HSC Weekly 2012-02-10
USC scientists make key colorectal cancer discovery
By Martin Booe
In an article published in the online scientific journal Nature Genetics, the Keck School of Medicine of 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.
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.
“This research represents a huge step forward in identifying the specific genetic instructions that a cancer cell is interpreting,” said Benjamin P. Berman, 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 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 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-specialty of epi-genomics 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.
For this setup, “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 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.
The USC Epigenome Center, established under the leadership of Laird to perform large-scale epigenomics studies, 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 to address the need for cutting-edge computational research in order to analyze and interpret high-throughput biomedical datasets.
The new paper is titled “Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains.”
Falling costs make sequencing easier
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.
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