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Knudson Gives NCI Partners in Research Lecture

By Robin Cline

As part of NCI's Office of Management series, "Partners in Research," Dr. Alfred Knudson recently presented a lecture on "Hereditary Predisposition to Cancer" to members of the administrative staff.

Knudson has had a long-standing history with NIH, having been a grantee and having served on many NIH advisory groups since 1964. Within NCI, he has served as acting director of the Human Genetics Program in the Division of Cancer Epidemiology and Genetics, cochaired the cancer genetics working group, and was a member of the executive committee. He has also been conducting research at Fox Chase Cancer Center in Philadelphia since 1976. His contributions to the field of cancer genetics have lead to a greater understanding of the genetic basis of cancer.

Dr. Alfred Knudson

In his lecture, Knudson reiterated the work with which his name is synonymous, the Two-Hit Hypothesis. While studying retinoblastoma, a rare childhood eye tumor, he developed a genetic model to explain how mutations in tumor suppressor genes play a role in the development of cancer for both sporadic and inherited forms of the disease.

Normal tumor suppressor genes perform like a brake pedal to limit cell growth and division. When this brake mechanism is lost from a cell or inactivated by a mutation, cells are allowed to grow and divide in an unregulated manner, which leads to cancer. Knudson illustrated that the loss of tumor suppressor gene function is involved in the development of both sporadic and hereditary cancers.

For example, in cases of retinoblastoma tumors, two genetic events or "hits" affect the two normal copies of the tumor suppressor gene, RB1. In sporadic retinoblastoma tumors, both mutations accumulate in the retinal cells spontaneously or as a result of environmental influences. In contrast, individuals who develop the hereditary form of retinoblastoma inherit the first defective copy of the RB1 gene from an affected parent.

Knudson's two-hit theory pointed out that because genes come in pairs, the loss of the function of the first tumor suppressor gene in both sporadic and hereditary cancers will not by itself lead to tumor development. Because the other normal copy is still functional the individual still has some cellular braking ability. It is when a second, possibly environmentally induced, mutation inactivates the remaining copy that cancer develops. Knudson's insights from his discovery of the RB1 gene as a tumor suppressor gene continue to serve as a model for other studies of genetic susceptibility to cancer.

His talk also focused on the differences in the genetics of cancers that affect children and those that affect adults. Pediatric tumors are more homogeneous, composed of one or a few clones (genetically identical cells), and usually involve 2-4 genetic changes. In contrast, adult tumors are heterogeneous and composed of multiple clones, which result from more than four genetic changes. These differences between pediatric and adult tumors help to explain the observation that tumors in children are more responsive to systemic therapy than tumors in adults. However, it should be noted that since adult tumors are the result of multiple genetic changes, prevention efforts are more likely to be successful in adults than in children.

Knudson reviews two-hit theory.

Knudson emphasized that basic research has given the scientific community a wealth of information about the role of genetics in cancer development. He said there is every reason to expect that an investment in basic research will produce better cancer prevention and treatment strategies in the days ahead.

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