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Biomarker May Predict Prostate Cancers Requiring Treatment

Not all early-stage prostate cancer diagnoses are alike. While some patients have aggressive tumors, others have slow-growing, low Gleason score tumors that may not require treatment, but instead can be monitored with regular clinical evaluations. But distinguishing between prostate cancers that require treatment and those that do not is still a major challenge.

Researchers at Columbia University in New York City have now identified a 3-gene signature that could indicate whether a particular early-stage prostate cancer is indolent. The test relies on a tissue sample, and along with a prostate-specific antigen (PSA) test and a histology assessment, could help clinicians make an accurate diagnosis. The early results, including a blinded retrospective analysis of 43 patients, show that the signature can accurately predict which patients with low-risk disease would develop metastatic prostate cancer and which patients would not progress. The study is published in Science Translational Medicine.

“These types of markers will, for the first time, give us the opportunity to measure biological features of cancer in the same patient, with multiple biopsies spread out over many years,” said Eric Klein, MD, chairman, Glickman Urological and Kidney Institute at the Cleveland Clinic in Ohio.
Cory Abate-Shen, PhD, professor of urological oncology at Columbia University; Andrea Califano, PhD, professor of systems biology at Columbia University; and colleagues used a computational approach that identified three genes—FGFR1, PMP22, and CDKN1A—all associated with aging, that could accurately predict outcomes of low-risk, low Gleason score prostate tumors. Protein and mRNA levels of all three genes were high in those patients who had non-aggressive, indolent disease and low in those who had aggressive tumors.

Clinicians still rely on the Gleason score, a histology and pathology evaluation that does not incorporate any molecular assessment. Those patients with a Gleason score of 8 or higher are candidates for immediate treatment, but whether men with a score of 6 or 7 require treatment is difficult to assess—no test exists to identify the small percentage of patients who have early-stage prostate cancer that is more likely to metastasize.

The 3-gene signature was validated using an independent prostate cancer cohort. According to the study authors, the signature was prognostic and improved prognosis compared with the use of PSA and clinical assessment.

“We would predict that the test would be beneficial for patients with low Gleason score prostate tumors,” said Abate-Shen. “These patients are now typically monitored on active surveillance protocols, and the patients get a biopsy periodically. The test would be conducted on the biopsy.”

Rather than focusing on the entire genome, the researchers focused on 377 genes involved in aging, predicting that genes involved in aging and senescence are critical for tumor suppression. Cellular senescence is known to play a role in tumor suppression and is associated with benign prostate tumors both in the clinic and in mouse models, according to the researchers. Using a computational analysis called gene set enrichment analysis (GSEA), they narrowed the long gene list to 19 genes, and then to a set of 3 genes that could identify indolent tumors.

“To focus on senescence genes is intellectually interesting,” said Klein. “There is already a body of work supporting the role of these genes in prostate cancer, but to my knowledge no one has looked at them in early-stage disease before.”

Forty-three patients, who had been under active surveillance for 10 years at Columbia University Medical School, were used for the blinded retrospective analysis to assess the predictive value of the gene signature. Each patient had been diagnosed with low-risk prostate cancer, with a Gleason score of 6 or less. The test was correctly able to identify all 14 patients who eventually developed advanced prostate cancer.

CDKN1A has been shown to be linked to senescence and to regulate the cell cycle. Previous studies have shown that downregulation of the gene is linked to cancer progression. The correlation of FGFR1 (fibroblast growth factor receptor 1) with indolent tumors was surprising, as fibroblast growth factors have been shown to play a role in prostate cancer development. But, as the authors highlight in their discussion, FGFR1 signaling in prostate cancer is likely complex. The third gene in the signature, PMP22, encodes a glycoprotein expressed in neurons and has not been previously associated with prostate cancer.

This 3-gene signature is different from previously identified biomarkers, which have largely focused on advanced tumors. The potential biomarker test could complement other approaches in development, such as urine or blood tests, according to the authors.

A trial to validate the genetic signature is underway at Columbia University, and a national trial is being planned.

