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- Posted Wednesday October 10, 2012
First whole genome sequencing of multiple pancreatic cancer patients outlined in study by TGen, Mayo Clinic and Scottsdale Healthcare
Method compares normal DNA with mutations from cancer cell
Whole genome sequencing - spelling out all 3 billion letters in
the human genome - "is an obvious and powerful method for advancing
our understanding of pancreatic cancer," according to a new study
from TGen, Mayo Clinic and Scottsdale Healthcare published
today.
The Translational Genomics Research Institute (TGen) demonstrated
that the use of WGS "represents a compelling solution to obtaining
detailed molecular information on tumor biopsies in order to
provide guidance for therapeutic selection," concluded the study
published by the journal PLOS ONE.
Examining three patients, the study spelled out the DNA of normal
cells and compared that to the DNA of cells from biopsies of
pancreatic adenocarcinoma (PAC), which makes up 95 percent of all
pancreatic cancer tumors. Pancreatic cancer is the fourth leading
cause of cancer death in the U.S.
Using next-generation sequencing, the study generated an average
of 132 billion mappable bases, or data points, for each patient,
resulting in the identification of 142 cellular genetic coding
events, including mutations, insertions and deletions, and
chromosomal copy number variants.
"This study is the first to report whole genome sequencing
findings in paired tumor/normal samples collected from (three)
separate PAC patients," said the report, which also was compiled
with the collaboration of Mayo Clinic in Arizona, Arizona State
University, and the Virginia G. Piper Cancer Center Clinical Trials
at Scottsdale Healthcare, which is a partnership between TGen and
Scottsdale Healthcare.
In all three case studies, the report found multiple potential
therapeutic targets, highlighting the need to study the full
spectrum of the genome and re-emphasizing the need to develop
multiple avenues of therapeutics to match the specific medical
challenges of each patient.
"Cancer, and specifically here pancreatic cancer, is a highly
complex disease that ultimately will require a variety of treatment
methods to control, and ultimately to cure," said Dr. Daniel Von
Hoff, TGen's Physician-In-Chief, and Chief Scientific Officer for
the Virginia G. Piper Cancer Center at Scottsdale Healthcare.
"This study shows that, as we continue to generate more
information by sequencing the whole genomes of patients, we will
continue to discover - with ever more confidence - the specific
mechanisms that cause this cancer," said Dr. Von Hoff, one of the
study's senior authors and one of the world's leading authorities
on pancreatic cancer.
"We are very pleased to be working together with TGen in bringing
hope and state of the art therapy to our patients at the Mayo
Clinic Comprehensive Cancer Center," said Keith Stewart, M.B., Dean
of Research at Mayo Clinic in Arizona, and the study's other senior
author.
In the case of Patient 1, for example, genes previously associated
with PAC were identified, including BRCA2, TP53, CDKN2A, MYC, SMAD4
and KRAS. But the study also made new discoveries. "Although BRCA2
mutations have been identified in PAC, the deletion we identify
here in exon 10 of BRCA2 has not been previously reported," the
study said.
Multiple therapeutics based on these findings were applied to
Patient 1, who initially "showed a complete response,'' but
developed drug resistance after six months.
"The BRCA2 deletion is likely the driving mutation in this patient
as the loss of DNA repair functions permits the occurrence of
mutations," the study said. "This finding and association provides
evidence of the utility of performing whole genome analysis of
patients in order to identify less common mutations that may be
relevant for therapeutic selection."
WGS for Patient 2 and Patient 3 also uncovered multiple potential
therapeutic targets through the identification of mutations and
copy-number changes. In addition, RNA sequencing, or whole
transcriptome analysis, of Patient 2 and Patient 3 revealed gene
expression data that provided more information about likely
affected biological processes.
Cellular pathway analysis of all sequencing data was also
performed to identify processes that may be the most heavily
impacted by cellular and gene expression alterations.
"As we continue to sequence patients, we will acquire a better
understanding of the compendium of events that have a role in the
disease, and strengthen our knowledge base for identifying and
developing improved therapeutics," said Winnie Liang, Ph.D.,
Assistant Director of TGen's Collaborative Sequencing Center and
one of the co-lead authors of the study.
"This study has demonstrated the feasibility of applying genome
sequencing approaches toward eventual personalization and precision
of therapy for patients with pancreatic cancer," said Dr. Mitesh
Borad, hematologist/oncologist at Mayo Clinic in Arizona and
co-author of the study. "Current studies are focusing on
application of this approach in the clinical setting in a real time
fashion."
