In a paper titled, “Diagnostic Assay Based on has-miR-205 Expression Distinguishes Squamous From Non-Squamous Non-Small-Cell Lung Carcinoma,” researchers looked at 252 patients with lung cancer and sent their tumor samples to a lab where a single microRNA biomarker identified squamous lung carcinomas with 96% sensitivity and 90% specificity. This is important because studies have shown that as many as 30% of squamous lung cancers are misclassified. If the type of lung cancer is not identified correctly, patients may have side effects due to treatment and medications. For example, squamous lung cancer carries increased risk of severe or fatal bleeding for certain targeted biological therapies including Bevacizumab (Avastin) and other drugs in development. Other approved therapies such as Pemetrexed (Alimta) are indicated for non-squamous lung cancer only.

The study, funded by Rosetta Genomics, was conducted at the NYU Cancer Institute at NYU Langone Medical Center in collaboration with researchers from Columbia University and Sheba Medical Center.

“The results of this study are very encouraging,” says Harvey Pass, MD, professor of cardiothoracic surgery and director, thoracic surgery and oncology at the NYU Cancer Institute at NYU Langone Medical Center. “The study has demonstrated that a microRNA biomarker successfully identifies squamous lung cancer with high reproducibility, sensitivity and specificity. “The study certainly demonstrates the power of microRNAs in correctly classifying lung cancer and hopefully can immediately translate into more accurate choices of targeted therapies as well as cytotoxics for the disease.”

Dr. Pass is the Vice chairman medical advisory board for Rosetta Genomics (Nasdaq: ROSG), the company who makes a test based on the same microRNA biomarker that was evaluated by the study. The test offers similar accuracy (97% sensitivity) and is now commercially available through Rosetta Genomics CLIA-certified lab in Philadelphia.

Notes:

About NYU Langone Medical Center

Located in the heart of New York City, NYU Langone Medical Center is a premier center for health care, biomedical research, and medical education. For over 167 years, NYU physicians and researchers have contributed to the practice and science of medicine. Today the Medical Center consists of NYU School of Medicine; Rusk Institute of Rehabilitation Medicine, the first and largest facility of its kind; NYU Hospital for Joint Diseases, a leader in musculoskeletal care; and such nationally recognized programs as the NYU Cancer Institute, the NYU Child Study Center, and the NYU Cardiac and Vascular Institute.

About NYU Cancer Institute

The NYU Cancer Institute is an NCI-designated cancer center. Its mission is to discover the origins of human cancer and to use that knowledge to eradicate the personal and societal burden of cancer in our community, the nation and the world. The center and its multidisciplinary team of experts provide access to the latest treatment options and clinical trials along with a variety of programs in cancer prevention, screening, diagnostics, genetic counseling and supportive services. For additional information, please visit: http://www.nyuci.org.

Proteins that repair damage to DNA are important for maintaining cells’ health, particularly for preventing the accumulation of genetic damage that could increase the chances of becoming cancerous. Researchers have found that, in the general population, there are variations in the genes that encode these DNA repair proteins. Research has also shown a link between reduced DNA repair and susceptibility to a variety of cancers, including breast, colon, and lung cancer.

To determine the potential role of genetic variants – or polymorphisms – in DNA repair genes in the development of Hodgkin disease, Dr. Randa El-Zein and colleagues at The University of Texas M.D. Anderson Cancer Center in Houston evaluated the relationship between polymorphisms in five DNA repair genes (XPC, XPD, XPG, XRCC1, and XRCC3) in a population of 200 Hodgkin disease patients and 220 healthy individuals.

These five genes are involved in different pathways that repair DNA by performing different modifications to damaged DNA. Changes in these genes can change the make-up and structure of the proteins that carry out these repair processes and therefore could influence how well DNA repair is performed.

The researchers found that variations in DNA repair genes may modify the risk of HD especially when interactions between the pathways are considered. Depending on the variant or combination thereof, people could be, up to four times more likely to develop the disease.