“It is really important to find novel ways to help to define early-stage tumors that may or may not progress to aggressive disease,” said Abate-Shen. “This will ultimately really help to minimize overtreatment, while capitalizing on the benefits of cancer screening.”

Other genomic approaches to distinguish indolent and aggressive disease are also underway. The first-generation expression-based tests, including Oncotype DX prostate and Prolaris, can facilitate clinical decisions based on the molecular characteristics of a prostate tumor. Both the available tests and the new ones “promise to reduce overtreatment and help men make the right decisions based on biology rather than uncertainty,” said Klein. 

Study: A Molecular Signature Predictive of Indolent Prostate Cancer [Science Translational Medicine]

Source: CancerNetwork

Droplet Digital PCR Enables Reproducible Quantification of microRNA Biomarkers

A study published online in Nature Methods recently demonstrated that Droplet Digital PCR (ddPCR™) technology can be used to precisely and reproducibly quantify microRNA (miRNA) in plasma and serum across different days, paving the way for further development of miRNA and other nucleic acids as circulating biomarkers.

“In the field of circulating microRNA diagnostics, droplet digital PCR enables us to finally perform biomarker studies in which the measurements are directly comparable across days within a laboratory and even among different laboratories,” said Dr. Muneesh Tewari, Associate Member in the Human Biology Division at the Fred Hutchinson Cancer Research Center and lead author of the study.

Challenges in miRNA quantification

miRNAs are small regulatory RNA molecules with diverse cellular functions. The human genome may encode over 1,000 miRNAs, which could target about 60 percent of mammalian genes. Because they are abundant in many cell types, exist in highly stable extracellular forms, and may provide direct information about disease processes, they are being actively studied as blood-based biomarkers for cancer and other diseases.

Quantitative real-time PCR (qPCR) has been used for the analytical measurement of miRNAs in blood samples; however, researchers have found that qPCR measurements of miRNAs in serum or plasma display unacceptably high interday variability, undermining the use of miRNAs as reliable blood-based biomarkers. An approach that yields more dependable results has therefore been sought by researchers in this field.

Advantages of ddPCR for miRNA detection

Digital PCR has many advantages over qPCR including the ability to provide absolute quantification without a standard curve and robustness to variations in PCR efficiency across different samples and assays. These and other advantages are embodied in Bio-Rad Laboratories’ QX100™ Droplet Digital PCR (ddPCR™) system, which was introduced in 2011.

“We chose to use Bio-Rad’s QX100 Droplet Digital PCR system because it was the first system on the market that could make digital PCR practical from a cost and throughput standpoint for routine use in the lab,” said Dr. Tewari.

To assess the imprecision introduced by each workflow step — serial dilution preparation, reverse transcription (RT), and PCR technical replicates — Dr. Tewari and his team conducted nested analyses of ddPCR vs. qPCR on cDNA from a dilution series of six different synthetic miRNAs in both water and plasma on three separate days. In comparison to qPCR, the researchers found that ddPCR demonstrated greater precision (48–72% lower coefficients of variation) with respect to PCR-specific variation

Next, the team performed a side-by-side comparison of qPCR to ddPCR for detecting miRNAs in serum. They collected sera samples from 20 patients with advanced prostate cancer and 20 age-matched male controls and measured the abundance of miR-141, which has been shown to be a biomarker for advanced prostate cancer. Samples were analyzed by qPCR and ddPCR with individual dilution series replicates prepared on three different days. They found that ddPCR improved day-to-day reproducibility seven-fold relative to qPCR. It was also able to demonstrate differences between case vs. control specimens with much higher confidence than qPCR (p=0.0036 vs. p=0.1199).

“Droplet digital PCR will allow us to accurately follow serum microRNA biomarker concentrations over time during a patient’s treatment course, something that has been nearly impossible to achieve with real-time PCR,” he said.

Study: Absolute quantification by droplet digital PCR versus analog real-time PCR [Nature Methods]

Source: EurekAlert! 

