PUBLIC RELEASE DATE:

29-Oct-2014

Contact: Krista Conger kristac@stanford.edu 650-725-5371 Stanford University Medical Center @sumedicine

The ability to pop a working copy of a faulty gene into a patient's genome is a tantalizing goal for many clinicians treating genetic diseases. Now, researchers at the Stanford University School of Medicine have devised a new way to carry out this genetic sleight of hand.

The approach differs from that of other hailed techniques because it doesn't require the co-delivery of an enzyme called an endonuclease to clip the recipient's DNA at specific locations. It also doesn't rely on the co-insertion of genetic "on" switches called promoters to activate the new gene's expression.

These differences may make the new approach both safer and longer-lasting. Using the technique, the Stanford researchers were able to cure mice with hemophilia by inserting a gene for a clotting factor missing in the animals.

"It appears that we may be able to achieve lifelong expression of the inserted gene, which is particularly important when treating genetic diseases like hemophilia and severe combined immunodeficiency," said Mark Kay, MD, PhD, professor of pediatrics and of genetics. "We're able to do this without using promoters or nucleases, which significantly reduces the chances of cancers that can result if the new gene inserts itself at random places in the genome."

Using the technique, Kay and his colleagues were able to insert a working copy of a missing blood-clotting factor into the DNA of mice with hemophilia. Although the insertion was accomplished in only about 1 percent of liver cells, those cells made enough of the missing clotting factor to ameliorate the disorder.

Kay is the senior author of the research, which will be published Oct. 29 in Nature. The lead author is postdoctoral scholar Adi Barzel, PhD.

A possible alternative to CRISPR

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New way of genome editing cures hemophilia in mice; may be safer than older method

PUBLIC RELEASE DATE:

29-Oct-2014

Contact: Pete Farley peter.farley@ucsf.edu 415-502-6397 University of California - San Francisco @ucsf

Scores of autoimmune diseases afflicting one in 12 Americans ranging from type 1 diabetes, to multiple sclerosis (MS), to rheumatoid arthritis, to asthma mysteriously cause the immune system to harm tissues within our own bodies. Now, a new study pinpoints the complex genetic origins for many of these diseases, a discovery that may lead to better diagnosis and ultimately to improved treatments.

A team of scientists from UC San Francisco, the Broad Institute of MIT and Harvard, and Yale School of Medicine developed a new mathematical tool to more deeply probe existing DNA databases. In so doing they discovered how certain DNA variations, when inherited, are likely to contribute to disease.

By applying their method to analyzing data from previous studies of 21 different autoimmune diseases, the research team has deepened scientific understanding of the genetic underpinnings of a wide range of these disorders. They also found the specific immune cells most responsible for the diseases. Their study is published online on October 29, 2014 in Nature.

The researchers examined a wealth of data from 39 large-scale studies called genome-wide association studies (GWAS). Teams of scientists in recent years have conducted GWAS typically enlisting thousands of study participants to identify large blocks of DNA within the human genome within which genetic variants are implicated as risk factors for common diseases. But examination of GWAS data to date has seldom pointed to altered proteins, as surprisingly few protein-encoding gene variants within these broad swaths of DNA have been associated with the diseases under investigation.

Instead, the genetic risks identified through GWAS more often appear to be associated with DNA variations that do not reside within genes. The nature of this risk has defied understanding until now, fueling a perception that few medical benefits have thus far emerged from large-scale studies of human genetic variation being conducted in the wake of the initial Human Genome Project.

In the new study the researchers found that the presence of specific genetic variants in different autoimmune diseases can alter patterns of activity of genes in particular ways that affect functions of the immune system. This was true despite the fact that the genetic variants are not within genes.

To make their discoveries, the researchers developed software and used next-generation sequencing techniques to probe "epigenetic" characteristics of specialized immune cells, in which gene activity is affected without changes to the DNA sequence itself within the affected genes.

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In autoimmune diseases, researchers pinpoint genetic risks, cellular culprits

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Newswise Scores of autoimmune diseases afflicting one in 12 Americans ranging from type 1 diabetes, to multiple sclerosis (MS), to rheumatoid arthritis, to asthma mysteriously cause the immune system to harm tissues within our own bodies. Now, a new study pinpoints the complex genetic origins for many of these diseases, a discovery that may lead to better diagnosis and ultimately to improved treatments.

A team of scientists from UC San Francisco, the Broad Institute of MIT and Harvard, and Yale School of Medicine developed a new mathematical tool to more deeply probe existing DNA databases. In so doing they discovered how certain DNA variations, when inherited, are likely to contribute to disease.

By applying their method to analyzing data from previous studies of 21 different autoimmune diseases, the research team has deepened scientific understanding of the genetic underpinnings of a wide range of these disorders. They also found the specific immune cells most responsible for the diseases. Their study is published online on October 29, 2014 in Nature.

The researchers examined a wealth of data from 39 large-scale studies called genome-wide association studies (GWAS). Teams of scientists in recent years have conducted GWAS typically enlisting thousands of study participants to identify large blocks of DNA within the human genome within which genetic variants are implicated as risk factors for common diseases. But examination of GWAS data to date has seldom pointed to altered proteins, as surprisingly few protein-encoding gene variants within these broad swaths of DNA have been associated with the diseases under investigation.

Instead, the genetic risks identified through GWAS more often appear to be associated with DNA variations that do not reside within genes. The nature of this risk has defied understanding until now, fueling a perception that few medical benefits have thus far emerged from large-scale studies of human genetic variation being conducted in the wake of the initial Human Genome Project.

