Whole-genome sequencing yields knowledge, hope for future of cancer care

  • HemOnc Today, February 25, 2013

Compared with other disciplines of scientific discovery, cancer genomics is in its infancy.

However, emerging data from comprehensive cancer genome analysis suggest that the burgeoning field will forever alter the future of cancer diagnosis and treatment.

The largest whole-genome sequencing program in the United States, The Cancer Genome Atlas (TCGA), debuted as a 3-year pilot program in 2006. Today, TCGA — an initiative of NCI and National Human Genome Research Institute (NHGRI) — includes more than 150 researchers at dozens of institutions across the nation.

Investigations conducted during the past 6 years have produced valuable insights into the mechanisms of breast, colorectal and lung cancers, and breakthroughs in other malignancies appear within reach.

“The data generated by the TCGA program comprise a vast resource that investigators will be analyzing for years to come,” said Eric D. Green, MD, PhD, director of the NHGRI. “The resource of information … will undoubtedly fuel myriad discoveries by the cancer research community.”

The success comes with a price.

Early opponents balked at the $275 million initial investment required for TCGA. Questions also remain about whether the molecular diagnostics that will be required to keep pace with the discovery of new pathways — as well as efforts to develop new therapeutic agents — will be cost effective.

David S. Strayer, MD, PhD 

David S. Strayer

Yet, proponents such as David S. Strayer, MD, PhD, medical director of the molecular analysis lab at the Kimmel Cancer Center of Thomas Jefferson University in Philadelphia, said the return on investment could be significant.

“I don’t know how you put a dollar sign on how valuable these efforts are,” Strayer, who is not directly involved with TCGA, told HemOnc Today. “Developing and testing targeted drugs is a very costly process. The information we get from these studies allows us to target our developmental therapeutics more specifically and accurately. That could make the delivery of care much more efficient and eventually decrease the cost of care. In the long run, the investment in these projects may be money well spent.”

Data integration

When TCGA launched, NCI officials established a goal to collect up to 500 specimens of each tumor type, including breast, colorectal, head and neck, lung, gynecologic, hematologic, skin, thoracic and urologic.

Investigators quickly accrued the target number of samples for common malignancies, but analysis on other less common tumor types began after the collection of 200 to 250 samples.

Still, the sample sizes are large, and normal tissue samples have been collected to allow determination of which genetic changes are only present in tumor cells.

During genomic research, the same samples are analyzed for several different types of genetic information.

Marc Ladanyi, MD, a molecular pathologist at Memorial Sloan- Kettering Cancer Center, said efforts are under way to develop highly efficient technical platforms that can genotype the few  hundred genes that underlie the vast majority of human cancers. 

Marc Ladanyi, MD, a molecular pathologist at Memorial Sloan-Kettering Cancer Center, said efforts are under way to develop highly efficient technical platforms that can genotype the few hundred genes that underlie the vast majority of human cancers.

Source: Photo courtesy of Marc Ladanyi, MD, reprinted with permission.

This in-depth investigation allows potentially important discoveries, according to Marc Ladanyi, MD, a molecular pathologist at Memorial Sloan-Kettering Cancer Center and co-director of the center’s TCGA group.

“There are many different levels of data integration,” Ladanyi said. “This data integration is helpful in identifying which amplified genes are also overexpressed, or which genes are the likely targets of overlapping genetic deletions, for instance.”

Researchers also are evaluating how the presence of mutations in one gene relate to mutations in other genes, he said. Some mutually exclusive mutations may be in the same pathway, and this points to biological relationships and critical oncogenic pathways.

Also, integrating new data with known pathways may show that a given pathway is almost always deregulated in a given cancer.

“All of this integration can highlight relationships that might not be obvious from looking at only one data type,” Ladanyi said.

‘Treasure trove’ of genetic information

One of the most recent discoveries, related to breast cancer, was uncovered by researchers who used genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays.