Cancer is typically thought to develop after genes gradually mutate over time, finally overwhelming the ability of a cell to control growth. But a new closer look at genomes in prostate cancer by an international team of researchers reveals that, in fact, genetic mutations occur in abrupt, periodic bursts, causing complex, large scale reshuffling of DNA driving the development of prostate cancer.
In the April 25 issue of Cell, the scientists, led by researchers from Weill Cornell Medical College, the Broad Institute, Dana-Farber Cancer Institute and the University of Trento in Italy, dub this process "punctuated cancer evolution," akin to the theory of human evolution that states changes in a species occur in abrupt intervals. After discovering how DNA abnormalities arise in a highly interdependent manner, the researchers named these periodic disruptions in cancer cells that lead to complex genome restructuring "chromoplexy."
"We believe chromoplexy occurs in the majority of prostate cancers, and these DNA shuffling events appear to simultaneously inactivate genes that could help protect against cancer," says the study's co-lead investigator Dr. Mark Rubin, who is director of the recently-established Institute for Precision Medicine at Weill Cornell Medical College and NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
"Knowing what actually happens over time to the genome in cancer may lead to more accurate diagnosis of disease and, hopefully, more effective treatment in the future," says Dr. Rubin, also the Homer T. Hirst III Professor of Oncology, professor of pathology and laboratory medicine and professor of pathology in urology at Weill Cornell and a pathologist at NewYork-Presbyterian/Weill Cornell. "Our findings represent a new way to think about cancer genomics as well as treatment in prostate and, potentially, other cancers."
The discovery of "chromoplexy" came after the research team worked collaboratively to sequence the entire genomes of 57 prostate tumors and compare those findings to sequences in matched normal tissue.
Co-lead investigator Dr. Levi Garraway, of the Broad Institute and Dana-Farber Cancer Institute, and his collaborators then tracked how genetic alterations accumulated during cancer development and progression. They used advanced computer techniques to identify periodic bursts of genetic derangements.
"We have, for the first time, mapped the genetic landscape of prostate cancer as it changes over time," says Dr. Garraway, a senior associate member of the Broad Institute and associate professor at the Dana-Farber Cancer Institute and Harvard Medical School. "The complex genomic restructuring we discovered, which occurs at discrete times during tumor development, is a unique and important model of carcinogenesis which likely has relevance for other tumor types."
Co-senior author Dr. Francesca Demichelis, assistant professor at the Centre for Integrative Biology at the University of Trento who also serves as adjunct assistant professor of computational biomedicine at Weill Cornell, worked with her collaborators to understand how widespread the DNA mutations and alterations seen in the tumors were across the cancer samples, and what that might mean in terms of cancer progression and, potentially, treatment. "Information about what alterations are common, and which aren't, will most likely help guide us in terms of cancer drug use and patient response," says Dr. Demichelis.
The researchers also report that future targeted cancer therapy may depend on identifying complex sets of genetic mutations and rearrangements in each patient.
"Every cancer patient may have individual patterns of genetic dysfunction that will need to be understood in order to provide precise treatment. Multiple drugs may be needed to shut down these genetic derangements," says Dr. Rubin. "Providing those tests now on every patient isn't possible, but our study suggests that punctuated cancer evolution may occur to provide a subset of genes that offer a selective advantage for tumor growth. If that is true, we may be able to zero in on a limited number of genetic drivers responsible for an individual's prostate cancer."
Astonishing Degree of Genetic Alterations
The collaborators have been working together for a number of years exploring and mapping the prostate cancer genome. They believe that structural genomic alterations are key to prostate cancer development and progression, and their approach has been to model those changes and tease apart the significance of those alterations.
This study sequenced 57 prostate cancer genomes as well as the entire genomes of matched normal tissue. Researchers revealed an astonishing number of genetic alterations in the prostate cancer cells -- 356,136 base-pair mutations and 5,596 rearrangements that were absent from normal DNA. Of those rearrangements, 113 were validated by re-sequencing and other methods.
"We saw wholesale rearrangements of chromosomes -- the cutting up and retying of chromosomes -- mutations we have never seen on that scale," Dr. Garraway says. "Our research teams then charted a path of oncogenic events that appeared to drive prostate cancer."
Using advanced computer techniques that modeled the genomic rearrangements and copy number alterations, the scientists at the Broad Institute inferred that the chromosomal disarray in a typical tumor might accumulate over a handful of discrete events during tumor development.
"The rearrangement of chromosomes can coordinately affect specific genes, which provides a selective advantage for cancer growth," according to Dr. Garraway.
"Chromoplexy is a common process by which geographically-distant genomic regions may be disrupted at once, in a coordinated fashion," says Dr. Rubin. "The unifying feature is that these alterations seem to occur in a sequential, punctuated pattern which is designed to eliminate cancer-fighting genes. This suggests that genes that are active at the end of these events may drive progression of the cancer."
"This study represents a wonderful example of a team science that embraces multidisciplinary competencies," says Dr. Demichelis.
The study required the development of special computational tools to go beyond the pure detection -- presence or absence -- of any particular aberration, and to quantify the dosage of the mutation; meaning, how many tumor cells have that specific mutation in the patient's tumor.