In the new study the researchers found that the presence of specific genetic variants in different autoimmune diseases can alter patterns of activity of genes in particular ways that affect functions of the immune system. This was true despite the fact that the genetic variants are not within genes.

To make their discoveries, the researchers developed software and used next-generation sequencing techniques to probe epigenetic characteristics of specialized immune cells, in which gene activity is affected without changes to the DNA sequence itself within the affected genes.

The team discovered that a majority of key DNA changes associated with autoimmune diseases occur in functional bits of DNA known as enhancers.

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In Autoimmune Diseases Affecting Millions, Researchers Pinpoint Genetic Risks, Cellular Culprits

By Randy Dotinga HealthDay Reporter

FRIDAY, Oct. 24, 2014 (HealthDay News) -- As more genetic tests are developed that spot increased risks for certain cancers, one might think that high-risk people would be more proactive about getting screened.

But a new study suggests that, at least with colon cancer, knowledge does not change behavior: People who found out their genes doubled their risk of colon cancer were no more likely than people with average risk to get screened.

"It didn't make any difference, not at all," said study author Dr. David Weinberg, chairman of medicine at Fox Chase Cancer Center in Philadelphia.

Weinberg cautioned against using the findings to come to conclusions about the impacts of genetic tests for other cancers. Still, he said, the "modest amount of available data" suggests that genetic tests like the colon cancer one -- which don't confirm a huge increased risk of disease -- don't alter health habits.

The researchers were surprised by the results. "Our hypothesis was that this would be effective," Weinberg said, especially considering that a person's genetic makeup is so personal and "might be a more compelling motivator than something like their cholesterol level or a lifestyle choice like smoking."

Dr. Durado Brooks, director of prostate and colorectal cancer with the American Cancer Society, agreed with Weinberg that the finding was surprising.

"The theory around genetic testing is that if you tell people they're at a higher risk of disease XYZ, the hope is that they'll modify their behavior," Brooks said. "This does not support that hope or theory."

Genetic tests have been a hot topic for several years as companies have begun offering them to the public along with insight about people's risks of developing various diseases. One big question remains largely unanswered: What will people do differently, if anything, once they get a glimpse into what their medical futures may hold?

In this latest study, the researchers focused on 783 people aged 50 to 79 who hadn't been screened for colon cancer recently. Of those, 541 of them were told that their genetic tests revealed their risk of colon cancer was doubled (about 1 in 20).

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Knowing Genetic Risk for Cancer May Not Change Behavior

image courtesy Sheila Kambin

image courtesy Sheila Kambin

From the first time Dr. Sheila Kambin laid eyes on her newborn son Aidan, she knew something wasnt right.

Aidan had a sacral pita dimple on his lower backand low set ears. He was full term but weighed just 5 pounds and was sent to a neonatal intensive-care unit (NICU) where he was evaluated for low platelet count, low blood sugar, problems with temperature regulation and feeding.

He was never able to latch, but I never knew why, she said.

At just 4 months old, Aidan had surgery to repair an inguinal hernia, a bulge in the abdominal muscles. He also had ligament laxity (loose ligaments), hammer toes, distinct facial features, long tapered fingers, and the uvula in the back of his throat was split into two. Kambin later learned Aidan had a submucous cleft palate, or a cleft palate covered by a membrane, the reason for his feeding troubles.

Perhaps one of the most concerning symptoms to Kambin was that Aidan wasnt reaching his developmental milestones.

We started to notice he was delayed by about 6 months on every single one of them, she said.

His preschool teacher was also concerned.

His teacher said, Ive been teaching preschool for 30 years and Im not sure what exactly is wrong with Aiden but something is wrong with him.

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Genetic disorder discovered

Although LDL is an important risk factor for aortic valve disease, the precise role it plays has been uncertain. Lipid-lowering therapy in people with established aortic valve disease has not been shown to be beneficial. Now, however,a new genetic study published inJAMAsuggests that LDL cholesterol may in fact cause an increase in aortic valve calcium and aortic valve stenosis. This may mean that LDL-lowering therapy could prove beneficial when given earlier in the disease process.

Researchers in theCohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium used Mendelian randomization to assess in nearly 7,000 people the association of a genetic risk score with the presence of aortic valve calcium. They founda strong association between the genetic risk score for LDL and the presence of aortic valve calcium.

The researchers also analyzed data from more than 28,000 participants in thethe Malm Diet and Cancer Study (MDCS). The genetic risk score for LDL was significantly associated with the incidence of aortic stenosis as ascertained from national registries.

Our findings link a genetically mediated increase in plasma LDL-C with early subclinical valve disease, as measured by aortic valve calcium, and incident clinical aortic stenosis, providing supportive evidence for a causal role of LDL-C in the development of aortic stenosis, write the authors. The authors speculate that LDL lowering may not be effective in established valve disease once valve calcification and remodeling are well established But, they write, our results suggest that early lipid lowering, prior to the development of even mild forms of aortic stenosis, may be required to prevent aortic valve disease.

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Genetic Study Suggests Possible Causal Role for Cholesterol In Heart Valve Disease

The Icahn School of Medicine at Mount Sinai is opening a satellite Genetic Testing Lab in Branford, in space formerly occupied by 454 Life Sciences.

The managing director of Mt. Sinai Testing Lab-Connecticut was vice president of research and development at 454, and the director of laboratory operations was the director of the sequencing center at 454.