The authors concluded that “these data suggest that genetic polymorphisms in DNA repair genes may modify the risk of Hodgkin disease especially when interactions between the pathways are considered.” They added that genetic variants in the different DNA repair pathways should be further evaluated to better understand their role in Hodgkin disease susceptibility in individuals.

Notes:

Article: “Genetic polymorphisms in DNA repair genes as modulators of Hodgkin disease risk.” Randa El-Zein, Claudia M. Monroy, Carol J. Etzel, Andrea C. Cortes, Yun Xing, Amanda L. Collier, and Sara S. Strom. CANCER; Published Online: March 9, 2009 (DOI: 10.1002/cncr.24205); Print Issue Date: April 15, 2009.

Also Included In: Genetics; Colorectal Cancer; Lung Cancer

The study, published in the most recent issue of Cancer, also finds that the emotional worry was a strong factor leading women – both BRCA mutation carriers and others at high risk for the disease – to opt for the surgery.

It’s estimated that .1 to .2 percent of the general population carry either the BRCA 1 or 2 mutation, both of which are associated with an increased risk of breast and/or ovarian cancer. For those with the BRCA1 mutation, their lifetime risk of developing breast cancer is 47-66 percent, with some estimates even higher; those with BRCA2 have a lifetime risk of 40-57 percent.

Women are referred to genetic counseling because of a personal diagnosis of breast cancer at a very young age, or a strong family history of the breast and/or ovarian, explained Jennifer Litton, M.D., assistant professor in M. D. Anderson’s Department of Breast Medical Oncology.

“Women who are even suspected to have a BRCA mutation are highly motivated and need to make important decisions regarding their treatment options, even if they don’t have cancer,” said Litton the study’s senior author. “With the study, we wanted to determine the reasons why women make different choices in either screening – including breast-self exams, mammograms, or MRIs – or prophylactic measures, such as medications like Tamoxifen or surgeries.”

In conducting the study, the researchers sent surveys to 540 women who received genetic counseling and were screened for the BRCA mutations at M. D. Anderson between 1997 and 2005. Of those surveys, 312 (58 percent) were returned: 217 (70 percent) had breast cancer and 86 (28 percent) tested positive for the BRCA1 or 2 mutation.

In the surveys, patients were asked questions regarding their fear of developing the disease, as well as their feelings on: the screening techniques mammograms and breast-self exams; the drug Tamoxifen and its known side effects, and prophylactic surgeries.

Regarding mammograms and self breast exams, the study found little difference between the BRCA positive and negative cohorts. Neither group felt that mammograms were too difficult to get because of discomfort, nor did either report being too embarrassed to perform breast-self exams. In addition, there was no statistical difference in the two groups’ feelings toward Tamoxifen: 37.9 percent of the BRCA positive patients and 46.5 percent of the BRCA negative patients felt that the concerns associated with the drug outweighed its benefits for reducing risk of developing breast cancer.

In evaluating the response to questions regarding prophylactic mastectomies, the researchers began to see significant differences between the two groups, and “worry” as a recurring concern.

When comparing BRCA positive to BRCA negative cohorts: 70 percent versus 40 percent respectively felt that prophylactic mastectomies were the most effective way to reduce their risk of developing the disease; 36.1 percent versus 40.5 percent respectively felt it was too drastic of a measure to prevent breast cancer; 23.9 percent versus 12.5 percent respectively had difficulty in deciding between surgery and screening.

Regarding their degree of worry, 64.7 percent of BRCA positive patients thought a prophylactic mastectomy was the only way to reduce their fear of the disease, compared to 34.4 percent of BRCA negative patients.

When combining both groups, after excluding women with bilateral breast cancer, 81 percent who thought surgery was their best way to reduce their risk, and 84 percent of those who felt that it was their best way to reduce their worry ultimately underwent the procedure. In contrast, 19.1 percent of those who did not feel that the surgery was the best way to reduce their risk and 15.8 percent of women who did not think it was their only way to decrease their worry opted to have a prophylactic mastectomy.

