05:03pm Saturday 16 December 2017

Genome study identifies seven genetic subtypes of prostate cancer

Massimo Loda, MD

Investigators published the in-depth analysis of 333 prostate cancer tumors online Nov. 5 in Cell. TCGA is jointly supported and managed by the National Human Genome Research Institute and the National Cancer Institute, both parts of the National Institutes of Health.

While 90 percent of prostate cancers are now identified as clinically localized tumors, once diagnosed, these cancers tend to have a heterogeneous and unpredictable course of progression, ranging from slow-growing to fatal disease.

“We have identified seven clearly defined subtypes of prostate cancer based on genetic alterations,” said Massimo Loda, MD, director of the Center for Molecular Oncologic Pathology at Dana-Farber/Brigham and Women’s Cancer Center, and a co-principal director of the study.

Loda added, “Interestingly, it is clear that there is substantial diversity within each of these subtypes. We can now put this critical information into clinical and pathological context and, by developing biomarkers for the different genetic variants, use them to guide therapeutic options.”

“Until now, we haven’t had a reliable way of predicting the way a primary prostate cancer will act by looking at the genome,” said Chris Sander, PhD, principal investigator and chair of the computational biology program at Memorial Sloan Kettering Cancer Center. “The TCGA study gives us much more information about the spectrum of alterations in tumors and can help us predict the development of the disease. This will also inform the design of new clinical trials.”

 According to the American Cancer Society, prostate cancer will be newly diagnosed in more than 220,000 men in the United States in 2015, making it the second most common cancer affecting men and the second leading cause of death from cancer in men. Most prostate cancers are detected early while still confined to the prostate, a walnut-sized gland located below the bladder. While most cases remain harmless – benign – for decades, other subtypes of prostate cancers can be aggressive, and spread to other parts of the body (metastasize), making them extremely difficult to treat. It is currently difficult for healthcare providers to distinguish which cancers will remain harmless and which will metastasize.

The scientists studied five aspects of the prostate tumors:

  1. The number and kinds of genetic mutations.
  2. Gene fusions (when genes attach to each other or otherwise combine).
  3. The number of copies of DNA segments (abnormal differences in the cell’s number of copies of DNA segments can contribute to cancer).
  4. Gene activity, including when genes are turned on or off, and how much activity is seen.
  5. DNA methylation (methyl chemical groups are added to many places on a cell’s DNA and act like on/off switches for a gene). Mistakes in DNA methylation can turn genes on or off at the wrong time and contribute to cancer.

Of the seven subtypes, the investigators found that four are characterized by gene fusions, while the other three are defined by mutations in the SPOPFOXA1 and IDH1 genes. The subtypes with SPOP and FOXA1 mutations share several genomic characteristics, suggesting that mutations in these genes cause similar disruptions in the cell to bring about cancer. 

Investigators discovered that mutations in the IDH1 gene are similar to those found in leukemia and brain cancer. Such a cancer subtype could be a candidate for a “basket” clinical trial, which tests for similar mutations across cancer types. The goal of this type of trial would be to personalize a patient’s treatment based on the mutations, not on the anatomical location of the cancer.

Sander said that while previous studies have examined gene copy number or the number and kinds of genetic mutations or the level of gene activity in prostate tumors, the TCGA study is the first to comprehensively and systematically examine many different types of data together on a large scale.

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A bizarre result of a routine lab experiment has led researchers at the University of Virginia School of Medicine to an unexpected new way to trigger the production of red blood cells. This could represent a significant step forward in the battle against anemia, and also benefit people with diabetes, kidney disease or cancer.

While more work needs to be done before the method could be used in people, the possibilities are tantalizing. For example, the approach could:

  • allow doctors to turn on red blood cell production whenever necessary;
  • be used on the battlefield to triage wounded soldiers until they could receive a blood transfusion; and
  • be used to treat people who cannot receive blood transfusions because of religious beliefs.

People with anemia – the most common blood disorder – lack sufficient red blood cells, which transport oxygen. People with anemia often experience fatigue and lack energy because their cells aren’t getting enough oxygen. There are many causes, including iron deficiency, vitamin deficiencies and diseases such as kidney disease and cancer. Anemia is particularly prevalent in older adults.

The UVA researchers, however, were not investigating anemia when they made their discovery. Instead, Dr. Thomas J. Braciale and his team members were looking into the role of dendritic cells in the lungs. Dendritic cells have traditionally been thought to be sensors of infection and inflammation, but a lab test involving the flu virus produced a surprising effect in mice that ultimately revealed an entirely new aspect to the cells’ function.

After injecting mice with the flu virus and an antibody that blocked a certain molecule expressed by dendritic cells, the researchers discovered that the experiment had an unexpected effect: The mice’s spleens enlarged massively, which indicated they were producing red blood cells. The researchers were baffled, so they repeated the experiment, only to get the same results.