The Icahn Institute for Genomics and Multiscale Biology announced the move in September, and Gov. Dannel P. Malloy toured the facility Thursday and talked about the government incentives offered to the medical school.

The Department of Economic and Community Development gave it a $9.5 million subsidized loan and, if the institute meets hiring projections and reaches a staff or 142 people over the next five years, $7.25 million of the loan will be forgiven.

454 Life Sciences, the DNA sequencing machine company that had occupied the space, employed about 200 people in 2007, when it was bought by Roche for $155 million. Roche announced a year ago that it would close and lay off 100 employees.

Glenn Farrell, a spokesman for the Icahn genomics institute, said Mt. Sinai has been working for months to renovate the former 454 space and has shipped equipment there. The facility has hired 10 people, and is recruiting for about 10 more, including entry-level technicians, early career technicians, a quality assurance professional, managers and an accessioning specialist. He said it should open in December.

Currently, the Genetic Testing Lab in New York employs about 100 people. The largest part of its work is doing genetic screening for couples planning to have a child. The lab also does more comprehensive screening for patients whose illness is a mystery and cancer target-specific gene testing.

The Institute had 340 employees at the end of last year in New York, including 188 staff, 87 professors and 65 post-doctorate researchers. It has been aggressively expanding in all those areas, and in its 2013 annual report, boasted of recruiting a Yale University professor. Mt. Sinai's medical school is ranked in the top 20 nationally, and its genetics specialty is ranked 15th.

In New York, it is exploring genetic markers in cancer, autism, schizophrenia, colitis and Crohn's disease, congenital heart disease and Alzheimer's.

It outgrew its testing lab space in New York, and Farrell said New York City is a difficult place to find affordable space where you can expand quickly.

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Genomics Research Lab Planned For Branford

PUBLIC RELEASE DATE:

24-Oct-2014

Contact: Lori Sundeen Soderbergh lori.soderbergh@utsouthwestern.edu 214-648-3404 UT Southwestern Medical Center @UTSWNews

DALLAS October 24, 2014 Genetic screening services for rural and underserved populations will expand from six to 22 counties in North Texas under a $1.5 million grant from the Cancer Prevention and Research Institute of Texas (CPRIT) to UT Southwestern Medical Center.

The goal is to identify patients with Hereditary Breast-Ovarian Cancer (HBOC) and Lynch syndrome, two of the most commonly inherited cancer predisposition syndromes. For those carrying these mutations, the lifetime risk for breast, ovarian, colorectal, and uterine cancer is as high as 85 percent.

"Overall, about 10 percent of cancer diagnoses are hereditary," said Linda Robinson, Assistant Director of Clinical Cancer Genetics at UTSouthwestern. "The power of genetic testing is that we can lessen the amount of treatment for these people by finding the cancer early, and for some patients we can prevent it from happening altogether."

Cancer Genetic Services for Rural and Underserved Populations in Texas is part of the Genetics Department at the Harold C. Simmons Cancer Center, in partnership with Parkland Memorial Hospital in Dallas and the Moncrief Cancer Institute and JPS Health Network in Fort Worth. The cost of the genetic evaluation and testing is covered through the CPRIT grant and other external funding sources.

"This support from CPRIT is crucial in enabling us to offer genetic counseling to populations who have never received these services," said Dr. James K.V. Willson, Dean of Oncology Programs, Professor and Director of the Harold C. Simmons Comprehensive Cancer Center, Professor of Internal Medicine, and holder of The Lisa K. Simmons Distinguished Chair in Comprehensive Oncology.

The principal investigator on the grant is Dr. Keith Argenbright, Director of the Moncrief Cancer Institute, Associate Professor at the Harold C. Simmons Cancer Center and Department of Clinical Science, UT Southwestern.

"We now have the ability to connect with patients through telemedicine, a high tech communications system linking patients in outlying counties with our genetic specialists," said Dr. Argenbright. "With this new grant, we are building on the success of a similar program CPRIT funded three years ago, which brought state-of-the art genetic testing closer to home for our patients."

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UTSW researchers receive CPRIT funding to expand genetic screening program

TIME Health Cancer Heres How Well Your Genes Can Predict Your Breast Cancer Risk Researchers say genetic sequencing can predict breast cancer risk better than previously thought

Your genes have a lot to say about who you are and how healthy you are. But for certain diseases, including cancer, so many genes are likely involved that its hard for doctors to come up with a useful, reliable way to turn your DNA information into a precise risk score.

But in a paper published in the journal Cancer Epidemiology, Biomarkers & Prevention, researchers say that combining the known genetic players in breast cancer can predict with much higher accuracy a newborn girls theoretical risk of developing the disease.

MORE: Angelina Jolies Surgery May Have Doubled Genetic Testing Rates at One Clinic

Alice Whittemore, a professor of epidemiology and biostatistics at Stanford University School and Medicine, and her colleagues included 86 known genetic variants that have been associated with breast cancerincluding BRCA1 and BRCA2, which are relatively rare but confer a very high risk of disease compared to those that have a smaller contributionand created a computer model that took into account the rates of breast cancer among 120,000 women who had these genetic variants.

This model served as a predictor for breast cancer based on womens genetic makeup. When researchers looked at the top 25% of risk scores, they found that these would account for about half of breast cancer cases in the future. Using previous models, genetic variants could account for only 35% of future cancer cases.

Our results are more optimistic than those that have been previously published, says Whittemore, because we took 86 known genetic variants associated with breast cancer, and took what was in the worlds literature about how common those variants are, and by how much a factor they increase risk. And the more genetic variants that are identified, the better we will get at this.