In her clinical experience, Litton has seen many high-risk women, particularly those who test positive for the BRCA 1 or 2 mutation, that initially opt for intensive screening, but after several mammograms, MRIs and biopsies, eventually decide to have a prophylactic mastectomy.

“For clinicians, this study shows that when we’re counseling women about prophylactic mastectomies, we need to not just talk about the surgery, but understand their lifestyles,” said Litton. “When the worry of developing cancer is interfering with a patient’s day-to-day activities, then their quality of life is impacted. These women with a high risk of developing breast cancer may find that despite the surgery and subsequent recuperation, a prophylactic mastectomy improves their quality of life.”

Women at highest risk need to ask themselves some very important, personal questions that only they have the answers to, said Litton.

“When making such a personal decision, these women at highest risk need to ask themselves about how they feel about their breast as far as their body image, sexuality, relationship with and support of their partner, as well as their concern for breast cancer. If that worry comes in the way of their day-to-day activities, it should be taken into consideration as part of the patient’s decision-making process.”

Litton cautioned that the results should not be generalized for the majority of the breast cancer population. Additionally, high risk women, of course, should also be counseled on the risk associated with surgery.

As a follow up to this study, Litton plans to conduct a study with high-risk women of child-bearing age pre- and post-genetic counseling to determine their degree worry, their guilt of possibly passing on the gene to their offspring and thoughts on pre-gestational diagnosis.

Notes:

The study was funded in part by the Nellie B. Connally Breast Cancer Research Fund and a grant from the National Institutes of Health.

In addition to Litton, other authors on the all-M. D. Anderson study include: Gabriel Hortobagyi, M.D., Banu Arun, M.D., Ana Gonzalez-Angulo, M.D., Kaylene Ready, all of the Department of Breast Medical Oncology; Karen Lu, M.D., Diane Bodurka, M.D., Charlotte Sun, DRPH, Shannon Westin, M.D., all of the Department of Gynecologic Oncology; Funda Meric-Bernstam, M.D., Department of Surgery; and Susan Peterson, Ph.D., Department of Behavioral Science.

About M. D. Anderson

The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world’s most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For four of the past six years, including 2008, M. D. Anderson has ranked No. 1 in cancer care in “America’s Best Hospitals,” a survey published annually in U.S. News & World Report.

Even today, glioblastomas are untreatable – something which even the new combination therapy cannot change. Nevertheless, Professor Dr. Ulrich Herrlinger of Bonn University´s Schwerpunkt Klinische Neuroonkologie speaks of an outstanding success: “This unusually manifest extension of the survival time has surprised even us. Our results offer the opportunity to improve our grip on this aggressive form of cancer. Now, further investigations involving a larger number of patients are needed to optimise this therapy. Planning for this is already in hand in Bonn”.

Up to now, doctors have treated glioblastomas using radiotherapy with concomitant chemotherapy. The “gold standard” for this for the last few years has been the active agent temozolomide. This is still celebrated as the most important breakthrough in the treatment of glioblastomas. The researchers combined this preparation with the drug lomustine. At the same time, the patients were given radiotherapy. The 39 patients thus treated survived the tumour for an average of 23.1 months. With the standard therapy, this time is over one third shorter. Seven patients even survived for over four years.

Genes decide the Success of the Therapy

It would appear that certain changes in the genotype are critical for the success of this therapy. “With eleven participants in the study, the information of one gene had been subjected to a characteristic modification”, Ulrich Herrlinger declares. “These patients survived on average a good 34 months. With the other patients, these drugs appeared to bring no apparent advantage vis-à-vis pure radiotherapy – at least, not in the dosage we tested. It is possible that a simple gene test could decide for whom a concomitant chemotherapy might be of benefit”. One disadvantage of the new method are the side-effects. However, these mostly occur during the several months of the treatment phase. “After that they normally disappear completely, and the patients have no further complaints about them”, Herrlinger stresses.

