2004 Kyoto Prize Laureates

Basic Sciences

Life Sciences(Molecular Biology, Cell Biology, Neurobiology)

Alfred George Knudson, Jr.

/  Geneticist and Physician

1922 - 2016

Senior Advisor, Fox Chase Cancer Center

Commemorative Lectures

Reflections on a Life


11 /11 Thu

Place:Kyoto International Conference Center


Two Genetic Hits to Cancer : Past, Present and Future


11 /12 Fri

13:00 - 17:30

Place:Kyoto international Conference Hall

Achievement Digest

Seminal contribution to the establishment of the theory of the tumor suppressor gene in the mechanism of human carcinogenesis

In the early 1970s, Dr. Knudson proposed the “two-hit” hypothesis as a genetic mechanism of carcinogenesis through an elegant statistical analysis of retinoblastoma, a pediatric eye cancer. He soon advanced this hypothesis and reached the concept that mutational changes in “anti-oncogene”, now termed “tumor suppressor gene”, underlie the development of cancer. His “two-hit” hypothesis and the concept of “tumor suppressor” opened a new horizon in modern cancer genetics and played a pivotal role in the major developments in cancer researches.


Dr. Knudson proposed the “two-hit” hypothesis as a genetic mechanism of carcinogenesis, long before “oncogenes” or “tumor suppressor genes” were identified. He reached this hypothesis through a statistical analysis of retinoblastoma, a pediatric cancer often found with familial predisposition. Based on his “two-hit” hypothesis, Dr. Knudson also explained the recessive nature of the target genes affected by the two-hits at the cellular level, and coined such genes as “anti-oncogenes”, now called “tumor suppressor genes”. The hypothesis helped the discoveries of tens of key tumor suppressors, and is now established as one of the basic principles of cancer genetics.

By early 1970s, it was established that viral infections can cause cancers in animals , and transform cultured cells. Based on etiologic and chemical carcinogen studies, it was also proposed that successive multiple mutations accumulated for many years lead to cancer. Although these advances predicted dominant “oncogenes”, they could not explain hereditary or early-onset cancers.

Dr. Knudson who was trained as a physician and geneticist, focused on retinoblastoma patients who develop the tumor of the retina mostly in infancy, and often bilaterally. Using a statistical method, he found that bilateral hereditary cases fit for a one-hit phenomenon. The unilateral cases with no family history showed a distribution of two mutations. Because the hereditary form already harbored a germline mutation, both hereditary and nonhereditary forms of the tumor entailed the same number of events; hence “two-hit” hypothesis (1971).

Dr. Knudson soon advanced this hypothesis and proposed that the two mutational hits take place in the two alleles of the same recessive gene (1973) that he termed “anti-oncogene” (1982). He also predicted that the second event could be caused by mutation, deletion, chromosomal loss, recombination etc. This was proven by the other researchers in 1983, which led to the identification of RB1 as a tumor suppressor and its cloning in 1986.

Based on the “two-hit” hypothesis and using modern technology, researchers cloned some other tumor suppressor genes in the successive years, including WT1 (Wilms tumor) and BRCA1 (familial breast cancer). Another key tumor suppressor cloned independently also turned out to be inactivated by “two-hits”.

Based on his deep insights in clinical studies, Dr. Knudson formulated the simple and clear principle of the “two-hit” mutations to shed light on a complex mechanism of clinical cancer. His achievements stand high in today’s diversified and specialized life science researches.

For these reasons, the Inamori Foundation is pleased to present the 2004 Kyoto Prize in Basic Sciences to Dr. Alfred George Knudson, Jr.


Born in Los Angeles, California, U.S.A.
Columbia University M.D.
California Institute of Technology Ph.D. (Biochemistry & Genetics)
Chairman, City of Hope Medical Center
Associate Dean, Health Sciences Center, State University of New York at Stony Brook
Professor, University of Texas at Houston
Senior Member, Fox Chase Cancer Center (1980-1982 President, 1992- Fox Chase Distinguished Scientist, Senior Advisor to the President)
Adjunct Professor, Pediatrics and Human Genetics, School of Medicine, University of Pennsylvania
Selected Awards and Honors
Charles S. Mott Prize, General Motors Cancer Research Foundation, Washington, D.C.
Gairdner Foundation International Award, Toronto
IBM—Princess Takamatsu Cancer Research Fund Lectureship and Award, Tokyo
Albert Lasker Award for Clinical Medical Research
National Academy of Sciences, American Philosophical Society, American Academy of Arts and Sciences
Selected Publications
Mutation and cancer: statistical study of retinoblastoma, Proc. Natl. Acad. Sci. USA 68-4:820-823, 1971.
Mutation and human cancer, Adv. Cancer Res. 17:317-352, 1973.
Chromosomal deletion and retinoblastoma (with Meadows, A.T., Nichols, W.W. and Hill, R.) , New Engl. J. Med. 295:1120-1123, 1976.
Antioncogenes and human cancer, Proc. Natl. Acad. Sci. USA, 90:10914-10921, 1993.
Chasing the cancer demon, Annu. Rev. Genet. 34:1-19, 2000.
Two genetic hits (more or less) to cancer, Nature Reviews 1:157-162, 2001.
Endogenous DNA double-strand breaks: Production, fidelity of repair, and induction of cancer (with Vilenchik, M.M.), Proc. Natl. Acad. Sci. USA 100-22:12871-12876, 2003.
Cancer genetics through a personal retrospectroscope, Genes chromosomes & Cancer 38-4:288-291 (Special Issue for Knudson), 2003.

Profile is at the time of the award.