MORE: BRCA Gene Can Be A Cancer Triple Whammy, Study Finds

Since the paper was submitted, several new genetic variants have been linked to breast cancer, and adding those to the model, says Whittemore, could make it more effective.

But just because a woman may have been born with a high genetic risk for breast cancer doesnt mean that she cant change that risk. The model found that lifestyle factors, which are in a womans control, can generally lower the genetic risk by half. And the higher a womans genetic risk, the more she can reduce it with healthy behaviors. So avoiding excessive amounts of alcohol and smoking, or maintaining a healthy weight, for example, can bring a genetic risk of 30% down to around 15%, while a woman with a 4% genetic risk of developing breast cancer can reduce her risk by 2%.

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Heres How Well Your Genes Can Predict Your Breast Cancer Risk

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Newswise DALLAS October 24, 2014 Genetic screening services for rural and underserved populations will expand from six to 22 counties in North Texas under a $1.5 million grant from the Cancer Prevention and Research Institute of Texas (CPRIT) to UT Southwestern Medical Center.

The goal is to identify patients with Hereditary Breast-Ovarian Cancer (HBOC) and Lynch syndrome, two of the most commonly inherited cancer predisposition syndromes. For those carrying these mutations, the lifetime risk for breast, ovarian, colorectal, and uterine cancer is as high as 85 percent.

Overall, about 10 percent of cancer diagnoses are hereditary, said Linda Robinson, Assistant Director of Clinical Cancer Genetics at UTSouthwestern. The power of genetic testing is that we can lessen the amount of treatment for these people by finding the cancer early, and for some patients we can prevent it from happening altogether.

Cancer Genetic Services for Rural and Underserved Populations in Texas is part of the Genetics Department at the Harold C. Simmons Cancer Center, in partnership with Parkland Memorial Hospital in Dallas and the Moncrief Cancer Institute and JPS Health Network in Fort Worth. The cost of the genetic evaluation and testing is covered through the CPRIT grant and other external funding sources.

This support from CPRIT is crucial in enabling us to offer genetic counseling to populations who have never received these services, said Dr. James K.V. Willson, Dean of Oncology Programs, Professor and Director of the Harold C. Simmons Comprehensive Cancer Center, Professor of Internal Medicine, and holder of The Lisa K. Simmons Distinguished Chair in Comprehensive Oncology.

The principal investigator on the grant is Dr. Keith Argenbright, Director of the Moncrief Cancer Institute, Associate Professor at the Harold C. Simmons Cancer Center and Department of Clinical Science, UT Southwestern.

We now have the ability to connect with patients through telemedicine, a high tech communications system linking patients in outlying counties with our genetic specialists, said Dr. Argenbright. With this new grant, we are building on the success of a similar program CPRIT funded three years ago, which brought state-of-the art genetic testing closer to home for our patients.

The new grant funds the program for an additional three years. The initial $1.6 million CPRIT grant from 2011 included Tarrant, Dallas, Wise, Hood, Johnson, and Parker counties, a population of 3,511,623. The expansion includes a population increase of 1,156,449 and covers an estimated additional 13,480 square miles, more than double the size of Massachusetts. In Texas, 43 percent of the population is uninsured or underinsured. CPRIT funding allows for genetic services for patients who have never had access to these services before.

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UT Southwestern Researchers Receive CPRIT Funding to Expand Genetic Screening Program to Reach Medically Underserved ...

Health and Medicine for Seniors

Many Elderly Found with Puzzling Mutations Linked to Leukemia, Lymphoma

Researchers find no connection with blood cancer that seldom strikes senior citizens

Oct. 22, 2014 A surprisingly large percentage 5 percent of senior citizens over age 70 have been found to have genetic mutations linked to leukemia and lymphoma in their blood cells. The vast majority won't get blood cancer, however, as the incidence of these cancers is less than 0.1 percent among the elderly, according to the researchers at Washington University School of Medicine in St. Louis.

Mutations in the body's cells randomly accumulate as part of the aging process, and most are harmless. For some people, genetic changes in blood cells can develop in genes that play roles in initiating leukemia and lymphoma even though such people don't have the blood cancers, the scientists reported Oct. 19 in Nature Medicine.

"But it's quite striking how many people over age 70 have these mutations," said senior author Li Ding, PhD, of The Genome Institute at Washington University. "The power of this study lies in the large number of people we screened. We don't yet know whether having one of these mutations causes a higher than normal risk of developing blood cancers. More research would be required to better understand that risk."

The researchers analyzed blood samples from 3,000 people enrolled in The Cancer Genome Atlas project, a massive endeavor funded by the National Cancer Institute and the National Human Genome Research Institute at the National Institutes of Health (NIH). The effort involves cataloguing the genetic errors involved in more than 20 types of cancers.

The patients whose blood was analyzed for the current study had been diagnosed with cancer but were not known to have leukemia, lymphoma or a blood disease.

They ranged in age from 10 to 90 at the time of diagnosis and had donated blood and tumor samples before starting cancer treatment. Therefore, any mutations identified by the researchers would not have been associated with chemotherapy or radiation therapy, which can damage cells' DNA.

The researchers, including Genome Institute scientists Mingchao Xie, Charles Lu, PhD, and Jiayin Wang, PhD, zeroed in on mutations that were present in the blood but not in tumor samples from the same patients. Such genetic changes in the blood would be associated with changes in stem cells that develop into blood cells, but not to the same patient's cancer.

