Posts Tagged ‘major’

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

Blueprint for next generation of chronic myeloid leukemia treatment

Drugs already in use, called tyrosine kinase inhibitors (TKIs), target BCR-ABL and are effective at controlling the disease. They do not cure CML but control it in a way that allows patients to get back to normal life and a normal expected lifespan. Before the advent of TKIs, the five-year survival rate for CML was 30% at best; now that number is above 95%. However, 20-30% of patients with CML become resistant to one or more of the TKIs.

Most cases of CML resistance result from a single mutation in BCR-ABL, and drugs to control resistance to TKI treatment caused by various single mutations have already been discovered. But BCR-ABL compound mutants that contain two mutations in the same molecule render some or all of the available TKIs ineffective.

The research team focused on BCR-ABL compound mutants observed in patients and tested them against all approved TKIs, creating a dataset that can potentially help clinicians decide which drug will be most effective for each mutation combination. They found that none of the TKIs are effective for some compound mutations, indicating the need for further research to accommodate the growing population of CML patients. The results were published online August 14 in the journal Cancer Cell.

“Fortunately, the problems we are studying affect a minority of CML patients, but still this leaves some patients with no good treatment option at all,” said Thomas O’Hare, PhD, an HCI investigator and co-senior author of the study. He is also a research associate professor of Internal Medicine, Division of Hematology and Hematologic Malignancies. “Our goal is to have a TKI option for every patient.”

“We were able to sequence about 100 clinical samples, which gave us a very large body of data to shed light on the number of compound mutations and how they develop,” said Michael Deininger, MD, PhD, co-senior author of the study, a professor of Internal Medicine, and an HCI investigator. “One key finding was that compound mutations containing an already known mutation called T315I tend to confer complete resistance to all available TKIs.”

Working with HCI computational chemist Nadeem Vellore, PhD, the research team modeled at the molecular level why the drugs do not bind to certain BCR-ABL compound mutants. “This puts us in position to evaluate new drug candidates and work toward developing new treatments,” said O’Hare.

“Computational analysis was one of the most interesting parts of the study. It not only confirmed what we found but showed the reason behind it,” said Matthew Zabriskie, BS, co-lead author of the study. “We’ve established what the next level of TKI resistance is going to entail.”

According to O’Hare, it is only a matter of time until analogous compound mutations emerge in many other cancers, including non-small cell lung cancer (NSCLC) and acute myeloid leukemia (AML). In these diseases, scientists and clinicians are still learning how to control single mutation-based resistance. “Our findings in CML will provide a blueprint for contending with resistance in these highly aggressive diseases as well,” he said.

In addition to Zabriskie, Deininger, and O’Hare, the study’s authors included 39 other researchers representing HCI, the University of Utah, and 22 other institutions worldwide. The article was dedicated to the legacy of Professor John M. Goldman of Imperial College London, whose work and mentorship made a major mark on the field of CML. “His passing in December 2013 left a very big gap in the CML community,” said Deininger.

source : http://www.sciencedaily.com/releases/2014/08/140820183458.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