Working in co-operation with the Life&Brain-Zentrum in Bonn, the search is now on for more compatible, more effective, drugs. “Amongst other things, we now want to use cell cultures from original tumours to study precisely what the preparations we used in the study really effect”, Dr. Martin Glas, one of the authors of the study, declares.

Notes:

Long-Term Survival of Patients With Glioblastoma Treated With Radiotherapy and Lomustine Plus Temozolomide. Martin Glas, Caroline Happold, Johannes Rieger, Dorothee Wiewrodt, Oliver Bähr, Joachim P. Steinbach, Wolfgang Wick, Rolf-Dieter Kortmann, Guido Reifenberger, Michael Weller, and Ulrich Herrlinger. Journal of Clinical Oncology, February 2009 The combination of two drugs produces a critical improvement in the treatment of certain brain tumours. This has been demonstrated by researchers at Bonn University working in co-operation with German and Swiss colleagues in a current study. They treated 39 patients who had been diagnosed with a so-called gliablastoma. The patients survived on average 23 months; with the standard therapy the mean would have been 14.6 months. Glioblastomas are the most aggressive and the commonest brain tumours. Left untreated, they prove fatal within just a few weeks. The study has been published in the Journal of Clinical Oncology (doi: 10.1200/JCO.2008.19.2195).

Even today, glioblastomas are untreatable – something which even the new combination therapy cannot change. Nevertheless, Professor Dr. Ulrich Herrlinger of Bonn University´s Schwerpunkt Klinische Neuroonkologie speaks of an outstanding success: “This unusually manifest extension of the survival time has surprised even us. Our results offer the opportunity to improve our grip on this aggressive form of cancer. Now, further investigations involving a larger number of patients are needed to optimise this therapy. Planning for this is already in hand in Bonn”.

Up to now, doctors have treated glioblastomas using radiotherapy with concomitant chemotherapy. The “gold standard” for this for the last few years has been the active agent temozolomide. This is still celebrated as the most important breakthrough in the treatment of glioblastomas. The researchers combined this preparation with the drug lomustine. At the same time, the patients were given radiotherapy. The 39 patients thus treated survived the tumour for an average of 23.1 months. With the standard therapy, this time is over one third shorter. Seven patients even survived for over four years.

Genes decide the Success of the Therapy

It would appear that certain changes in the genotype are critical for the success of this therapy. “With eleven participants in the study, the information of one gene had been subjected to a characteristic modification”, Ulrich Herrlinger declares. “These patients survived on average a good 34 months. With the other patients, these drugs appeared to bring no apparent advantage vis-à-vis pure radiotherapy – at least, not in the dosage we tested. It is possible that a simple gene test could decide for whom a concomitant chemotherapy might be of benefit”. One disadvantage of the new method are the side-effects. However, these mostly occur during the several months of the treatment phase. “After that they normally disappear completely, and the patients have no further complaints about them”, Herrlinger stresses.

Working in co-operation with the Life&Brain-Zentrum in Bonn, the search is now on for more compatible, more effective, drugs. “Amongst other things, we now want to use cell cultures from original tumours to study precisely what the preparations we used in the study really effect”, Dr. Martin Glas, one of the authors of the study, declares.

Notes:

Long-Term Survival of Patients With Glioblastoma Treated With Radiotherapy and Lomustine Plus Temozolomide. Martin Glas, Caroline Happold, Johannes Rieger, Dorothee Wiewrodt, Oliver Bähr, Joachim P. Steinbach, Wolfgang Wick, Rolf-Dieter Kortmann, Guido Reifenberger, Michael Weller, and Ulrich Herrlinger. Journal of Clinical Oncology, February 2009

By this measure, T cells, or white blood cells, from patients with the autoimmune disease rheumatoid arthritis are worn out and prematurely aged, scientists at Emory University School of Medicine have discovered.

Compared with cells from healthy people, T cells from patients with rheumatoid arthritis have trouble turning on the enzyme that replenishes telomeres, they found. Reversing this defect could possibly help people prone to the disease maintain a balanced immune system.