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Many Elderly Found with Puzzling Mutations Linked to Leukemia, Lymphoma

Women of Latin American descent, particularly those with indigenous ancestry, may carry a genetic variant that protects them from breast cancer.

Previous epidemiological studies have shown that Latinas seem to be less susceptible to developing breast cancer than women of other ethnicities. Now an international group of scientists, led by UCSF researchers, have identified the spot on the DNA sequence responsible for that protective effect.

The research is still a long way from making testing for the variant available. Scientists still have a lot more work to do to figure out what the variant means and exactly how it interacts with the body to reduce breast cancer risk.

Its good news in a very general sense. But ... I dont think anyone should stop mammograms because of the variant, said Laura Nejerman, lead author of the study published earlier this week and assistant professor of medicine at UCSF. Now what we are trying to do is think of how best to incorporate this genetic information with other risk-factor information to better provide a picture of breast cancer risk.

But the discovery highlights the existence of genetic risk factor differences between racial groups and ethnicities, and the advent of genome decoding allows researchers to explore those differences. Understanding these variations could shed light on who is most at risk for breast cancer and why some people are less likely to develop the disease and knowing those could lead to a better understanding of cancer overall.

White women of European descent have about a 13 percent lifetime risk of breast cancer, according to National Cancer Institute data from 2007 to 2009. For African American women the risk is about 11 percent; for Asians and Pacific Islanders the risk is about 10 percent.

For Latinas, the risk is 9.8 percent, but its even lower in the 7 percent range among those with indigenous American ancestry, including those from Alaska.

The researchers initially focused on trying to figure out whether there was a genetic variant in European populations that put them at higher risk. Research has identified various mutations, particularly the BRCA genes most closely associated with those of European Jewish descent, that put certain people at higher risk of breast cancer. But their work eventually led them to discover the protective variant in Native American and Latina populations.

Significant impact

Theres no question this is the real thing, said Dr. Elad Ziv, professor of medicine at UCSF and senior author of the study, which was published this week in the journal Nature Communications.

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Genetic variant helps protect Latinas from breast cancer

Chuck Bednar for redOrbit.com Your Universe Online

Scientists at the Baylor College of Medicine Medical Genetics Laboratories and the UCLA Clinical Genomics Center are at the forefront of a new technique that could be a powerful tool for diagnosing rare genetic conditions.

The technique is known as whole-exome sequencing and involves using cutting edge sequencing techniques to analyze the coding regions or exomes of thousands of genes at the same time, Baylor researchers Dr. Yaping Yang, Dr. Christine M. Eng and their colleagues explained in a recent edition of the Journal of the American Medical Association (JAMA).

Sequencing a patients exome and comparing it to a normal reference sequence allows researchers to identify variations in that individuals DNA sequence. Those variations can then be related back to the patients health issues in an attempt to locate the specific genetic cause of that medical condition, the authors added.

The researchers studied a group of 2,000 patients that had been referred for evaluation of suspected genetic conditions, and found that the use of whole-exome sequencing led to the discovery of a molecular diagnosis (meaning that a genetic mutation or variation associated with a specific disease) in roughly 25 percent of them.

The findings in this report, I believe, will forever change the future practice of pediatrics and medicine as a whole, study co-author Dr. James R. Lupski, a professor of molecular and human genetics and pediatrics at Baylor, said in a statement. It is just a matter of time before genomics moves up on the physicians list of things to do and is ordered before formulating a differential diagnosis. It will be the new family history that, better yet, gets you both the important variants inherited from each parent and the new mutations that contribute to disease susceptibility.

In the study, the use of whole-exome sequencing identified ways in which medical professionals could clinically intervene in order to alleviate or eliminate symptoms and give patients families more information about the disease and treatment. Furthermore, many of the diagnoses made using the technique involved patients inheriting a new mutation previously undetected in their parents, the researchers will report Tuesday at the annual meeting of the American Society of Human Genetics (ASHG) in San Diego.

The clinical whole-exome sequencing analyzed as part of the study took place between June 2012 and August 2014, and the tests had been ordered by the patients physician for suspected genetic conditions. The process involved the collection of peripheral blood, tissue, or extracted DNA samples which were collected from patients or their parents, and the majority (87.8 percent) of those analyzed were found to have neurological disorders or developmental delay.

A molecular diagnosis was reported for 504 patients (25.2 percent), with 58 percent of the diagnostic mutations not previously reported, the researchers said. Molecular diagnosis rates for the physical manifestation or phenotypic category was 27.2 percent for the neurological group, 24.6 percent for the neurological plus other organ systems group, 36.1 percent for the specific neurological group, and 20.1 percent for the nonneurological group.

Clinical exome sequencing can assist diagnosis in a wide range of disorders that are diagnostic dilemmas, said Lupski. Rare variants and Mendelian disease are important contributors to disease populations We find rare variants in aggregate actually contribute to disease susceptibility in a big way. The individual diseases may be rare, but there are thousands of such diseases and many more being defined through genomics.

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Exome Sequencing Becoming A Powerful New Diagnostic Tool For Genetic Disorders

An international research collaboration led by UC San Francisco researchers has identified a genetic variant common in Latina women that protects against breast cancer.

The variant, a difference in just one of the three billion "letters" in the human genome known as a single-nucleotide polymorphism (SNP), originates from indigenous Americans and confers significant protection from breast cancer, particularly the more aggressive estrogen receptor-negative forms of the disease, which generally have a worse prognosis.

