Posts Tagged ‘united’

Sequence of rare kidney cancer reveals unique alterations involving telomerase

The collaboration, a project of the National Institutes of Health’s Cancer Genome Atlas initiative, completed the sequence of chromophobe renal cell carcinoma and published the results today in the journal Cancer Cell.

“The Cancer Genome Atlas is a federally funded national effort that has already completed the sequence of many major types of cancer (breast, lung, ovarian, for example), but this project is now branching out to sequence more rare types of cancer,” said Dr. Chad Creighton, associate professor of medicine and a biostatistician in the NCI-designated Dan L. Duncan Cancer Center at Baylor and the lead and corresponding author on the report. “The idea is that with a better understanding of these more rare types of cancers, we gain new insight that might be relevant to how we study other types of cancer. The findings in this study are a perfect example of that.”

Chromophobe renal cell carcinoma is a rare type of kidney cancer, with approximately 2,000 new cases diagnosed each year in the United States. A majority of patients survive the disease.

Clinical impact

“Although most patients are reassured when the pathology of their kidney tumor comes back as chromophobe, we all have cared for patients who developed and died from metastatic chromophobe kidney cancers,” said Dr. Kimryn Rathmell, associate professor of hematology and oncology in the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill and a co-senior author on the study. “This report is incredibly exciting for physicians who care for these patients because all of the treatment plans we have had to this point have been based on the biology of the more common kidney cancer type, as if chromophobe must be a close relative of that disease.”

The project shows with no uncertainty that chromophobe renal cell carcinoma represents a distinct cancer entity, and reveals exciting biology inherent to the disease that we hope in the future will allow new therapies to be developed specifically for the chromophobe type of kidney cancer, Rathmell said.

The team sequenced 66 tumor samples at Baylor’s Human Genome Sequencing Center. Other types of data were collected on these samples and integrated with the sequencing, including gene expression and epigenetic data. In addition to sequencing known genes, DNA from mitochondria and from the entire genome was also sequenced.

Chromosomes

A majority (86 percent) of the samples were missing one copy or a major part of chromosomes 1, 2, 6, 10, 13 and 17. Losses of chromosomes 3, 5, 8, 9, 11, 18 and 21 also were noted with significant frequencies (12 — 58 percent).

Chromosomes are the packaging of our DNA. Normally, each person receives a copy of each of 23 chromosomes from each parent for a total of 46.

When scientists looked for genes that were altered or missing, only two genes, TP53 and PTEN, were identified with a sizable frequency.

Extra step in analysis

The most surprising and significant finding came after the team took an “extra step” with their analysis, Creighton said.

“Instead of just looking specifically at the exome, we also analyzed the entire genome, something not typically done in these genomic studies,” said Creighton. The exome, the part of the genome used to make proteins, constitutes only 1 percent of the total genome, where the other 99 percent is often ignored in studies.

With whole exome analysis, scientists are just looking within the boundaries of known genes, to see which are broken and may have caused the disease, he explained.

“However, when you look outside of the genes, there is much more going on,” said Creighton. “For example, gene regulatory features of the genome can be altered.”

TERT promoter region

From whole genome analysis, the team observed a significant amount of structural rearrangements or breakpoints involving the promoter region of a gene called TERT, which encodes for the most important unit of the telomerase complex.

Telomerase represent the “clock” of the cell, Creighton said. “This plays a critical role in cell division, and with many cancer cells, telomerase levels are really high and time never really runs out, which allows the cell to never die. “

It was the promoter region, not the actual gene, that was affected, Creighton clarified. “Since there isn’t a breakdown in the actual gene, this malfunction is not picked up in whole exome analysis.”

The study also raised intriguing questions about the roles of mitochondrial DNA alterations and of the cell of origin involved in cancer initiation, the authors noted.

This could signify new approaches for how scientists should conduct molecular studies of cancer, he said. “We need to survey the regulatory regions for other cancer types as well.”

Data from all projects of The Cancer Genome Atlas are available for scientists around the world to study. “This effort has had a huge impact on how we study cancer as a whole,” said Creighton.

source : http://www.sciencedaily.com/releases/2014/08/140821124829.htm

New mouse model points to therapy for liver disease

Development of effective new therapies for preventing or treating NASH has been stymied by limited small animal models for the disease. In a paper published online in Cancer Cell, scientists at the University of California, San Diego School of Medicine describe a novel mouse model that closely resembles human NASH and use it to demonstrate that interference with a key inflammatory protein inhibits both the development of NASH and its progression to liver cancer.