The results are published online this week in Proceedings of the National Academy of Sciences.

In rheumatoid arthritis, T cells are chronically over-stimulated, invading the tissue of the joints and causing painful inflammation. This derangement can be seen as a result of the loss of the immune system’s ability to discriminate friend from foe, says senior author Cornelia Weyand, MD, PhD, co-director of the Kathleen B. and Mason I. Lowance Center for Human Immunology at Emory University.

In childhood, new T cells are continually produced in the thymus, she says. But after about age 40, the thymus “involutes” – or shrinks and ceases to function. After that, the immune system has to make do with the pool of T cells it already has.

“What we see in rheumatoid arthritis is an aged and more restricted T cell repertoire,” she says. “This biases the immune system toward autoimmunity.”

Weyand, postdoctoral fellow Hiroshi Fujii, MD, PhD, and their colleagues were interested in mechanisms of T cells’ premature aging, because scientists had previously observed that in rheumatoid arthritis, T cells tend to shift the molecules on their surface and function differently.

They found the answer in telomerase, the enzyme that renews telomeres and is necessary to prevent loss of genetic information after repeated cell division.

Telomerase adds short repeated DNA sequences to the ends of chromosomes to protect them. The enzyme is active in embryonic development but is usually switched off in adult cells. Many cancer cells reactivate it to enable runaway growth.

T cells are some of the very few cells in adults that can turn on telomerase when stimulated, probably because they have to divide many times and stay alive for decades.

Weyand and Fujii found that T cells from patients with rheumatoid arthritis make 40 percent less telomerase enzyme when stimulated. The cells came from 69 patients, 92 percent female, with an average age of 50, and were compared with cells from healthy people with similar demographics.

Shutting off a gene encoding part of the enzyme made normal T cells vulnerable to programmed cell death, and transferring telomerase into patients’ T cells rescued them from dying.

The finding suggests that restoring defective telomerase to T cells could possibly help “reset” the immune system in rheumatoid arthritis, Weyand says.

Pharmaceutical industry researchers have been looking for drugs that could elevate or depress telomerase activity, with the goal of either prolonging life or treating cancer. However, turning on telomerase indiscriminately could lead to cancer, so any treatment would have to be targeted to the right cells, she says.

Notes:

The research was funded by the National Institutes of Health and the Diane Wolf Discovery Fund.

Fujii is now an assistant professor of hematology and rheumatology at Tohoku University School of Medicine in Japan.

Reference: H. Fujii, L. Shao, I. Colmegna, J. Goronzy and C.M. Weyand. Telomerase insufficiency in rheumatoid arthritis. http://www.pnas.org/cgi/doi/10.1073/pnas.0811332106

The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service. Its components include schools of medicine, nursing and public health; the Yerkes National Primate Research Center; the Emory Winship Cancer Institute; and Emory Healthcare, the largest, most comprehensive health system in Georgia. The Woodruff Health Sciences Center has a $2.3 billion budget, 17,000 employees, 2,300 full-time and 1,900 affiliated faculty, 4,300 students and trainees, and a $4.9 billion economic impact on metro Atlanta.

Dan Valenzuela, President of Safeway’s Phoenix Division, which includes 116 stores throughout Arizona, thanked the grocery chain’s customers and employees for stepping up for scientific research.

“We’re very proud to donate to such an organization as TGen. I think everybody recognizes that, with the economy the way it is, it gets tougher to ask people for donations,” Valenzuela told about 50 TGen employees gathered Tuesday for the announcement. “Because of your research, and the things that you do, we’re honored to present you with a check.”

Safeway’s donation represents a 37 percent increase from the $500,000 the company gave TGen last year. The contributions both years were based on month-long campaigns at Arizona’s Safeway stores in October 2007 and October 2008.

“You can’t give enough credit to our customers and employees,” Valenzuela said, adding that a major reason Safeway chose to support Phoenix-based TGen was that the research dollars would stay in Arizona.