Mayo Clinic Hosts NIH Genomics Director at Individualizing Medicine Conference

From Promise to Practice is the title and the main message of the second annual Individualizing Medicine Conference at Mayo Clinic, Sept. 30-Oct. 2. Physicians from more than 40 states and several countries will be arriving in Minnesota to hear and learn about the latest developments and research in genomic research and how to move these discoveries into the medical practice. “Our goal is to inform practicing physicians, but other care providers, students, media and the public as well,” says Richard Weinshilboum, M.D., chair of this year’s conference held by Mayo Clinic’s Center for Individualized Medicine. “Individualizing prevention, diagnosis and treatment is the core of medical genomics and the future of medicine. Even if you missed the last 13 years since the mapping of the human genome, we’ll help you catch up in three days.”

Opening keynote speaker on Monday, September 30, will be Eric Green, M.D., Ph.D., director of the National Institute of Genomic Health Research, Bethesda, M.D. Co-hosts for the conference will be Richard Besser, M.D., chief health and medical editor for ABC News and former acting director of the Centers for Disease Control, and Ceci Connolly, managing director of the Health Research Institute, PwC.

The conference offers expert speakers, focused breakout sessions, and real-life case studies so participants can discover and discuss emerging topics in medical genomics. Topics range from translating genomic findings into clinical care to communicating accurately and ethically with patients. Also this year, on Sunday, Sept. 29, an “Omics 101” seminar will be offered at a lay level for those new to individualized medicine. This course is being offered separately and is ideal for students and media who will be working in or reporting on the genomics field.

Individualized medicine is a growing field of patient care based on the increasing knowledge of the human genome, mapped just a decade ago. Mayo Clinic is a leader in transferring medical genomics to medical practice clinomics as evidenced by its Individualized Medicine Clinic, launched a year ago. Mayo’s Center for Individualized Medicine also includes programs in biomarker discovery, pharmacogenomics, epigenomics and the human microbiome.

Source: Mayo Clinic

Ruggles Family Foundation and Mr. and Mrs. Rudy L. Ruggles, Jr. Make $1.25M Donation to J. Craig Venter Institute for New Study to Identify and Elucidate Healthy Aging Biomarkers

The J. Craig Venter Institute (JCVI), a not-for-profit genomic research organization, recently announced that the Ruggles Family Foundation and Mr. and Mrs. Rudy L. Ruggles, Jr. have made a $1.25 million donation to JCVI to identify and study biomarkers associated with healthy aging. As part of the four year grant, JCVI will collaborate with the Western Connecticut Health Network (WCHN), located in Danbury, CT.

The study, conducted by a team of scientists and clinicians from JCVI and WCHN, will focus on two groups of elderly individuals aged 65 to 85 years by correlating genetics with a variety of human genomic, gut microbiome and other “omics” profiles and integrating these data with the individuals’ health record. One group will consist of healthy individuals, and the other will have individuals with a variety of diagnosed health conditions. The team will then compare the microbiome and molecular profiles of the healthy aging group with those of the non-healthy aging group to identify biomarker candidates. The investigators hope that in the future these data can be used to develop cost-effective, clinically relevant tests.

“As traditional modes of funding for science become less and less plentiful, the need for informed and supportive philanthropic donors is more important than ever. We are grateful for the support of Rudy and Sara and the Ruggles Family Foundation as this will enable us to better understand what healthy aging looks like at the genomic level,” said J. Craig Venter, Ph.D., JCVI Founder and CEO.

“The time is right for pursuing the complex question of healthy aging given the rapid advances in analytical technologies and the expanding knowledge of the human genome and microbiome and their interactions. JCVI’s capabilities in this realm are unparalleled, and I am confident that this ground breaking study will expand materially the horizons of this area of fundamental understanding,” said Rudy Ruggles, a physicist and Adjunct Professor at JCVI, who is a healthy 74 years old and a participant in this study. He is also Chairman of the Research Advisory Council of WCHN’s Biomedical Research Institute.

