Unlike most cancers, colon cancer can be detected early, before symptoms arise, with routine screening tests such as colonoscopy. Despite this, the disease remains among the most common and deadly cancers in the U.S., and its incidence in Israel has more than doubled in the past 30 years. But if an international research effort involving Weizmann Institute scientists reaps the benefits its collaborators hope for, better diagnosis of colon cancer and more individualized therapies for patients could be on the horizon.
Taking advantage of recent advances in DNA technology, the researchers are working to find out what goes wrong, at the molecular level, when colon cancer develops — what are the defects in genes, or in the "expression" of those genes, that allow abnormal cells to grow out of control?
Speaking at an American Committee for the Weizmann Institute of Science (ACWIS) forum in New York, Prof. Eytan Domany of the Weizmann Institute's Department of Physics of Complex Systems, likened DNA — that familiar double-stranded carrier of genes inside every cell of the body — to a cookbook. Each gene is like a single recipe for a dish which is akin to a protein, whose chemical formula is "written" on the gene. The gene is expressed when the corresponding protein is actually produced.
As Prof. Domany noted, there are many opportunities for errors in this cookbook, just like a misprinted ingredient in one of the recipes. In cooking, the result is a ruined meal; in the body, the result is a flawed protein, leading possibly to cancer.
To try to discover where the recipes are going wrong in colon cancer, Prof. Domany and his colleagues have begun with tissue samples from 144 individuals — including samples of colon cancer, colon growths called polyps that can become cancerous, and normal colon tissue. The job of creating an initial "profile" of gene expression for each of these individuals goes to Dr. Daniel A. Notterman, a professor of pediatrics and molecular genetics at the University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School.
To do this, Dr. Notterman focuses on the amount of messenger RNA (mRNA) in the cells of each tissue sample. mRNA is the molecule that takes the instructions from a gene in the cell's nucleus and carries the information to the cell's protein-making machinery, which in turn churns out the appropriate protein. Sticking with the culinary analogy, mRNA is a photocopy of the recipe, sent to the cook.
Proteins are the workhorses that actually carry out all the functions in the body. When a gene acquires a defect, the result may be an abnormal protein or protein levels within a cell that are too high or too low — that is, a problem in the way the gene is being expressed. Cancer arises when such cells continue to grow and spread unchecked.
For technical reasons, it's easier to study a gene's expression by looking at RNA levels in the cells of a tissue sample rather than by studying proteins, Dr. Notterman explained at the briefing. Using a DNA "chip" that allows the simultaneous analysis of thousands of RNA molecules over a matter of hours, his lab was able to create expression profiles for the roughly 30,000 genes in each of the 144 tissue samples.
Those data, in the form of what looks like a sea of numbers, then go to Prof. Domany, whose job is to find meaningful patterns in the "noise" — pulling out the relative handful of "candidate" genes most likely to play essential roles in colon cancer. To begin to make sense of the numbers, Prof. Domany color-codes the data, with different shades of color representing the expression levels of the thousands of genes in each patient.
The aim, as Prof. Domany explained, is to separate the patients into groups based on similarities in their gene expression profiles. "We take a picture that looks very random and reorganize it so that we can reveal the structure," he said. What his lab has come up with so far is roughly 200 genes that are altered at the level of RNA and appear key in colon cancer progression.
That list of genes then moves on to Dr. Francis Barany of the Weill Medical College of Cornell University, who tries to uncover the changes in DNA — the master cookbook — that contribute to colon cancer. "The problem is, how do you distinguish the really important cancer-specific defect from the ‘bystander' defect," said Dr. Barany. The foundation of this research project, he explained, is that "candidate genes that are consistently altered at the DNA level are likely to be cancer-specific."
Cancer-gene research, Dr. Barany noted, generally focuses on three types of genes: oncogenes, which promote cancer growth; tumor suppressor genes, which act like the name implies; and genome integrity genes, which act like the body's "mechanic." Among the problems that can arise are mutations in the structure of the DNA, as well as so-called "epigenetic" changes, which refer to alterations in the way genes are expressed in the absence of structural defects in the gene.
The future of cancer treatment, Dr. Barany said, is to move away from "blanket treatments" that try to slow down cancer cells — and harm healthy cells in the process — toward targeted drugs aimed at specific gene defects in cancer. The ultimate hope is to be able to test a patient for the specific molecular characteristics of his or her tumor, and then choose the right treatment from an arsenal of targeted drugs.
Reaching that goal will, of course, take a continuing effort to identify the genetic culprits in cancer. As Prof. Domany noted, colon cancer, on the molecular level, varies widely from person to person, and much work remains in untangling the genetic underpinnings. The collaboration he and his colleagues have undertaken is currently in the early, data acquisition and "data mining" phase of what is expected to be a 5- to 10-year effort.
Prof. Eytan Domany is the incumbent of the Henry J. Leir Professorial Chair.The Weizmann Institute of Science in Rehovot, Israel, is one of the world's foremost centers of scientific research and graduate study. The American Committee for the Weizmann Institute of Science is a community of dedicated people who share a common vision in support of the Institute. The generous assistance the Institute receives from individuals, foundations, and corporations is vital for its future. Committee members show their devotion to the advancement of the Institute's goals by becoming partners in the search for answers to the most difficult challenges facing humanity.
