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TCGA study reveals new clues to the genomic diversity of prostate cancers

A health professional and a patient looking at a computer screen where prostate is illustratedNew findings on prostate cancer may enable doctors to make better diagnoses and prognoses for patients and provide novel directions for therapies, according to a study from The Cancer Genome Atlas (TCGA) Network. Investigators published the in-depth analysis of 333 prostate cancer tumors online November 5, 2015 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.

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.

"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, Ph.D., principal investigator and chair of the computational biology program at Memorial Sloan Kettering Cancer Center in New York. "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."

TCGA researchers studied five aspects of prostate cancer 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.

Researchers - including co-prinicipal investigators Nikolaus Schultz, Ph.D., Head of Knowledge Systems in the Marie-Josée and Henry R. Kravis Center for Molecular Oncology at MSKCC and Massimo Loda, M.D., director of the Center for Molecular Oncologic Pathology at Dana-Farber/Brigham and Women's Cancer Center in Boston - identified seven cancer or tumor subtypes based on these aspects. Of the seven subtypes, the investigators found that four are characterized by gene fusions, while the other three are defined by mutations in the SPOP, FOXA1 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.

Dr. 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.

"The integration of our prior understanding of genes and alterations in cancer with these new genomic details gives us greater confidence that these new classifications of prostate tumors will be useful in the clinic, both for prognosis and treatments of subtypes," said Dr. Sander.

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Posted: November 5, 2015

On Other Sites:

The Molecular Taxonomy of Primary Prostate Cancer
Cell, Nov. 5, 2015