“The benefit (of TGen’s research) is far-reaching. The big thing is, where do the funds go? It (TGen) is local,” Valenzuela said.

Dr. Jeffrey Trent, TGen’s President and Scientific Director, said the significant and timely contribution by Safeway is an example of the generosity repeatedly shown by local businesses and the people of Arizona.

“This donation will be put to immediate use to help develop treatments and, eventually, find a cure for breast cancer, a major priority for us at TGen and a goal that would benefit everyone,” Dr. Trent said.

Michael Bassoff, President of the TGen Foundation, the fundraising arm of the non-profit biomedical research institute, described Safeway’s contribution as a special tribute to TGen researchers as they work to conquer cancer and other debilitating diseases.

“Contributors are looking hard at their charitable opportunities and are looking for the organizations that are run efficiently and produce results,” Bassoff said. “But today’s donation by Safeway is a tribute to you, the work you do in the laboratories, and the many Arizonans who came forward to support TGen,” Bassoff told the assembled TGen employees.

Dr. Heather Cunliffe, a TGen breast cancer researcher, said Safeway’s donation would help accelerate work towards new treatments for breast cancer patients.

Bassoff also credited the “extra gumption” and hard work of Safeway employees who were willing to ask customers if they would contribute to breast cancer research.

Notes:

About TGen

The Translational Genomics Research Institute (TGen) is a non-profit organization dedicated to conducting groundbreaking research with life changing results. Research at TGen is focused on helping patients with diseases such as cancer, neurological disorders and diabetes. TGen is on the cutting edge of translational research where investigators are able to unravel the genetic components of common and complex diseases. Working with collaborators in the scientific and medical communities, TGen believes it can make a substantial contribution to the efficiency and effectiveness of the translational process. For more information, visit: http://www.tgen.org/.

The p53 gene makes sure that cells with damaged DNA either repair themselves or commit suicide. If p53 itself is damaged, which is the case in roughly half of all cancer tumours, cells that are on their way to becoming cancerous are allowed to survive. Much cancer research revolves around the cell processes that p53 induces.

A group of researchers at Karolinska Institutet have now identified a new gene, called Wrap53, that regulates the activity of p53. The study, which is published in the journal Molecular Cell, demonstrates that Wrap53 gives rise to a molecule, called antisense RNA, the presence of which is necessary for the production of sufficient quantities of p53 protein in the event of DNA damage.

According to Marianne Farnebo, one of the scientists involved in the study, the results indicate that damage to Wrap53 can indirectly cause cancer. Wrap53 is therefore a new potential target for future cancer therapies.

“Mutations in the p53 gene contribute to about half of all cancer cases,” she says. “In the remaining half, p53 is probably inactivated in other ways, such as damage to Wrap53 knocking out the production of the p53 protein.”

The study is also one of the first to show how antisense RNA regulates genes in the human body. It is already a well-known fact that genes often control each other through the influence of their end products – usually proteins – on gene expression. With antisense regulation, control is effected instead through the production of mutually stabilising or destructive RNA molecules by genes with overlapping sequences, which determines whether or not the RNA molecules form proteins.

“At least 20 per cent of all genes can be regulated by antisense RNA, making it a potentially very common control mechanism,” says Dr Farnebo. “But it’s been difficult to show that antisense RNA really does serve important functions in the body, as we’ve managed to do in this study.”

Publication: “Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage”, Salah Mahmoudi, Sofia Henriksson, Martin Corcoran, Cristina Méndez-Vidal, Klas G. Wiman & Marianne Farnebo, Molecular Cell, 27 February 2009

Karolinska Institutet is one of the leading medical universitiesin Europe. Through research, education and information, Karolinska Institutet contributes to improving human health. Each year, the Nobel Assembly at Karolinska Institutet awards the Nobel Prize in Physiology or Medicine.

