09:24pm Wednesday 19 February 2020

USC Research Finds Clues to Genetic Instructions

Benjamin P. Berman of the USC Epigenome Center led research that holds promise for the development of personalized cancer treatment.

The study appeared in the online scientific journal Nature Genetics.

USC Research Finds Clues to Genetic Instructions

“This research represents a huge step forward in identifying the specific genetic instructions that a cancer cell is interpreting,” said Benjamin P. Berman, assistant professor in the Department of Preventive Medicine, 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 center, which was established in 2007 to bring innovative molecular and computational analysis techniques to the study of epigenetics. Peter W. Laird, the center’s director, 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 epigenomics, which seeks to analyze the unique interactions between cells and their DNA, is essential to understanding the 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 easily can be recovered from a broad range of tissue or blood samples, Berman said.

In the new study, using a unique sequencing technique, the center’s research team is one of the first groups to profile the complete methylome from a sample of a clinical colon tumor – 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,” said Berman, one of the founding members of the Epigenome Center.

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, the researchers found that hypermethylation and hypomethylation – two common types of methylation changes – were linked to the physical three-dimensional organization of the cell nucleus, with the regions gaining alterations mostly being restricted to a specific compartment called the nuclear lamina.

This nuclear organization, which plays a key role in turning specific genes on and off, 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 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 Epigenome Center currently is applying this new technique, called whole-genome bisulfite sequencing, to a number of tumor types as part of The Cancer Genome Atlas consortium.

Berman credited 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, Berman noted.

“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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