Benjamin P. Berman, Ph.D.
In an article published in the online scientific journal Nature Genetics, the Keck School of Medicine USC Epigenome Center
reports a significant breakthrough in cancer research expected to have
a long-term impact on both the diagnosis and treatment of cancer.
“This research represents a huge step forward in identifying the
specific genetic instructions that a cancer cell is interpreting,” said
Benjamin P. Berman, Ph.D., who led the study. “It brings the cancer
research community closer to our goal of providing treatment that is
more specific, more personalized, and more effective.”
The paper, “Regions of focal DNA hypermethylation and long-range
hypomethylation in colorectal cancer coincide with nuclear
lamina–associated domains,” also represents a landmark sequencing study
for the USC Epigenome Center. The Center was established in 2007 to
bring innovative molecular and computational analysis techniques to the
study of epigenetics. Center director Peter W. Laird, Ph.D., is the
paper’s senior author.
The genome is the instruction manual for building all cells, and genome
sequencing is the prominent focus of most current large-scale cancer
mapping projects. While all cells within an individual have identical
or very similar genomes, different cells “read” those instructions in a
highly selective manner.
The sub-speciality of epigenomics seeks to analyze the unique
interactions between cells and their DNA, and is essential to
understanding molecular biology of cancerous or diseased cells.
Clinical cancer research focuses on DNA methylation, a biochemical
process crucial to the development of organisms, because methylation
information can be easily recovered from a broad range of tissue or
blood samples, Berman said.
In the new study, using a cutting-edge sequencing technique, the
Center’s research team is one of the first groups to profile the
complete “methylome” from a clinical colon tumor sample – in other
words, the complete methylation profile of the tumor at the smallest
unit of the tumor’s genetic information.
“We sequenced the complete methylome of a colon tumor and matched adjacent tissue samples from the same patient,” Berman said.
By comparing the tumor's methylome to normal colon tissue from the same
individual, the group identified several important new classes of
alteration. Most importantly, they found that two common types of
methylation changes, “hypermethylation” and “hypomethylation,” were
linked to the physical three-dimensional organization of the cell
nucleus, with those regions gaining alterations being mostly restricted
to a specific compartment called the “Nuclear Lamina.” This nuclear
organization plays a key role in turning specific genes on and off, and
therefore has important implications for the basic biology of cancer
and the changes that take place during tumor growth. This basic
mechanism provides important clues as to which aspects may be targeted
therapeutically, according to Berman.
A second important finding was that methylome profiling could be used
to monitor the state of an important class of DNA sequences called
“gene enhancers.” Enhancers have a critical role in controlling the
cell type specific expression level of genes, but have not been widely
studied at the DNA methylation level. The USC Epigenome Center group is
currently applying this new technique, called Whole-Genome Bisulfite
Sequencing (WGBS) to a number of tumor types as part of the The Cancer
Genome Atlas consortium.
Berman credits the
USC Center for High-Performance Computing and Communications for helping to analyze the many terabytes of genomic data involved.
As sequencing time and costs decrease, the approach used in Berman’s
study could have clinical applications in the future, especially for
personalized treatment. New sequencing technologies have resulted in a
more than 10,000-fold decrease in the cost to sequence a human genome -
from about $70 million in 2005 to about $5,000 now, according to
Berman.
“We’re looking for the cost to decrease even further, to $1,000, which
would put this technology within reach of large numbers of cancer
patients,” he said.
The USC Epigenome Center was established in 2007 under the leadership
of Dr. Peter W. Laird to perform large-scale epigenomics studies. It
was created with a $10 million gift from the Kenneth T. and Eileen L.
Norris Foundation, which also funded the methylation study. The Center
provides the epigenomics component of The Cancer Genome Atlas, an
NIH-sponsored, multi-institution, national consortium whose mission is
to unlock the cellular underpinnings of cancer by comprehensively
studying thousands of tumors.
Berman is one of the founding members of the USC Epigenome Center and
an assistant professor in USC’s new Division of Bioinformatics in the
department of
Preventive Medicine.
This new division was created in 2010 under the leadership of Paul D.
Thomas, Ph.D. to address the need for cutting edge computational
research in order to analyze and interpret high-throughput biomedical
datasets.