detected prostate cancers, investigators reported online in the Journal of Clinical Oncology.

“The importance of this paper is that it shows a remarkably low risk of dying of prostate cancer within 15 years for treated men and supports the concept that men with slow-growing cancers may not need immediate treatment,” Peter Scardino, MD, of Memorial Sloan-Kettering Cancer Center in New York, said in a statement.

For patients with more aggressive prostate cancer, the study demonstrated the effectiveness of radical prostatectomy, he added.

The findings also emphasize the need for molecular or genetic testing to identify patients most likely to benefit from immediate treatment.

Models that predict the risk of PSA recurrence after definitive treatment of prostate cancer have become the primary tools for counseling patients, clinical decision-making, and risk-stratifying patients in clinical trials.

However, PSA recurrence cannot be considered a surrogate for prostate cancer-specific mortality, the authors said. Fifteen years after PSA recurrence, men are as likely to die from competing causes as from prostate cancer.

“Treatment decision-making for localized prostate cancer and the powering of clinical trials for clinically significant endpoints require accurate estimations of prostate cancer-specific mortality that account for the stage migration induced by PSA screening,” the authors said.

Seeking to hone the accuracy of estimation, Dr. Scardino and colleagues analyzed data on 12,677 men treated with radical prostatectomy from 1987 to 2005. They used competing risk regression analysis to predict prostate cancer-specific mortality.

The analysis resulted in a 15-year overall mortality of 38%, as well as the 12% risk of dying of prostate cancer.

Estimated prostate cancer mortality ranged from 5% to 38% in the lowest and highest quartiles of predicted risk for PSA recurrence. Biopsy Gleason grade, PSA level, and year of surgery all had significant associations with prostate cancer-specific mortality.

“Only 4% of contemporary patients had a predicted 15-year prostate cancer-specific mortality of greater than 5%,” the authors stated.

“Given the limited ability to identify contemporary patients at substantially elevated risk of prostate cancer-specific mortality on the basis of clinical features alone, the need for novel markers specifically associated with the biology of lethal prostate cancer is evident,” they added.

The authors noted several limitations, including the fact that “the nomogram predicts the probability of prostate cancer-specific mortality for 15 years, but patients seem to be at risk of PCSM for up to 20 years after treatment.”

Also, the authors noted that the model does not consider health-related quality-of-life issues. The latter are important as “all treatments for localized prostate cancer affect urinary, sexual, and bowel function to varying degrees, which the patient must also consider when formulating a treatment decision.”

The authors reported no potential conflicts of interest.

Primary source: Journal of Clinical Oncology

Source reference:

Stephenson AJ, et al “Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era” J Clin Oncol 2009; DOI: 10.1200/JCO.2008.18.2501.