Genetic code of cancers mapped

Hopkins researchers find new leads on breast, colon tumors

September 08, 2006|By Jonathan Bor | Jonathan Bor,Sun reporter

In a step that could lead to new ways of detecting and treating cancer, Johns Hopkins researchers reported yesterday that they had deciphered the genetic code of breast and colon tumors.

The discovery, described in the online version of the journal Science, is the first time anyone has spelled out the complete genetic makeup - or genome - of a human cancer. In doing so, the scientists identified close to 200 genes whose mutations play a role in the formation and spread of the disease.

Dr. Bert Vogelstein, one of three Hopkins University researchers who spearheaded the effort, said the discovery gives cancer researchers precise targets for new drugs and screening tests. Some in the field said the study might have opened a new era in cancer research, showing scientists the methods to crack the genomes of other malignancies as well.

"It's like viewing the enemy's game plan," said Vogelstein, a professor of oncology, adding that the team will next turn its attention to mapping brain and pancreatic cancers.

"There are numerous ways the information can be exploited. The first is viewing the enemy, seeing what its weak points are and formulating an attack plan."

Also leading the effort were Dr. Kenneth W. Kinzler and Dr. Victor E. Velculescu. Together, the three head a lab that is widely regarded as one of the most fertile in cancer research.

The report comes less than a year after the National Institutes of Health announced a three-year, $100 million project to begin mapping cancer's genetic underpinnings. The agency plans to announce two "milestones" in the effort next week.

Though it dovetails with the federal program, the Hopkins project was conducted independently and largely with private money. Still, federal officials lauded the Hopkins program, saying it demonstrates the feasibility of the larger effort.

"We anticipate that as [the federal program] scales up, we may be able to identify the majority of genetic changes that cause the most important and common forms of the major cancers," Dr. Francis Collins, director of the National Human Genome Research Institute, said in a written statement.

"In fact, the large number of mutations reported in this paper offers a glimpse of what is yet to come and provides exciting new directions for drug discovery in breast and colon cancer."

In both a historical and practical sense, the Hopkins study was an outgrowth of federal and private programs that, by 2003, mapped the composition of the approximately 20,000 genes that make up each human cell.

Genes contain the blueprint for the proteins that make up every tissue in the body.

Each cell in the body contains the same complement of genes, though some acquire mistakes - or mutations - that give rise to improvements or abnormalities. Unlike normal cells that die and are replaced, a cancer cell lives on, multiplying into a tumor that can spread to other parts of the body.

The Hopkins scientists studied 11 breast tumors and 11 colon tumors of patients who had undergone treatment.

To identify the genes that had gone awry, they determined the chemical sequence of the tumors' DNA - and compared that information with the sequence of normal cells. The differences led scientists to identify the cancer genes.

Specifically, the team discovered 69 colon cancer genes and 122 breast cancer genes. Only two altered genes appeared both in colon and breast tumors.

To become cancerous, a cell needs to accumulate only some of these mutations. Vogelstein said the precise number, though not yet known, could be in the neighborhood of 20.

Though some people might inherit genes that predispose them to cancer, most mutations are acquired during a person's lifetime, he said. Mutations can be caused by diet or environmental influences.

"From the first mutation to a full-blown malignancy, it takes literally 20 to 40 years," said Vogelstein, noting that only a small number of cancers occur during childhood. "This data could explain why it takes so long."

One colon cancer patient, for instance, might have accumulated 20 of the 69 altered genes that are known to play a role in the disease. Another patient might have accumulated a similar number, with only some overlap between that patient and the other.

The differences could explain why cancers that seem alike behave differently in different patients.

Dr. Kurtis E. Bachman, a breast cancer specialist from the University of Maryland Greenebaum Cancer Center who collaborated in the study, said some mutations might figure into the early formation of a tumor, while others might trigger tumor growth.

Still others could influence the ability of tumor cells to break off, enter the bloodstream and invade other parts of the body.

"Some may be very instrumental in cancer being resistant to therapy," Bachman said. "We have cases where tumors look the same, but one person will respond to therapy while another won't. This opens up the possibility of explaining why they respond differently."

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