"The effect is quite significant," said Elad Ziv, MD, professor of medicine and senior author of the study. "If you have one copy of this variant, which is the case for approximately 20% (the range being 10 to 25 percent) of U.S. Latinas, you are about 40 percent less likely to have breast cancer. If you have two copies, which occurs in approximately 1% of the US Latina population, the reduction in risk is on the order of 80 percent."

Published in the October 20, 2014 issue of Nature Communications, the new study showed that women who carry the variant have breast tissue that appears less dense on mammograms. High "mammographic density" is a known risk factor for breast cancer.

"We have detected something that is definitely relevant to the health of Latinas, who represent a large percentage of the population in California, and of other states such as Texas," said first author Laura Fejerman, PhD, assistant professor of medicine and a member of UCSF's Institute of Human Genetics. "This work was done as a collaboration of multiple investigators, many of us originally from Latin America. As a Latina myself, I am gratified that there are representatives of that population directly involved in research that concerns them."

Epidemiological data have long demonstrated that Latina women are less susceptible to breast cancer than women of other ethnicities. According to National Cancer Institute data from 2007 to 2009, whites have about a 13 percent lifetime risk of breast cancer, blacks about 11 percent, and Hispanics less than 10 percent. The lifetime risk among Hispanics with indigenous American ancestry is even lower.

For several years Fejerman and Ziv have studied Latina populations in search of genetic and biological explanations for these differences. "After our earliest studies we thought there might be a genetic variant that led to increased risk in European populations," said Ziv. "But what this latest work shows is that instead there is a protective variant in Native American and Latina populations."

In the new study, Fejerman, Ziv, and colleagues performed successive genome-wide association analyses of datasets from the Cancer Prevention Institute of California (CPIC) and a study known as the Multiethnic Cohort. They replicated their initial findings in data from the Women's Health Initiative study, from a study of breast cancer in Colombian women known as COLUMBUS, and from a study conducted in Mexico, ultimately incorporating DNA data from a total of 3,140 women with breast cancer and 8,184 healthy controls.

"Our breast cancer registry has recruited and followed more than 4,000 breast cancer families. For this study, we provided cases and controls who self-identified as Latina or Hispanic," said CPIC Senior Scientist Esther M. John, PhD, MSPH. "The DNA samples and data shared from these cases, combined with other samples from the San Francisco Bay Area, contributed to a total of 977 breast cancer cases and 722 controls that led to this important genetic discovery."

The newly discovered SNP is on Chromosome 6, near a gene coding for an estrogen receptor known as ESR1. Fejerman and Ziv said that the biological basis of the association between the variant and reduced breast cancer risk is still not known, but their preliminary experiments indicate that the variant interferes with the action of transcription factors, proteins that regulate the expression of the ESR1 estrogen receptor.

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Genetic variant protects some Latina women from breast cancer

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Newswise At least 2 percent of people over age 40 and 5 percent of people over 70 have mutations linked to leukemia and lymphoma in their blood cells, according to new research at Washington University School of Medicine in St. Louis.

Mutations in the bodys cells randomly accumulate as part of the aging process, and most are harmless. For some people, genetic changes in blood cells can develop in genes that play roles in initiating leukemia and lymphoma even though such people dont have the blood cancers, the scientists report Oct. 19 in Nature Medicine.

The findings, based on blood samples from nearly 3,000 patients, dont mean that people with these genetic mutations are destined to develop a blood cancer. In fact, the vast majority of them wont as the incidence of blood cancers such as leukemia or lymphoma is less than 0.1 percent among the elderly.

But its quite striking how many people over age 70 have these mutations, said senior author Li Ding, PhD, of The Genome Institute at Washington University. The power of this study lies in the large number of people we screened. We dont yet know whether having one of these mutations causes a higher than normal risk of developing blood cancers. More research would be required to better understand that risk.

The researchers analyzed blood samples from people enrolled in The Cancer Genome Atlas project, a massive endeavor funded by the National Cancer Institute and the National Human Genome Research Institute at the National Institutes of Health (NIH). The effort involves cataloguing the genetic errors involved in more than 20 types of cancers.

The patients whose blood was analyzed for the current study had been diagnosed with cancer but were not known to have leukemia, lymphoma or a blood disease. They ranged in age from 10 to 90 at the time of diagnosis and had donated blood and tumor samples before starting cancer treatment. Therefore, any mutations identified by the researchers would not have been associated with chemotherapy or radiation therapy, which can damage cells DNA.

The researchers, including Genome Institute scientists Mingchao Xie, Charles Lu, PhD, and Jiayin Wang, PhD, zeroed in on mutations that were present in the blood but not in tumor samples from the same patients. Such genetic changes in the blood would be associated with changes in stem cells that develop into blood cells, but not to the same patients cancer.

They looked closely at 556 known cancer genes. In 341 patients ages 40-49, fewer than 1 percent had mutations in 19 leukemia- or lymphoma-related genes. But among 475 people ages 70-79, over 5 percent did. And over 6 percent of the 132 people ages 80-89 had mutations in these genes.

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Many Older People Have Mutations Linked to Leukemia, Lymphoma in Their Blood Cells

PUBLIC RELEASE DATE:

18-Oct-2014

Contact: Glenna Picton picton@bcm.edu 713-798-4710 Baylor College of Medicine @bcmhouston

HOUSTON -- (Oct. 18, 2014) Approximately one-fourth of the 3,386 patients whose DNA was submitted for clinical whole exome testing received a diagnosis related to a known genetic disease, often ending a long search for answers for them and their parents, said researchers from the Baylor College of Medicine departments of molecular and human genetics and pediatrics and the Baylor Human Genome Sequencing Center and the University of Texas Health Science Center at Houston.