“We did it again and I didn’t believe it, and we did it again and I didn’t believe it,” Braciale recalled. “I asked whether you needed to flu-infect the mice when you injected this antibody. So the postdoc [a lab member] did the experiment, and he just injected the antibody without flu-injecting the mice. Giant spleens. After much consultation, after talking with my colleagues in Pathology, we decided we were inducing stress erythropoiesis.”

Stress erythropoiesis refers to the body producing red blood cells because of injury or some other stress. In discovering an unexpected molecular trigger for the process, Braciale had found a switch he could flip to prompt red blood cell production.

“In the very basic way, what we’ve discovered is that the process of regulating stress in the body is mediated – certainly in part, at least – by these dendritic cells,” he explained. “And stress can be a variety of different stresses. It doesn’t have to be infection, it doesn’t have to be inflammation. It can be anemia. It can be hemorrhage. And these cells act to initiate this response that, until this report, there’s been really no evidence that these [dendritic] cells ever participate in making red blood cells.”

Braciale has more work to do before researchers can begin testing the approach in people. He’s optimistic, however, based on his findings so far.

“We’re very excited to see where this goes,” he said. “We know that the same things can be done in humans in the following sense. There are mice called humanized mice. These are mice that are engineered so they have a human blood system. And if you inject these mice with this antibody, they’ll make red blood cells.”

The discovery has been described in an article in the Journal of Clinical Investigation written by Taeg S. Kim, Mark Hanak, Paul C. Trampont and Braciale.

 

Media Contact

Josh Barney

UVA Health System

– See more at: https://news.virginia.edu/content/baffling-lab-mystery-leads-major-red-blood-cell-discovery#sthash.gzXGjJsD.dpuf

Digital holographic microscopy image of red blood cells. An unanticipated lab result may have led to the discovery of a new way to trigger the production of such cells – with many potential applications. (Credit: Egelberg)

November 03, 2015

 

A bizarre result of a routine lab experiment has led researchers at the University of Virginia School of Medicine to an unexpected new way to trigger the production of red blood cells. This could represent a significant step forward in the battle against anemia, and also benefit people with diabetes, kidney disease or cancer.

While more work needs to be done before the method could be used in people, the possibilities are tantalizing. For example, the approach could:

  • allow doctors to turn on red blood cell production whenever necessary;
  • be used on the battlefield to triage wounded soldiers until they could receive a blood transfusion; and
  • be used to treat people who cannot receive blood transfusions because of religious beliefs.

People with anemia – the most common blood disorder – lack sufficient red blood cells, which transport oxygen. People with anemia often experience fatigue and lack energy because their cells aren’t getting enough oxygen. There are many causes, including iron deficiency, vitamin deficiencies and diseases such as kidney disease and cancer. Anemia is particularly prevalent in older adults.

The UVA researchers, however, were not investigating anemia when they made their discovery. Instead, Dr. Thomas J. Braciale and his team members were looking into the role of dendritic cells in the lungs. Dendritic cells have traditionally been thought to be sensors of infection and inflammation, but a lab test involving the flu virus produced a surprising effect in mice that ultimately revealed an entirely new aspect to the cells’ function.

After injecting mice with the flu virus and an antibody that blocked a certain molecule expressed by dendritic cells, the researchers discovered that the experiment had an unexpected effect: The mice’s spleens enlarged massively, which indicated they were producing red blood cells. The researchers were baffled, so they repeated the experiment, only to get the same results.

“We did it again and I didn’t believe it, and we did it again and I didn’t believe it,” Braciale recalled. “I asked whether you needed to flu-infect the mice when you injected this antibody. So the postdoc [a lab member] did the experiment, and he just injected the antibody without flu-injecting the mice. Giant spleens. After much consultation, after talking with my colleagues in Pathology, we decided we were inducing stress erythropoiesis.”

Stress erythropoiesis refers to the body producing red blood cells because of injury or some other stress. In discovering an unexpected molecular trigger for the process, Braciale had found a switch he could flip to prompt red blood cell production.

“In the very basic way, what we’ve discovered is that the process of regulating stress in the body is mediated – certainly in part, at least – by these dendritic cells,” he explained. “And stress can be a variety of different stresses. It doesn’t have to be infection, it doesn’t have to be inflammation. It can be anemia. It can be hemorrhage. And these cells act to initiate this response that, until this report, there’s been really no evidence that these [dendritic] cells ever participate in making red blood cells.”

Braciale has more work to do before researchers can begin testing the approach in people. He’s optimistic, however, based on his findings so far.

“We’re very excited to see where this goes,” he said. “We know that the same things can be done in humans in the following sense. There are mice called humanized mice. These are mice that are engineered so they have a human blood system. And if you inject these mice with this antibody, they’ll make red blood cells.”

The discovery has been described in an article in the Journal of Clinical Investigation written by Taeg S. Kim, Mark Hanak, Paul C. Trampont and Braciale.

– See more at: https://news.virginia.edu/content/baffling-lab-mystery-leads-major-red-blood-cell-discovery#sthash.gzXGjJsD.dpuf


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