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UCSF-Led Team Decodes Evolution of Skin and Ovarian Cancer Cells

June 29, 2011
News Office: Jason Bardi (415) 502-6397

A team of researchers led by scientists at the University of California, San Francisco (UCSF) has developed a way to uncover the evolution of human cancer cells, determining the order in which mutations emerge in them as they wend their way from a normal, healthy state into invasive, malignant masses.

The work may give doctors a new way to design diagnostics for detecting the signs of early cancers, when they are generally more treatable than in their later stages.

This approach relies on teasing apart the DNA of cancer cells, and it is something like genetic archeology. Just as archeologists sometimes date objects found at an excavation site by the age of the objects found around them, the new technique allows scientists to dig into the DNA of cancer cells and determine which genetic mutations came first by looking at surrounding genetic material.

Using the new technique, the researchers were able to identify not just the mutations that differentiate two types of human cancer from normal cells, but the actual order in which some of the most key mutations occurred.

"You can tell which mutations come really early and which come late," said UCSF dermatologist Raymond Cho.

Cho and his UCSF colleagues developed the technique in collaboration with researchers led by Paul Spellman and Joe Gray at Oregon Health & Science University, Elizabeth Purdom at the University of California, Berkeley and scientists at Samsung Advanced Institute of Technology. The work appears this week in the journal Cancer Discovery.

Cancer is a profoundly heterogeneous disease, making it more like thousands of diseases than just one. Different types of cancer differ in terms of the organs they affect, how they behave in the body, how they respond to treatment and even how they look under the microscope. And most fundamentally, they differ genetically.

Cancer emerges because of mutations in the DNA of cells. Any number of things can cause these mutations — for instance, family genetics, infections, toxins, radioactivity, sunlight or some combination of each. Over time these mutations shut down some genes, crank up the production of others and lead in the end to the cell's proliferation, growth, spread and all the other ominous hallmarks of cancer.

Interested in finding which mutations come first, Cho and his colleagues developed a way of teasing them apart by virtue of the fact that long pieces of DNA in cancers often abnormally double in number. The technique relies on determining the sequence of the cancer DNA to see which mutations are also doubled, indicating they occurred before the duplication.

They worked with a type of skin cancer known as cutaneous squamous cell carcinoma, which has among the highest numbers of mutations of any cancer, and also with a common type of ovarian cancer. By examining the accumulation of copies of TP53, a gene known to be involved with these forms of cancer, they found that complex changes in TP53 occurred earlier in most cases, rather than later, as had been previously believed.

The results are significant, said Dr. Cho, because the ability to identify the actual sequence of mutations will help scientists determine which mutations lead to precancerous lesions and which produce invasive carcinomas.

The article, "Temporal Dissection of Tumorigenesis in Primary cancers" is authored by Steffen Durinck, Christine Ho, Nicholas J. Wang, Wilson Liao, Lakshmi R. Jakkula, Eric A. Collisson, Jennifer Pons, Sai-Wing Chan, Ernest T. Lam, Catherine Chu, Kyunghee Park, Sung-woo Hong, Joe S. Hur, Nam Huh, Isaac M. Neuhaus, Siegrid S. Yu, Roy C. Grekin, Theodora M. Mauro, James E. Cleaver, Pui-Yan Kwok, Philip E. LeBoit, Gad Getz, Kristian Cibulskis, Jon C. Aster, Haiyan Huang, Elizabeth Purdom, Jian Li, Lars Bolund, Sarah T. Arron, Joe W. Gray, Paul T. Spellman, and Raymond J. Cho. It appears in the July 2011 issue of the journal Cancer Discovery.

In addition to UCSF, the authors on the study are affiliated with Lawrence Berkeley National Laboratories, the University of California, Berkeley, San Francisco Dermatopathology Service, Samsung Advanced Institute of Technology, Samsung Electronics Headquarters, the Eli and Edythe L. Broad Institute of Harvard and MIT, Brigham and Women's Hospital in Boston, Beijing Genomics Institute–Shenzhen in China, Aarhus University in Denmark, and Oregon Health and Science University.

This work was funded through grants from the National Institute of Arthritis, Musculoskeletal, and Skin Diseases, the National Cancer Institute, the National Center for Research Resources, the U.S. Department of Energy, the Department of the Army, the Department of Veterans Affairs, the University of California Cancer Coordinating Committee, the UCSF–Clinical & Translational Science Institute, by an unrestricted gift grant from the Samsung Advanced Institute of Technology, and by a Stand Up To Cancer–American Association for Cancer Research Dream Team Translational Cancer Research Grant.

Further support was provided through multiple Dermatology Foundation Psoriasis Career Development Awards, through a Canary Foundation/American Cancer Society Postdoctoral Fellowship for the Early Detection of Cancer, and through the Samsung Biotechnology Scholar-in-Residence program.

About UCSF Medical Center

UCSF Medical Center consistently ranks as one of the top 10 hospitals in the United States. Recognized for innovative treatments, advanced technology, collaboration among health care professionals and scientists, and a highly compassionate patient care team, UCSF Medical Center serves as the academic medical center of the University of California, San Francisco. The medical center's nationally preeminent programs include children's health, the brain and nervous system, organ transplantation, women's health and cancer. It operates as a self-supporting enterprise within UCSF and generates its own revenues to cover the operating costs of providing patient care.

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