"The approach developed in my laboratory takes advantage of the genetic information of each individual and classifies every aberration as homogenous or heterogeneous across the tumor cells," Dr. Demichelis says. "This classification allows us then to chart the order in which mutations occur and to learn how far the tumor is in its progression. It suggests to us that patients with heterogeneous aberrations may not respond as effectively to a drug as patients with homogenous alterations."
"The punctuated changes we see occur in a single cycle of cell growth, and we believe this leads to tumor cells that have a growth advantage," says Dr. Rubin. "This new model of cancer growth tells us that cells gain an advantage mutating multiple genes simultaneously as opposed to gradually."
"These are exciting findings in a field of prostate cancer genomics that our research team's collaboration has redefined. We have made a lot of progress, but we have much more work to do," adds Dr. Rubin.
The study was supported by the U.S. National Human Genome Research Institute Large Scale Sequencing Program, the Kohlberg Foundation, the Starr Cancer Consortium, the Prostate Cancer Foundation, U.S. Department of Defense Synergy Awards and New Investigator Award, the Dana-Farber/Harvard Cancer Center Prostate Cancer SPORE (NIH), the U.S. National Cancer Institute, Early Detection Research Network, the Fondazione Trentina per la Ricerca sui Tumori, the Swiss Science Foundation, the National Institute of General Medical Sciences award and a U.S National Institutes of Health Director's New Innovator Award.
Other study authors include: Dr. Sylvan C. Baca, Dr. Gregory V. Kryukov, Dr. Alex H Ramos, Dr. Eric S. Lander from Harvard Medical School/the Broad Institute at MIT and Harvard; Dr. Philip W. Kantoff from Dana-Farber Cancer Institute; Dr. Matthew Meyerson from Dana-Farber Cancer Institute and the Broad Institute; Dr. Jean-Philippe Theurillat, Dr. Elizabeth Nickerson, Dr. Daniel Auclair, Dr. Candace Guiducci, Dr. Andrey Sivachenko, Dr. Scott L. Carter, Dr. Gordon Saksena, Dr. Douglas Voet, Dr. Wendy Winckler, Dr. Michelle Cipicchio, Dr. Kristin Ardlie, Dr. Stacey B. Gabriel, Dr. Gad Getz, Dr. Michael S. Lawrence, Dr. Yotam Drier, Dr. Mahmoud Ghandi, Dr. Eliezer Van Allen, Dr. Robert C. Onofrio, and Dr. Kristian Cibulskis from the Broad Institute; Dr. Todd R. Golub from the Broad Institute and Dana-Farber/Children's Hospital Cancer Center; Dr. Davide Prandi and Dr. Alessandro Romanel from the University of Trento; Dr. Juan Miguel Mosquera, Dr. Kyung Park, Dr. Naoki Kitabayashi, Dr. Theresa Y. MacDonald, Dr. Andrea Sboner, Dr. Gunther Boysen, Dr. Christopher E. Barbieri, Dr. T. David Soong, Dr. Ashutosh Tewari, Dr. Himisha Beltran, and Dr. Olivier Elemento from Weill Cornell Medical College; and Dr. Michael F. Berger from Memorial Sloan-Kettering Cancer Center.
Weill Cornell Medical College
Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston. For more information, visit weill.cornell.edu.
Broad Institute of Harvard and MIT
The Eli and Edythe L. Broad Institute of Harvard and MIT was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.
Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to http://www.
Dana-Farber Cancer Institute
Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women's Hospital as Dana-Farber/Brigham and Women's Cancer Center and it provides pediatric care with Children's Hospital Boston as Dana-Farber/Children's Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding. Follow Dana-Farber on Twitter: @danafarber or Facebook: facebook.com/danafarbercancerinstitute.
University of Trento
The University of Trento is different from other universities. From its very beginning, the University of Trento has been known for its propension towards international relations and mobility and for the quality of its research and education offer. These features have led the University of Trento to reach prominent positions in national and international university rankings. The figures describing the University - 16.000 students and about 600 professors and researchers - mirror the capacity of the University to offer an ideal environment to boost studies and research, through services designed on the needs of individual users. The University has remained small in size, since it has always aimed at training learned men and women capable to think critically, rather than simply training professionals.The 10 Departments and the 3 University research centres are structured in 54 degree courses, many first and second level master courses and life-long learning courses. Further the University includes 2 Advanced Training Schools and 13 Doctoral Schools. The University of Trento aims at attracting the most talented and deserving students, granting them equal opportunities. The surrounding environment is rich in opportunities and inputs for the students, thus allowing them to cultivate their skills in a responsible manner. For more information, visit unitn.it/en.
The Centre for Integrative Biology - CIBIO - at the University of Trento pursues the task of creating a suitable environment for merging classical cellular and molecular biology approaches with the new powerful tools of systems and synthetic biology, and with the contribution of chemistry, physics, informatics, mathematics, and engineering in an integrative view of basic biological processes and of their derangement in disease. For more information, visit unitn.it/en/cibio.