“These findings strongly call for clinical testing of relevant drugs in human NASH and its complications,” said senior author Michael Karin, PhD, Distinguished Professor of Pharmacology in UC San Diego’s Laboratory of Gene Regulation and Signal Transduction. “Our research has shown that, at least in this mouse model, chemical compounds that include already clinically approved drugs that inhibit protein aggregation can also be used to prevent NASH caused by a high fat diet.”

The increasing prevalence of NAFLD is linked to the nation’s on-going obesity epidemic. In the past decade, the rate of obesity has doubled in adults and tripled in children, in large part due to a common diet rich in simple carbohydrates and saturated fats. NASH is characterized by inflammation and fibrosis, which damage the liver and can lead to cirrhosis, hepatocellular carcinoma (HCC), the major form of liver cancer, and loss of function. Often, the only remedy is organ transplantation.

“Developing new strategies for NASH that successfully block progression to cirrhosis or HCC required the creation of appropriate small animal models that are amenable to genetic analysis and therapeutic intervention,” said first author Hayato Nakagawa, PhD, a member of Karin’s lab who headed the research effort and is currently an assistant professor at the University of Tokyo School of Medicine.

The resulting new mouse model takes advantage of an existing mouse strain called MUP-uPA that develops liver damage similar to humans when fed a high-fat diet (in which 60 percent of calories are fat derived) similar to the so-called “American cafeteria diet.” The mice show clinical signs characteristic of NASH within 24 weeks and full-blown HCC after 40 weeks. “The pathological characteristics of these tumors are nearly identical to those of human HCC,” said Nakagawa.

Using the new mouse model, Nakagawa and colleagues showed that a protein called tumor necrosis factor (TNF), involved in the body’s inflammatory response, plays a critical role in both NASH pathogenesis and progression to fibrosis and HCC. By interfering with TNF synthesis or its binding to its receptor, using genetic tools or an anti-psoriasis and rheumatoid arthritis drug called Enbrel, the researchers inhibited both development of NASH and its progression to HCC in the mouse model.

“Given the dramatic and persistent increase in the incidence of obesity and its consequences in the United States and elsewhere, these studies have a high impact on a major public health problem. In addition to developing a more suitable model for the study of NASH, this new work suggests some immediate targets for prevention and therapeutic intervention,” said Karin, who is an American Cancer Society Research Professor and holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases.

source : http://www.sciencedaily.com/releases/2014/08/140818134912.htm

Prostate cancer diagnosis improves with MRI technology

An ultrasound machine provides an imperfect view of the prostate, resulting in an under-diagnosis of cancer, said J. Kellogg Parsons, MD, MHS, the UC San Diego Health System urologic oncologist who, along with Christopher Kane, MD, chair of the Department of Urology and Karim Kader, MD, PhD, urologic oncologist, is pioneering the new technology at Moores Cancer Center.

“With an ultrasound exam, we are typically unable to see the most suspicious areas of the prostate so we end up sampling different parts of the prostate that statistically speaking are more likely to have cancer,” said Parsons, who is also an associate professor in the Department of Urology at UC San Diego School of Medicine. “The MRI is a game-changer. It allows us to target the biopsy needles exactly where we think the cancer is located. It’s more precise.”

Armondo Lopez, a patient at Moores Cancer Center, had been given a clean bill of health using the traditional ultrasound biopsy method, but when his prostate-specific antigen (PSA) levels, a protein that is often elevated in men with prostate cancer, started to rise he began to worry. Parsons recommended a MRI-guided prostate biopsy. The new technology led to the diagnosis of an aggressive prostate cancer located in an area normally not visible using the ultrasound machine alone. The tumor was still in its early stage and treatable, said Parsons.

An early diagnosis typically improves a patient’s prognosis. In the United States, prostate cancer is the second leading cause of cancer death in men with more than 29,000 estimated deaths expected this year. The average age at the time of diagnosis is about 66.

Lopez is thankful he will be able to celebrate his 58th wedding anniversary with his wife.

“Life is going on as normal,” said Lopez. “This is the wave of the future. I see this new technology as the way to save thousands of lives. I commend Dr. Parsons for taking the lead in San Diego in this area.”

For patients, the only added step to the prostate examination is the addition of MRI imaging which occurs in a separate visit in advance of the biopsy exam. Working with David Karow, MD, PhD, a UC San Diego Health System radiologist, Parsons uses sophisticated new tools and software — DynaCAD for Prostate with the UroNav fusion biopsy system — to combine the MRI with real-time, ultrasound-guided biopsy images in the clinic resulting in what he calls a 3D road map of the prostate.

“The MRI-guided prostate biopsy will enhance the patient experience by reducing the number of false-positive biopsies and resulting in earlier diagnosis when cancer is present,” said Parsons.

source : http://www.sciencedaily.com/releases/2014/08/140812133501.htm