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The newspaper of The Johns Hopkins University September 11, 2006 | Vol. 36 No. 2
Genome Code Cracked for Breast and Colon Cancers

JHU scientists identify close to 200 mutated genes not previously linked

By Vanessa Wasta
Johns Hopkins Medicine

Johns Hopkins Kimmel Cancer Center scientists have completed the first draft of the genetic code for breast and colon cancers. Their report, published online in the Sept. 7 issue of Science Express, identifies close to 200 mutated genes, now linked to these cancers, most of which were not previously recognized as associated with tumor initiation, growth, spread or control.

"Just as sequencing the human genome laid the groundwork for subsequent research in genetics, these data lay the foundation for decades of research on colon and breast cancers," said Victor Velculescu, assistant professor of oncology at the Johns Hopkins Kimmel Cancer Center.

Although gene discoveries by independent scientists scattered around the world have provided clues, Velculescu says that relatively few genes have been shown to be altered in cancers. The Johns Hopkins gene hunters say the number of genes that were altered in breast and colorectal cancer genomes surprised them. "We expected to find a handful of genes, not 200," said Tobias Sjoblom, a lead author and postdoctoral fellow at the Kimmel Cancer Center.

Despite the potential rewards envisioned by cancer biologists, efforts to map cancer genes have drawn criticism from other scientists who say that funding dollars should be spent on projects yielding more immediate benefits for detection and treatment.

Kenneth Kinzler, professor of oncology and co-director of the Ludwig Center at Johns Hopkins, said, "These are good debates to have, [but] we are convinced that this kind of study will provide one of the best road maps possible for beating cancer. Who would pass up the opportunity to read the enemy's game plan?"

Some gene alterations already have led to successful detection and treatment strategies. These include the breast cancer drug Herceptin, which targets a breast cancer cell receptor made by the Her2/neu gene, and blood tests for hereditary colon cancer, based on the APC gene and others identified by the Johns Hopkins group.

Bert Vogelstein, an investigator at the Howard Hughes Medical Institute and co-director of the Ludwig Center at Johns Hopkins, said, "Cancer scientists recognize that merely identifying pieces of DNA that have a role in the disease is a beginning, not an end to our work. But by using a more systematic method to identify genes that play an essential role in cancer, we will be able to guide that work."

The Johns Hopkins team began its project with 11 samples each from breast and colon cancers removed from patients during surgery.

Within each tumor cell, billions of individual chemicals called nucleotides pair together in a preprogrammed fashion to build the rungs of a DNA ladder that compose genetic instructions. Changes called mutations in the nucleotides can create coding errors that transform a normal cell into a cancerous one.

To locate the altered nucleotides, the scientists compared the genetic code of their tumor samples with normal ones. First, they used the Human Genome Project to identify the sequences of best-known genes — more than 13,000 in all — roughly two-thirds of the total number of genes identified by the HGP. The actual number of human genes is still in dispute but is estimated to be about 20,000.

Then, in each tumor, the scientists examined the DNA code of these 13,000 genes by dividing each gene into overlapping sections, about 10 per gene, to get 130,000 sections for analysis. Each segment was amplified through a process called polymerase chain reaction, purified and its sequence determined using more than 3 million biochemical reactions. The sequences were fed through computer software that matches up normal sequences with those from tumor samples. The software highlighted more than 800,000 suspicious regions that were visually inspected, one by one, to verify that they were true mutations that altered protein code rather than normal variations or minor changes with no effect on the gene product.

In total, the Johns Hopkins team combed through 465 million nucleotides — several encyclopedias' worth of letters — to find approximately 1,500 DNA nucleotides that differed from the normal code in important ways. Virtually all these mistakes were mere single nucleotide "typos." Some 200 genes were significantly mutated; the mutated genes in breast and colon cancers were almost completely distinct, suggesting very different pathways for the development of each of these cancer types.

Kinzler said, "This gives us some understanding of why breast and colon cancers, and most likely other cancers as well, are very different diseases and develop through different processes. When we say this will drive cancer research for the next couple of decades, this is one of the reasons. Now researchers will study how these mutations occur in breast and colon cancers, perhaps searching for environmental agents or cellular processes that drive these changes."

The Johns Hopkins team also found that the average number of mutant genes in each cancer is about 100, and at least 20 of them are likely to be crucial for tumor formation. "Each cancer has a different blueprint. No two patients are identical," Velculescu said.

Other cancers also can be evaluated using the Johns Hopkins approach, which the researchers say has been developed over the past two decades and made possible through recent advances in DNA sequencing and bioinformatics.

"These findings," Vogelstein said, "will guide and provide support for future comprehensive genetic studies including those envisioned by the Cancer Genome Atlas Project." Future research will include performing similar analyses on other tumor types, charting the pathways through which each mutant gene acts and looking for common mutations that can be targeted with cancer drugs or used to detect the disease earlier.

This research was supported by the Virginia and D.K. Ludwig Fund for Cancer Research, National Institutes of Health, Department of Defense, Pew Charitable Trusts, Palmetto Health Foundation, Maryland Cigarette Restitution Fund, State of Ohio Biomedical Research and Technology Transfer Commission, Clayton Fund, Blaustein Foundation, National Colorectal Cancer Research Alliance, Strang Cancer Prevention Center, Avon Foundation, Flight Attendant Medical Research Institute and V Foundation for Cancer Research.

The Johns Hopkins research team also includes Sian Jones, Laura D. Wood, D. Williams Parsons, Jimmy Lin, Thomas Barber, Diana Mandelker, Rebecca J. Leary, Janine Ptak, Natalie Silliman, Steve Szabo, Giovanni Parmigiani, Ben Ho Park and Nickolas Papadopoulos. Other authors include Phillip Buckhaults, Christopher Farrell and Paul Meeh, University of South Carolina; Sanford D. Markowitz, Case Western Reserve University, University Hospitals of Cleveland and Howard Hughes Medical Institute; Joseph Willis and Dawn Dawson, Case Western Reserve University and University Hospitals of Cleveland; James K.V. Willson and Adi F. Gazdar, University of Texas Southwestern Medical Center; James Hartigan, Agencourt Bioscience Corp.; Leo Wu and Changsheng Liu, SoftGenetics; and Kurtis E. Bachman, University of Maryland Greenebaum Cancer Cancer.


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