Category Archives: Genetic Research

Researchers find genetic rearrangements driving 5 to 7 percent of breast cancers

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ANN ARBOR, Mich. — Researchers at the University of Michigan Comprehensive Cancer Center have discovered two cancer-spurring gene rearrangements that may trigger 5 to 7 percent of all breast cancers.

These types of genetic recombinations have previously been linked to blood cancers and rare soft-tissue tumors, but are beginning to be discovered in common solid tumors, including a large subset of prostate cancers and some lung cancers.

Looking at the genetic sequencing of 89 breast cancer cell lines and tumors, researchers found two distinct types of genetic rearrangements that appear to be driving this subset of breast cancers. The recurrent patterns were seen in the MAST kinase and Notch family genes. The findings were published online in Nature Medicine ahead of print publication.

“What’s exciting is that these gene fusions and rearrangements can give us targets for potential therapies,” says Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology, Howard Hughes Medical Institute Investigator, and S.P. Hicks Professor of Pathology at the U-M Medical School. “This is a great example of why treating cancer is so challenging. There are so many different ways genes get recombined and so many molecular subtypes, that there’s not one solution that will work for all of them.”

“The research provides additional evidence that these types of genetic rearrangements seem to be a significant cause of solid tumors,” he adds.

The discoveries illuminate a promising path for future research, Chinnaiyan says. Gene sequencing offers opportunities to develop treatments for individuals whose tumors carry specific genetic combinations – a process commonly known as “personalized medicine.”

The study demonstrated that the genetic rearrangements had profound effects on breast cancer cells in the lab, both in tissue culture and in mouse models.

“We cloned each of these rearrangements and introduced them into normal breast cell lines, where they appeared to have cancer-causing effects,” Chinnaiyan says.

Previous U-M research showed that half of prostate cancers have a genomic rearrangement that causes the fusion of two genes called TMPRSS2 and ERG. This gene fusion, believed to be the triggering event for these prostate cancers, was initially discovered in 2005 by U-M researchers led by Chinnaiyan.

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Additional authors: Dan R. Robinson, Shanker Kalyana-Sundaram, Yi-Mi Wu, Sunita Shankar, Xuhong Cao, Bushra Ateeq, Irfan A. Asangani, Matthew Iyer, Christopher A. Maher, Catherine S. Grasso, Robert J. Lonigro, Michael Quist, Javed Siddiqui, Rohit Mehra, Xiaojun Jing, Thomas J. Giordano, Michael S. Sabel, Celina G. Kleer, Nallasivam Palanisamy, Chandan Kumar-Sinha, all of U-M. Kalyana-Sundaram also of Bharathidasan University, Tiruchirappalli, India

Rachael Natrajan, Maryou B. Lambros, Jorge S. Reis-Filho, of the Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.

Disclosures: The researchers report no conflicts of interest. U-M has filed for patent protection for these developments.

Funding: The specific aims of this project were supported by the Department of Defense Breast Cancer Research Program. The project was also supported in part by an American Association for Cancer Research Stand Up to Cancer (SU2C) breast cancer award, the National Functional Genomics Center supported by the Department of Defense, and the National Institutes of Health. Chinnaiyan is supported by the National Cancer Institute Early Detection Research Network, the Doris Duke Charitable Foundation and the Burroughs Welcome Foundation; he is also an American Cancer Society research professor and Taubman Scholar.

Source: Eurekalert

Study finds genetic ‘overlap’ between schizophrenia, bipolar disorder

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Knowledge about the biological origin of diseases like schizophrenia, bipolar disorder and other psychiatric conditions is critical to improving diagnosis and treatment.

In an effort to push the field forward, three UCLA researchers, along with scientists from more than 20 countries, have been taking part in one of the largest collaborative efforts in psychiatry — a genome-wide study involving more than 50,000 study participants aimed at identifying which genetic variants make people susceptible to psychiatric disease.

This collaborative, the Psychiatric Genome-Wide Association Study Consortium (PGC), now reports in the current online edition of the journal Nature Genetics that it has discovered that common genetic variants contribute to a person’s risk of schizophrenia and bipolar disorder.

The PGC’s studies provide new molecular evidence that 11 regions on the genome are strongly associated with these diseases, including six regions not previously observed. The researchers also found that several of these DNA variations contribute to both diseases.

The findings, the researchers say, represent a significant advance in understanding the causes of these chronic, severe and debilitating disorders.