As the most common congenital birth defect in male children, cryptorchidism may occur in 2-4% of all full-term male births. However, its cause is largely unknown, and the authors point out that, “although cryptorchidism is often considered a mild malformation, it can seriously affect men’s health, representing the best characterized risk factor for infertility and testicular cancer in adulthood.”

To investigate the potential cause of cryptorchidism, Alberto Ferlin, Ph.D., of the University of Padova, Italy, and colleagues performed a case-control study evaluating the frequency of genetic alterations in 600 male children with and 300 male children without the disease. the children were followed up for 2 to 3 years for persistence of the malformation.

In the genetic examination, abnormalities were low even in the group of cases (2.8%), but statistically significantly higher than those of the controls. This was true in for children with persistent cryptochidism (5.3%) and bilateral cryptorchidism (8.3%) in which both testes fail to descend at once. The odds of a genetic alteration in children with persistent cryptorchidism was 17 times that of controls; the odds of a genetic alteration in children with bilateral persistent cryptorchidism was 27 times that of controls.

The types of genetic mutation were varied. In the small proportion of cases with genetic abnormalities, the most common was Klinefelter syndrome, the most common genetic cause of male infertility. Additionally, several cases had mutations in the INSL3 receptor gene, which affects descent of the testes. Genetic alterations were found exclusively in children with normal weights and gestational ages.

The authors point out the exclusive presence of Klinefelter syndrome: “We found that chromosomal aberrations represent the most frequent genetic alteration in participants with isolated cryptorchidism, particularly in those with persistent cryptorchidism (1.6 percent in the unilateral forms and 4.2 percent in the bilateral forms), and that chromosomal alterations were exclusively represented by Klinefelter syndrome.”

They continue, summarizing the results of the study: “In this study, we found genetic alterations in a small percentage of boys with cryptorchidism. We found a significant association between bilateral and persistent cryptorchidism and genetic alterations, including mutations in the INSL3 receptor gene and Klinefelter syndrome. Genetic alterations were not found in participants with low birth weight or low gestational age …”

However, the authors finally caution against strong generalization of these results, noting the limitations of their study. “Our findings have the limitations of a case-control study, and the main limitation is the small number of genetic abnormalities found. Future studies involving a higher number of participants are necessary to confirm our findings. This study should therefore be considered preliminary, and strong conclusions about association cannot be drawn,” they write.

Malignant cells have lost control of the replication process, so detecting differences in cell cycle gene activation in normal and malignant cells provides important clues about how cancers develop, said Ziv Bar-Joseph, a Carnegie Mellon University computational biologist who led the study. These genes also are potential targets for drug therapy.

Unlike many cancer studies, which seek to identify “missing” genes that might cause cancer, this new research shows that genes can contribute to cancer in less obvious ways. “What we see is that there are many genes that are present and yet still involved in cancer because they are not activated, or expressed, in the way they normally are,” said co-lead author Itamar Simon, a molecular biologist at Hebrew University Medical School in Israel. Rather than cycling on and off as normally occurs when cell replication and development proceeds, these genes are expressed in a steady state or not at all.

The findings will be reported in the online Early Edition of the Proceedings of the National Academy of Science during the week of Jan.7.

The genes found to be deregulated in cancer cells include a few, such as PER2 and HOXA9 that already have been linked to cancer. Most have not, including at least three genes responsible for repairing genetic mutations that occur as DNA is duplicated in the cell.

The failure of the DNA repair genes to cycle in cancer cells raises the possibility that some mutations associated with cancer may not cause cancer. “Some of the mutations may be caused by the non-cycling genes, rather than the other way around,” said Bar-Joseph, an assistant professor of computer science and machine learning in the School of Computer Science and a member of Carnegie Mellon’s Lane Center for Computational Biology.

Determining if genetic mutations are a side effect of certain cancers rather than a cause will require further investigation, as will identifying which of the 118 genes that do not cycle in cancer cells are most significant.

“These genes seem to be important, but we don’t yet know which ones play key roles or might be targets for drug therapy,” Simon said. “We have narrowed down the field of candidates. Instead of looking at thousands of genes, now we can concentrate on about 100.”