Co-author Dr. Michael Demeure, Clinical Professor of TGen's Rare
Cancer Unit and Scientific Director of the Endocrine and Rare
Tumors Program at the Virginia G. Piper Cancer Center at Scottsdale
Healthcare, said, "Whole genome sequencing provides us with the
genetic blueprint and knowledge that is needed to crack the complex
mysteries surrounding pancreatic cancer. For rare cancers
where the data pool is relatively small, the potential for progress
is particularly encouraging."
This groundbreaking study - Genome-wide characterization of
pancreatic adenocarcinoma patients using next generation sequencing
- was funded by: the National Foundation for Cancer Research, the
Randy Pausch Scholarship Fund, and the Seena Magowitz Foundation.
Additional support was provided by the Mayo Clinic Comprehensive
Cancer Center, the U.S. Department of Health and Human Services,
and supercomputing resources funded by the National Institutes of
Health.
"This study represents a major step forward in the quest to find a
cure for this cancer, which took the life of my mother, Seena. We
are working harder than ever with TGen and others to continue this
fight," said Roger Magowitz, President and co-founder of the Seena
Magowitz Foundation.
"Whole genome sequencing is a new approach toward finding better
treatments and to making these treatments available to cancer
patients who need them now. We cannot emphasize enough the need for
this kind of research," said Franklin C. Salisbury Jr., President
of the NFCR.
Read the PLOS ONE paper at:
http://dx.plos.org/10.1371/journal.pone.0043192.
About Mayo Clinic
Mayo Clinic is a nonprofit worldwide leader in medical care,
research, and education for people from all walks of life. For more
information, visit www.mayoclinic.org/about/ and
www.mayoclinic.org/news.
Press Contact:
Jim McVeigh
Mayo Clinic Public Affairs
480-301-4368
[email protected]
About the Virginia G. Piper Cancer Center at Scottsdale Healthcare
The Virginia G. Piper Cancer Center at Scottsdale Healthcare in
Scottsdale, Ariz. offers comprehensive cancer treatment and
research through Phase I clinical trials, diagnosis, prevention and
support services in collaboration with leading scientific
researchers and community oncologists. Scottsdale Healthcare is the
nonprofit parent organization of the Virginia G. Piper Cancer
Center at Scottsdale Healthcare, Scottsdale Healthcare Research
Institute, Scottsdale Healthcare Osborn Medical Center, Scottsdale
Healthcare Shea Medical Center and Scottsdale Healthcare Thompson
Peak Hospital. For more information, visit www.shc.org.
Press Contact:
Keith Jones
Public Relations Director
Virginia G. Piper Cancer Center
480-323-1383
[email protected]
About the National Foundation for Cancer
Research
The National Foundation for Cancer Research (NFCR) is a leading
cancer research charity dedicated to funding cancer research and
public education relating to cancer prevention, earlier diagnosis,
better treatments and, ultimately, a cure for cancer. NFCR promotes
and facilitates collaboration among scientists to accelerate the
pace of discovery from bench to bedside. Since 1973, NFCR has
provided over $300 million in support of discovery-oriented basic
cancer research. NFCR scientists are discovering cancer's molecular
mysteries and translating these discoveries into therapies that
hold the hope for curing cancer. NFCR is about Research for a Cure
- cures for all types of cancer. For more information, please visit
www.NFCR.org.
About the Seena Magowitz Foundation
The Seena Magowitz Foundation is a 501(c)(3) non-profit
organization committed to advancing the awareness and eventual
prevention and cure of pancreatic cancer. The Foundation is
dedicated to funding top medical institutions on the leading edge
of translational pancreatic cancer research committed to diagnosis,
the advancement of life-extending treatment options and the
ultimate goal of eradicating this deadly killer. For more
information, visit: www.seenamagowitzfoundation.org.
About the Randy Pausch Scholarship Fund
The Randy Pausch Scholarship Fund has been established to support
students who are pursuing careers specializing in the development
of interactive entertainment. Possible career paths include (but
are not limited to) art, animation, programming, engineering, game
direction, game design, sound design, and music composition.
About TGen
The Translational Genomics Research Institute (TGen) is a
Phoenix-based non-profit organization dedicated to conducting
groundbreaking research with life changing results. Research at
TGen is focused on helping patients with diseases such as cancer,
neurological disorders and diabetes. TGen is on the cutting edge of
translational research where investigators are able to unravel the
genetic components of common and complex diseases. Working with
collaborators in the scientific and medical communities, TGen
believes it can make a substantial contribution to the efficiency
and effectiveness of the translational process. For more
information, visit: www.tgen.org.
Press Contact:
Steve Yozwiak
TGen Senior Science Writer
602-343-8704
[email protected]