The UCLA researchers who contributed to the schizophrenia study are Roel A. Ophoff, a professor of psychiatry and human genetics and one of the founding principal investigators of the schizophrenia portion of the study; Dr. Nelson Freimer, a professor of psychiatry and director of the Center for Neurobehavioral Genetics at the Semel Institute for Neuroscience and Human Behavior at UCLA; and Rita Cantor, a professor of psychiatry and human genetics.

Schizophrenia and bipolar disorder are common and often devastating brain disorders. Some of the most prominent symptoms of schizophrenia are persistent delusions, hallucinations and cognitive problems. Bipolar disorder is characterized by severe, episodic mood swings. Both affect about 1 percent of the world’s population and usually strike in late adolescence or early adulthood.

Despite the availability of treatments, these illnesses are usually chronic, and patients’ response to treatment is often incomplete, leading to prolonged disability and personal suffering. Family history, which reflects genetic inheritance, is a strong risk factor for both schizophrenia and bipolar disorder, and it has generally been assumed that dozens of genes, along with environmental factors, contribute to disease risk.

In the schizophrenia study, a total of seven locations on the genome were implicated in the disease, five of which had not been identified before. When similar data from the bipolar disorder study, which ran concurrently, were combined with results from the schizophrenia study, three gene locations were identified that proved to be involved in both disorders, suggesting a “genetic overlap” between schizophrenia and bipolar disorder.

“Genetic factors play an important role in the susceptibility to develop schizophrenia,” Ophoff said, “but identifying these genetic factors has been very difficult. We know that schizophrenia is not caused by a single gene that explains everything but an interplay of many genetic and non-genetic factors.”

At the same time, he said, the disease itself is not uniform but manifests itself in different ways; currently, there is no objective biological marker or “sign” that can be used for diagnosis.

“This so-called heterogeneity at the genetic and clinical level is the biggest challenge for genetic studies of neuropsychiatric disorders,” Ophoff said. “One way to deal with these difficulties is to increase the size of the study so there is sufficient ‘power’ to detect genetic effects, even amidst this clinical and genetic diversity.”

The fact that even this large study resulted in a limited number of schizophrenia and bipolar genes demonstrates once again, he said, the complex nature of the disease.

The research was funded by numerous European, American and Australian funding bodies. Funds for coordination of the consortium were provided by the National Institute of Mental Health in the U.S.

 

Gene that predisposes people to leukemia discovered

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Those at risk because of family history may soon obtain tests to detect the genetic error before symptoms emerge

A new genetic defect that predisposes people to acute myeloid leukemia and myelodysplasia has been discovered. The mutations were found in the GATA2 gene. Among its several regulatory roles, the gene acts as a master control during the transition of primitive blood-forming cells into white blood cells.

The researchers started by studying four unrelated families who, over generations, have had several relatives with acute myeloid leukemia, a type of blood cancer. Their disease onset occurred from the teens to the early 40s. The course was rapid.

The findings will be reported Sept. 4 in Nature Genetics. The results come from an international collaboration of scientists and the participation of families from Australia, Canada, and the United States.

In collaboration with Dr. Hamish Scott and Dr. Richard J. D’Andrea at the Centre for Cancer Biology, University of Australia, Adelaide, the U.S. portion of the study was conducted by Dr. Marshall Horwitz, University of Washington (UW) professor of pathology. Horwitz practices genetic medicine at UW Medical Center and the UW Center for Human Development and Disability, both in Seattle.

The genetic mutation was first discovered in a patient from central Washington. The research participant had been successfully treated for leukemia in 1992 through a bone marrow transplant at UW Medical Center. At that time, Horwitz decided to seek a possible genetic reason after learning his patient had several family members with myelodysplastic syndrome, myeloid leukemia, and intractable mycobacteria infections.

Myelodysplastic syndrome is a difficulty in producing certain kinds of blood cells. The problem originates in the bone marrow with a decline in the number and quality of blood-forming cells. Patients often have severe anemia and need frequent blood transfusions. The disease generally worsens due to bone marrow failure and low blood counts. About one- third of those with the syndrome soon develop acute myeloid leukemia, in which abnormal white cells build up in the bone marrow and interfere with normal blood production.

Horwitz’s Australian colleagues had described a family with a similarly inherited blood disorder. Eighteen years later, after rifling through many candidate genes, the researchers on both continents were relieved finally to have hit upon the mutated gene responsible for the leukemia that affect these families. They have gone on to identify abnormal GATA2 genes in more than 20 families and individuals.

“It’s likely that this inherited error is more common than we had thought,” the researchers noted. In some families with a GATA2 mutation, the over-riding concern has been leukemia, while others suffer dangerous infections from bacteria, viruses and fungi because of a lack of white blood cells to fight off germs.

Ongoing work in Seattle and Adelaide has identified a congenital syndrome associated with developmental delay and a risk of myelodysplasia. This syndrome results from chromosomal loss of GATA2 and adjacent genes.

Comparable GATA2 mutations also have been found in people with the more common, non-inherited leukemias.

Scientists are trying to figure out why apparently similar gene mutations in GATA 2 cause such assorted health problems. Also perplexing is how hard it has been to find genetic errors underlying blood cancers, compared with other cancers.

“While several genes have been discovered and linked to solid, malignant tumors such as breast cancer in families susceptible to those types of cancer, so far very few inherited mutations have been uncovered for blood cancers,” Horwitz said.

Previously, other scientists linked mutations in two other genes — RUNX1 and CEBPA – to injerited forms of myelodysplastic syndrome and acute myeloid leukemia. These genes bind to DNA and control the copying of information encoded in this molecule.

Keeping this in mind, researchers looked for mutations in similar genes in families who did not have the RUNX1 and CEBPA mutations and who had no other explanations for their inherited blood cancer. In so doing, the researchers identified the GATA2 mutations. They also observed that these mutations relate to loss of function by making the gene unable to perform the molecular duties necessary to manufacture healthy white blood cells.

According to Horwitz, the GATA2 mutations in DNA occur adjacent to an amino acid mutated in some patients with terminal chronic myeloid leukemia. This proximity suggests a common pathway may be critical for several types of myeloid malignancies, he said.

People at risk because of their pedigree eventually may obtain tests to detect this genetic error before symptoms emerge. Learning that they have the gene mutation might help patients and their doctors decide on appropriate follow-up for early diagnosis and treatment of problems that might arise.

Additional knowledge about how the GATA2 gene and its mutations operate may foster the development of new therapeutic agents.

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A clinical trial under way in the United States may point to specific treatment recommendations for persons with a GATA2 genetic mutation.

The research for “Heritable GATA2 Mutations Associated with Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia,” was supported by grants from the National Health and Medical Research Council of Australia, a Dora Lush Postgraduate Award, Leukaemia Foundation of Australia, the Cancer Council of South Australia, MedVet Pty Ltd., and the U.S. National Institutes of Health.

The researchers extend their gratitude to the families and individuals who participated in this project.

Horwitz has been invited to speak on the role of GATA2 in myelodysplastic syndromes at a National Institutes of Health conference Sept. 7-8 in Bethesda, Md.

New Multiple Sclerosis Gene Associations Discovered

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An international team of scientists has identified 29 new genetic variants linked to multiple sclerosis, providing key insights into the biology of an important and very debilitating neurological disease.

Multiple sclerosis (MS), one of the most common neurological conditions among young adults, affects around 2.5 million individuals worldwide. It is a chronic disease that attacks the central nervous system (CNS), which includes the brain, spinal cord and optic nerves, and can cause severe symptoms such as paralysis or loss of vision.

Vanderbilt University Medical Center’s Center for Human Genetics Research (CHGR) played an important role in the research published today in the journal Nature, which represents the largest MS genetics study ever undertaken and effectively doubles the number of genes known to be associated with the disease.

“We now know just how complex multiple sclerosis is,” said Jonathan Haines, Ph.D., director of the CHGR and one of the principal researchers in this effort. “These new genes give us many new clues as to what is happening in MS and will guide our research efforts for years to come.”

Researchers studied the DNA from 9,772 individuals with multiple sclerosis and 17,376 unrelated healthy controls. They were able to confirm 23 previously known genetic associations and identified a further 29 new genetic variants (and an additional five that are strongly suspected) conferring susceptibility to the disease.

Many genes implicated in the study are relevant to the immune system, shedding light onto the immunological pathways that underlie the development of multiple sclerosis.

One-third of the genes identified in the study have previously been implicated in playing a role in other autoimmune diseases such as Crohn’s Disease and Type 1 diabetes, Haines said.

Previous studies have also suggested a link between vitamin D deficiency and an increased risk of multiple sclerosis; researchers in this study identified two genes involved in the metabolism of vitamin D, providing additional insight into a possible link between genetic and environmental risk factors.

The international team led by the Universities of Cambridge and Oxford, and funded by the Wellcome Trust, includes contributions from nearly 250 researchers as members of the International Multiple Sclerosis Genetics Consortium and the Wellcome Trust Case Control Consortium.