'Two-Hit' Hypothesis

Much of what scientists know about the origins of cancer and the role of tumor suppressors can be traced back 28 years to the elegant theory of cancer researcher Alfred G. Knudson. Widely thought to be one of the most significant theories in modern biology, Knudson's "two-hit" hypothesis was recognized Nov. 19 at the John Scott Awards in Philadelphia, along with the revolutionary research of Benoit Mandelbrot, the discoverer of the powerful mathematical laws governing fractal geometry and self-s

Nov 22, 1999
Eugene Russo

Much of what scientists know about the origins of cancer and the role of tumor suppressors can be traced back 28 years to the elegant theory of cancer researcher Alfred G. Knudson. Widely thought to be one of the most significant theories in modern biology, Knudson's "two-hit" hypothesis was recognized Nov. 19 at the John Scott Awards in Philadelphia, along with the revolutionary research of Benoit Mandelbrot, the discoverer of the powerful mathematical laws governing fractal geometry and self-similarity.1


Alfred G. Knudson
For Knudson, now a senior member of the Institute for Cancer Research at the Fox Chase Cancer Center in Philadelphia, it's the latest of a long list of accolades. Past honors for his theory on the genetic and environmental basis of several common cancers include the 1997 Gairdner Foundation International Award and the 1998 Albert Lasker Clinical Medical Research Award.2

Even amid ongoing rumors of an impending Nobel, Knudson says that the recognition, while nice, does have a downside. "Awards tend to create an artificial separation between those people [who win] and the people who don't get awards but who are adding very much to science," he says. Knudson cites the famous example of bacteriologist Oswald T. Avery who, despite discovering that DNA was the genetic material, never received the Nobel because his ideas were only accepted posthumously. As for his own chances of making a trip to Sweden, Knudson admits it would be nice, but he suggests that he takes more pride in being a part of a biomedical science enterprise that's matured at a phenomenal rate in the last few decades. "The year I started medical school was the year of Avery's paper," he comments. "It's incredible when you stop to think what's happened in that interval."

The "two-hit" hypothesis was, according to many, among the more significant milestones in that rapid evolution of biomedical science. The theory explains the relationship between the hereditary and nonhereditary, or sporadic, forms of retinoblastoma, a rare cancer affecting one in 20,000 children. Years prior to the age of gene cloning, Knudson's 1971 paper proposed that individuals will develop cancer of the retina if they either inherit one mutated retinoblastoma (Rb) gene and incur a second mutation (possibly environmentally induced) after conception, or if they incur two mutations or hits after conception.3 If only one Rb gene functions normally, the cancer is suppressed. Knudson dubbed these preventive genes anti-oncogenes; other scientists renamed them tumor suppressors.

When first introduced, the "two-hit" hypothesis garnered more interest from geneticists than from cancer researchers. Cancer researchers thought "even if it's right, it may not have much significance for the world of cancer," Knudson recalls. "But I had been taught from the early days that very often we learn fundamental things from unusual cases." Knudson's initial motivation for the model: a desire to understand the relationship between nonhereditary forms of cancer and the much rarer hereditary forms. He also hoped to elucidate the mechanism by which common cancers, such as those of the breast, stomach, and colon, become more prevalent with age.

According to the then-accepted somatic mutation theory, the more mutations, the greater the risk of cancer. But this didn't jibe with Knudson's own studies on childhood cancers, which suggested that, in the case of cancers such as retinoblastoma, disease onset peaks in early childhood. Knudson set out to determine the smallest number of cancer-inducing events necessary to cause cancer and the role of these events in hereditary vs. nonhereditary cancers. Based on existing data on cancer cases and some mathematical deduction, Knudson came up with the "two-hit" hypothesis.

Not until 1986, when researchers at the Whitehead Institute for Biomedical Research in Cambridge, Mass., cloned the Rb gene, would there be solid evidence to back up Knudson's pathogenesis paradigm.4 "Even with the cloning of the gene, it wasn't clear how general it would be," says Knudson. There are, it turns out, several two-hit lesions, including polyposis, neurofibromitosis, and basal cell carcinoma syndrome. Other cancers show only some correspondence with the two-hit model. In the case of Wilm's tumor, for example, the model accounts for about 15 percent of the cancer incidence; the remaining cases seem to be more complicated.

Although out of the lab since 1993, Knudson continues to probe the fundamental roots of cancer. He's consumed, in particular, by the poorly understood roles of polyposis and neurofibromitosis genes. Researchers know that mutant Rb is causing an increased cell birth rate through cell cycle changes, and p53 a decreased death rate. Knudson regards polyposis and neurofibromitosis as a third class of genes; they may be at work at an earlier stage, regulating renewal tissues such as skin and increasing odds that there will be a cell that serves as a target for subsequent events involving genes like Rb and p53. "Some tumors don't seem to have this first part," explains Knudson. "So maybe that's why we have a tumor like retinoblastoma, because there are fewer events that are necessary to get there."

Some of the biggest challenges for the cancer genetics field, says Knudson, still revolve around finding and cloning cancer-associated genes. Despite the considerable success researchers have had describing common cancers, there are some cancer types where things are, according to Knudson, "still kind of a mess." The genetics of one of the most deadly cancers, pancreatic, for example, have yet to be worked out. Although Rb, p53, and the tumor suppressor p16 are known to have roles in the development of the disease, as-yet-unidentified genes that come into play at the cancer's earliest stages could hold the key to better diagnosis and treatment. The hereditary form of the cancer could provide the answer, but studying family histories is tough since pancreatic cancer victims die so quickly. "There are a bunch of important genes to be cloned," remarks Knudson. "Whether they're going to give any new principles that aren't apparent from the tumors we already know about is not yet clear.".

Eugene Russo can be contacted at erusso@the-scientist.com.

References

1. S. Bunk, "Do energy transport systems shape organisms?" The Scientist, 12[24]:14, Dec. 7, 1998.

2. E. Russo, "1998 Lasker Award recipients honored for their groundbreaking achievements," The Scientist, [20]12:1, Oct. 12, 1998.

3. A.G. Knudson, "Mutation and cancer: statistical study of retinoblastoma," Proceedings of the National Academy of Sciences, 68:820-3, 1971.

4. S.H. Friend et al., "A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma," Nature, 323:643-6, 1986.