In an online report in the Journal of the American Medical Association, the scientists led by Drs. Yaping Yang, laboratory director of the Whole Genome Laboratory at Baylor, and Christine Eng, professor of molecular and human genetics at Baylor and senior director of Baylor's Medical Genetics Laboratories, found a molecular diagnosis (meaning a genetic mutation or variation linked to a disease) in 25 percent of the large group of cases confirming in this much larger group of patients the diagnostic yield from their initial report on the first 250 cases that appeared in the New England Journal of Medicine a little more than a year ago.

Eng will also present results of the study on Oct. 21 during the American Society of Human Genetics Annual Meeting in San Diego, Calif.

"The findings in this report, I believe, will forever change the future practice of pediatrics and medicine as a whole," said Dr. James R. Lupski, professor of molecular and human genetics and pediatrics at Baylor and a coauthor of the report. "It is just a matter of time before genomics moves up on the physician's list of things to do and is ordered before formulating a differential diagnosis. It will be the new 'family history' that, better yet, gets you both the important variants inherited from each parent and the new mutations that contribute to disease susceptibility."

In fact, a large percentage of the diagnoses made were patients who inherited a new mutation (in the egg or sperm) that was not previously seen in their parents.

"The routine application of new genome methods in the clinic is not only benefitting patients but changing the way we think about research," said Dr. Richard Gibbs, director of the Baylor College of Medicine Human Genome Sequencing Center and an author of the report.

"It has been wonderful to watch this very large team of colleagues bridging from the patient in clinic to the very most cutting edge genomic technology to give families answers where previously there were none," said Dr. Arthur Beaudet, professor of molecular and human genetics who was chair of the department when the Whole Gene Laboratory was begun and who began the Baylor College of Medicine Medical Genetics Laboratories.

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Whole exome sequencing closer to becoming 'new family history'

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Newswise Audrey Lapidus adored her babys sunny smile and irresistible dimples, but grew worried when Calvin did not roll over or crawl by 10 months and suffered chronic digestive problems. Four neurologists dismissed his symptoms and a battery of tests proved inconclusive. Desperate for answers, Audrey and her husband agreed to have their son become UCLAs first patient to undergo a powerful new test called exome sequencing.

Using DNA collected from Calvins and his parents blood, a sophisticated sequencing machine rapidly scanned the boys genome, compared it to his parents and flagged a variant on his 18th chromosome. Calvin was diagnosed with Pitt-Hopkins Syndrome, a rare genetic disorder affecting only 250 children worldwide. At last Audrey and her husband had a concrete diagnosis and clear direction for seeking the best treatment for their son.

Now a landmark UCLA study makes a persuasive argument for the routine clinical use of exome sequencing as a valuable tool for diagnosing children like Calvin with rare genetic disorders. Published in the Oct. 18 online edition of the Journal of the American Medical Association, the findings show that exome sequencing produced a definitive diagnosis in 40 percent of UCLAs most complex cases a quantum leap from the fields 5-percent success rate two decades ago.

Our study is the first to show that sequencing a childs genome together with his or her parents dramatically improves geneticists ability to reach a firm diagnosis in rare disorders, said corresponding author Dr. Stan Nelson, vice chair of human genetics and a professor of pathology and laboratory medicine at David Geffen School of Medicine at UCLA. We discovered a genetic cause for the conditions affecting 40 percent of the hundreds of young children who come to UCLA for exome sequencing due to developmental delays or intellectual disabilities.

The UCLA Clinical Genomics Center was established in 2011 as one of three facilities in the world (including Baylor and Harvard) to put DNA sequencing to clinical use. Unlike earlier diagnostics that study one gene at a time, this test rapidly sifts through all of the 37-million base pairs in a persons 20,000 genes to tease out the single DNA change causing a rare genetic disorder. It focuses on the exome, the protein-coding portions of genes that account for only 1 percent of DNA but nearly 85 percent of the glitches known to cause human diseases.

In this two-year study, Nelson worked with first author Hane Lee, an assistant adjunct professor of pathology, to sequence and analyze the exomes of 814 children whose symptoms had baffled previous clinicians despite exhaustive genetic, biochemical and imaging tests.

Heres how it worked. The UCLA center funneled the raw data from sequencing the genomes of each child and their parents through its informatics pipeline to identify variants from the standard human genome. The average persons exome contains more than 20,000 variants, nearly all benign.

Next the team applied a series of filters to the data based on the patients family history and other relevant aspects of his or her condition. The researchers hunted for all genes and mutations linked by medical literature to the patients symptoms. Finally UCLAs Genomics Data Board, a multidisciplinary team of experts, reviewed the findings to reach a diagnosis.

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New Test Scans All Genes Simultaneously to Identify Single Mutation Causing Child's Rare Genetic Disease

PUBLIC RELEASE DATE:

17-Oct-2014

Contact: Robert Redmond rredmond@cshl.edu 516-422-4101 Cold Spring Harbor Laboratory @CSHLnews

Since the appearance of modern humans in Africa around 200,000 years ago, we have migrated around the globe and accumulated genetic variations that affect various traits, including our appearance, skin color, food tolerance, and susceptibility to different diseases. Large-scale DNA sequencing is now allowing us to map the patterns of human genetic variation more accurately than ever before, trace our ancestries, and develop personalized therapies for particular diseases. It is also reinforcing the idea that human populations are far from homogeneous, are highly intermixed, and do not fall into distinct races or castes that can be defined genetically.