According to a United Nations report, in 1950 there were 205 million people worldwide aged 60 or older. By 2000 there were 606 million aged 60 or older, and they project that by 2050 this figure will reach nearly 2 billion people who are 60 or older. Understanding the elderly patient and figuring out modes of intervention to better prevent and treat disease associated with aging will continue to be an important area of research.

In addition to more comprehensively studied human genetic factors, other areas of human health and biology that influence and define healthy aging in humans are emerging. For example, a healthy microbiome (the full complement of microbes that live on and in the human body) interacts with the human immune system establishing protective activities when necessary. Low-grade chronic inflammation in humans is a risk factor for the development of more serious diseases that reduce life spans. New tools and technologies developed since the first sequencing of the human and other genomes are now allowing researchers to explore the human body in more detail than ever before, including identifying biological signatures (biomarkers) indicative and even predictive of healthy aging.

According to JCVI President Karen Nelson, Ph.D., “JCVI’s extensive knowledge in human genomics, comparative genomics and the human microbiome, coupled with the clinical expertise of WCHN, should result in new insights into healthy aging. We are excited to add this new study to our repertoire of ongoing human microbiome studies as it will enhance our knowledge in this important area of research.”

For more information on how to support the genomics research programs at JCVI, contact Katie Collins, 858-200-1847.

Source: The J. Craig Venter Institute

Mount Sinai Launches First-ever Genetic Testing Program in the Primary Care Setting

The Icahn School of Medicine at Mount Sinai is partnering with the Institute for Family Health to launch the first-ever genetic testing program in the primary care setting to identify genetic risk for kidney disease in patients with hypertension.

The program will be funded through a $3.7 million grant from the National Human Genome Research Institute of the National Institutes of Health. Primary-care providers will use patients’ genomic information at the point-of-care to individualize treatment, testing and monitoring with Mount Sinai’s Clinical Implementation of Personalized Medicine through Electronic Health Records and Genomic Program, or CLIPMERGE, a novel clinical-decision support engine for delivering guidelines with genetic variants of clinical significance to enhance treatment.

Recent research has shown that one in eight African Americans have two copies of a version of the APOL1 gene, putting them at four to five times greater risk for developing chronic kidney disease or end-stage kidney disease if they have hypertension, or high blood pressure.

“Many patients do not have their blood pressure adequately controlled,” said Erwin Bottinger, MD, Director of the Charles Bronfman Institute for Personalized Medicine at the Icahn School of Medicine at Mount Sinai, and one of two principal investigators of the grant. “We believe that with genomic information made available to doctors through a patient’s electronic health record, we will be able to achieve better and stricter control of blood pressure and targeted use of medications that inhibit the renin angiotensin system, which are recommended in hypertensive patients at risk for kidney disease. More comprehensive tracking will also help ensure that optimal tests will be performed to stop progression of kidney disease.”

A cluster-randomized controlled trial will be conducted at 12 primary care sites in New York, including practices at The Mount Sinai Medical Center and the Institute for Family Health, which operates an independent network of community health centers in Manhattan and the Bronx.

“Genes are another piece of the puzzle that may help explain why people of African descent have poorer health outcomes than people of European descent,” said Carol Horowitz, MD, MPH, co-principal investigator and co-director of the Icahn School of Medicine at Mount Sinai’s new Center for Health Equity and Community Engaged Research. “We look forward to engaging with and helping educate our multicultural community partners, providers, and patients about the emerging role genetic testing will play in improving health.”

Neil Calman, MD, President and Chief Executive Officer of the Institute for Family Health, and Professor and Chair of Family Medicine and Community Health at Mount Sinai said, “Community-based primary care physicians have had little opportunity to incorporate genomics into the care of patients, and this grant offers us a tremendous opportunity. We hope to screen patients, identify those with increased genetic risk and work with them to prevent kidney disease. We will also train community-based primary care providers in how to discuss genetic risk with patients and their families and how to use genetic-based information in the electronic health record.”

Source: EurekAlert!