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In a 2004 Nature Medicine review paper, cancer genetics pioneer Bert Vogelstein, M.D., at the Johns Hopkins University School of Medicine, noted “Cancer is, in essence, a genetic disease…(but) no single gene defect ‘causes’ cancer.”
“Most people think it takes about seven to 10 years to go from a normal colon to a cancer, maybe longer,” says Robert Coffey, Jr., M.D., Ingram Professor of Cancer Research and professor of Cell and Developmental Biology at Vanderbilt-Ingram.
Recently, Vogelstein and colleagues estimated that it takes approximately 17 years for a large benign tumor to evolve into an advanced cancer, but only two additional years for that cancer to acquire the ability to metastasize, or spread throughout the body.
All told, the entire process – from the first genetic misstep that initiates abnormal cell growth to metastatic cancer – can take 30 to 40 years, according to Vogelstein’s estimates.
“This provides a huge window of opportunity to detect tumors at a stage when they are still curable by conventional
surgical methods,” wrote Vogelstein and colleague Kenneth Kinzler, Ph.D., in the Nature Medicine article. Perhaps more
promising, the extended lead-time presents opportunities for
prevention.
“Though less dramatic than cures,” they wrote, “prevention and early detection are perhaps the most promising and feasible means to reduce cancer deaths.”
Cannot predict now
Colon cancer starts in a single cell in the colon’s lining, or epithelium. This lone cell acquires a mutation – an error in the genetic code – that gives it a growth advantage. The most common mutations are in two categories of genes: tumor suppressors (which limit cell growth) and oncogenes (which promote cell growth). Researchers think that it takes at least five to seven mutations for
a colon cancer to develop.
The earliest visible sign of trouble may be the development of microscopic lesions, called aberrant crypt foci, in the colon lining. The normal colon epithelium is not a flat, smooth surface but an undulating array of peaks and valleys (termed crypts). Under the microscope, aberrant crypts appear larger than normal colon crypts with a thickening of the epithelium. Later, these lesions may develop into small – but still benign – polyps (adenomas) that can progress to a full-fledged colon cancer (carcinoma).
From decades of research, various genetic mutations have been identified that correspond with each of these steps.
In 1988, Vogelstein and Eric Fearon, M.D., Ph.D., laid out the first genetic model for colorectal cancer development – colloquially called a “Vogelgram” – that illustrates the mutations correlated with the various stages of the disease.
The model has provided an important but simplified framework for understanding colon cancer progression. Vanderbilt-Ingram investigators – and cancer researchers around the world – are building on this classic model, looking for additional genetic events that contribute to colon cancer development in hopes of identifying points at which clinicians can intervene to prevent, slow or stop the cancer’s spread.
While the sequence of mutations represented by the model appear linear, it is clear that the path to colon cancer is a bit more nuanced.
“Colon cancer represents an accumulation of genetic events,” says Coffey. “But they don’t necessarily have to occur in some lockstep order.”
The first and most well-established step – the genetic alteration that seems to initiate most colon cancers – is a loss of function of the APC (adenomatous polyposis coli) gene, a tumor suppressor gene.
“Most colon cancers are initiated, we think, in the same way,” says Beauchamp, the John Clinton Foshee Distinguished Professor of Surgery and the Chair of the Section of Surgical Sciences.
APC mutations are found in about 80 percent to 90 percent of colon cancers – both the rare inherited types and the more common sporadic types. When a cell loses function of APC, the cell’s natural ability to restrain cell growth and division is lost. This loosening of cell growth restrictions sets the stage for a cancer to form.
Because nearly every cell in our bodies has two copies of the gene – one from each parent – losing one copy of APC doesn’t automatically initiate cancer.
“If you have one mutation in APC, it’s not enough to immediately get a cancer or even a polyp,” Beauchamp explains. “The other copy of the gene has to be lost or silenced somehow.”
In a condition known as familial adenomatous polyposis (FAP), colon cancer already has a head start. People with FAP inherit one “bad” or dysfunctional copy of the APC gene from a parent. But this only predisposes them to colon polyps and colon cancer. It takes an additional insult to the other “good” copy of the gene to initiate the development of polyps (or adenomas). These are benign growths, but if not removed, they almost always develop into cancer.
“Knowing the initiating event does not help us predict who is going to get cancer, except when there is a hereditary syndrome (like FAP),” Beauchamp says. But the lessons learned from research on this pathway are providing potential targets for therapies that intervene to forestall the growth of a cancer.
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