Human Variation from Cold Spring Harbor Laboratory Press provides a state-of-the-art view of human genetic variation and what we can infer from it, surveying the genetic diversity seen in Africa, Europe, the Americas, and India. The contributors discuss what this can tell us about human history and how it can be used to improve human health. They also caution against assumptions that differences between individuals always stem from our DNA, stressing the importance of nongenetic forces and pointing out the limits of our knowledge. The book is thus essential reading for all human geneticists and anyone interested in how we differ and what this means.

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New book from CSHL Press with focus on genetics, personalized medicine and human diversity

PUBLIC RELEASE DATE:

16-Oct-2014

Contact: Sarah DeDeimar sdediemar@assurerxhealth.com 513-701-5162 Assurex Health @AssurexHealth

Mason, OH October 16, 2014 - Assurex Health and Canada's Centre for Addiction and Mental Health (CAMH) today announced they have received a $6 million grant from Genome Canada, an agency of the Canadian government, to study the benefits of genetic testing to guide medication decisions for patients with depression or schizophrenia.

The clinical trial is the first to evaluate Canadian patients, including patients with schizophrenia, using personalized decision guidance provided by the GeneSight Psychotropic test, developed by Assurex Health in Mason, Ohio. The grant funds a joint Genomic Applications Partnership Program (GAPP) to be managed by CAMH and Assurex Health, with administrative and programmatic support from the Ontario Genomic Institute.

GeneSight technology is based on combinatorial pharmacogenomics (CPGxTM), the study of how variations in multiple genes influence an individual's response to medications, as well as evidence-based medicine and clinical pharmacology. The technology analyzes response to medicines commonly prescribed to treat depression and schizophrenia, as well as anxiety, posttraumatic stress disorder (PTSD), bipolar disorder, and other behavioral health conditions.

Three Year Study to Examine Clinical Outcomes, Cost Benefits

"Genome Canada is pleased to support this partnership that will accelerate the translation of tailored treatments for mental health conditions, avoiding adverse drug reactions. This in turn will reduce burden and cost to Canada's health care system," said Dr. Pierre Meulien, President and CEO of Genome Canada.

The study, "Clinical Utility and Enhancements of a Pharmacogenomic Decision Support Tool for Mental Health Patients," will be funded over three years. Assurex Health and CAMH investigators, working with clinicians from the greater Toronto area, will conduct a 12 week randomized and blinded study with Canadian patients diagnosed with depression or schizophrenia. Healthcare providers of patients in both disease categories for whom prior prescription drug treatment has failed will receive personalized guidance for medication selection and dosing using the GeneSight Psychotropic test.

"The study will also evaluate the ability of genetic variants discovered at CAMH to predict important side effects of psychiatric medications, and will collect economic data on how testing impacts health care costs," said C. Anthony Altar, PhD, Senior Vice President, Neurosciences of Assurex Health and co-principal investigator on the grant. "We will look at how prescribing more appropriate medications specifically suited to individual patient's genetics correlates to clinical outcomes and cost benefits."

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Assurex Health and CAMH awarded $6 million grant from Genome Canada

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Actress Angelina Jolies decision to have a preventative double mastectomy after learning she carried the faulty gene BRCA1 has heighted awareness for genetic testing. The Angelina Jolie Effect has lead to an increase in testing for the BRCA1/2 mutations among North American women, according to a recent Canadian study. But, is genetic testing for everyone? And, what questions should women consider?

Gail Vance, MD, FCAP, a pathologist and a clinical geneticist specializing in cancer genetics for inherited diseases at the Indiana University School of Medicine, is available for interviews for breast cancer awareness stories on what women need to know when considering genetic testing for the breast cancer. She is available to answer such questions as:

In lieu of all the recent advancements in genetic testing, what questions should patients be asking their doctors? Why is it important for a pathologist to be involved? How affordable are these tests? Are these tests covered by health care providers?

Dr. Vance also can offer tips for patients who are weighing this important decision, including: Talk with your physician about which genetic testing is appropriate for you Discuss the risks and benefits of genetic testing Learn which treatment is right for you. If you have diagnosed with cancer, an evaluation of your tumor will assist your oncologist in determining the appropriate treatment

Pathologists are the physicians who use laboratory medicine to examine cells, tissues, and body fluids to identify and diagnose disease, including breast cancer. They are involved in every aspect of health care. Pathologists provide the medical interpretation of genetic testing, which is critical to help patients make informed decisions about their health.

About Dr. Gail Vance: Gail H. Vance, MD, FCAP, is the Sutphin professor of Cancer Genetics and interim chairperson of the Department of Medical and Molecular Genetics at the Indiana University School of Medicine. She also is director of the Division of Diagnostic Genomics and the Indiana Familial Cancer Program, which provides genetic counseling, risk assessment, and genetic testing to individuals with an elevated risk for developing cancer.

About the College of American Pathologists As the leading organization with more than 18,000 board-certified pathologists, the College of American Pathologists (CAP) serves patients, pathologists, and the public by fostering and advocating excellence in the practice of pathology and laboratory medicine worldwide. The CAPs Laboratory Improvement Programs, initiated 65 years ago, currently has customers in more than 100 countries, accrediting 7,600 laboratories and providing proficiency testing to 20,000 laboratories worldwide. Find more information about the CAP at cap.org. Follow CAP on Twitter: @pathologists.

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Pathologist and Genetic Counselor Available for Interviews on the "Angelina Jolie Effect" and What Patients Need to Know