Using conventional techniques even to identify a full complement of human cell cycle genes has been problematic. Molecular biologists have found cell cycle genes in yeast, plants and mice, as well as in a human cancer cell line known as HeLa. But a study that purported to identify cell cycle genes in normal human cells proved flawed and invalid.

The problem that molecular biologists encountered in studying human cells has to do with the fact that the cell development must be arrested so that micro array technology can be used to measure which genes are expressed at each stage of the cell cycle. When the cells are released from arrest, Simon said, some don’t resume cycling at all, while others resume at different intervals.

Why this is a problem in humans and not other species is not understood, Simon noted. But the result is that the cells – and these studies require millions of them – end up scattered among different stages of the cell cycle. Measurements of these unsynchronized cells are hopelessly “noisy.”

“People said you couldn’t solve this problem,” Bar-Joseph said. But a computer science method called deconvolution, which is widely used in such fields as image processing and signal processing, proved effective in eliminating noise from the data.

In experiments, the team arrested and released cells in culture and then measured DNA content to determine which ones had stopped cycling and which ones were at various stages of the cell cycle. This information was used to construct a model of cell behavior that could be used to reanalyze the gene expression data, enabling researchers to combine expression data from cells that are all at the same stage of the cell cycle.

Although this genetic “microdeletion” occurred in only four out of 712 subjects with autism (0.6%), it is the second most common recurrent genomic disorder associated with autism, which affects about one out of 160 children in the United States.

“We suspect that 16p11.2 microdeletions are a risk factor for autism spectrum disorders generally and may cause mild autism in some families,” said study author Susan Christian, PhD, associate professor of human genetics at the University of Chicago. “By disturbing the network of affected genes, this loss of selected genes may underlie the development of autism.”

The deletion results in the loss of about 25 known genes. “Twelve of those genes appear to be part of a single genetic network that includes genes involved in cell-to-cell signaling and interaction,” said first author Ravinesh A. Kumar, PhD. postdoctoral scientist in human genetics at the University of Chicago, “At least three of the deleted genes are primarily expressed in the brain and are thought to influence behavior,” he added, “which makes them very promising candidates for autism.”

The authors suspect the lost or damaged genes may also be involved in other cognitive, language and social impairments.

To find genes linked to autism, the researchers scanned the entire genomes of 180 subjects with autism searching for submicroscopic pieces of DNA that were either lost or mistakenly duplicated in patients diagnosed with autism. They first found that two out of those 180 (1.1%) had a deletion in region 16p11.2, on the short arm of chromosome 16. None of the 372 control subjects had the same deletion.

To confirm that result, the researchers screened DNA from an additional 532 subjects with autism. They found two additional subjects with the same deletion (0.4%), which was seen in none of the 465 controls. Combining the two samples produced a total prevalence of 16p11.2 deletions of 0.6 percent.

The 16p11.2 region is flanked on both sides by bands of segmental duplications, short strings of nearly identical DNA that predispose to the loss, shuffling or amplification of this region during genetic recombination. “Many human diseases are caused by these types of chromosomal rearrangements, however, this is the first recurrent microdeletion in autism too small to be seen under a microscope,” said Christian.

The most common known genetic cause of autism, linked to about one to three percent of cases, is a much larger duplication of part of chromosome 15, involving about a dozen genes. The chromosome 15 abnormality is associated with autism as well as intellectual disability (www.idic15.org). The chromosome 16 deletion, by contrast, is not consistently associated with intellectual disability.

“Although this only explains about one-half of one percent of autism,” said co-author William Dobyns, professor of human genetics and pediatrics at the University of Chicago, “it provides the best clues yet for finding the specific genetic changes that lead to the disease. This is a small region with a limited number of genes, including several strong candidates, each of which merits a closer look. The next step is to find the specific gene or genes involved. There may be one gene within that deletion that is at the core of the problem.”