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.
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.
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.
As an octogenarian I am happy even to be alive and still more so to be the recipient of a Kyoto Prize that celebrates the values of work, knowledge, and idealism. My contemporary cohort reached adu1thood after the Great Depression and during World War II. The Depression was a world-wide tragedy, and strongly affected my family. My parents were in their early 30’s, with a new home, two young children, and rising expectations. They were suddenly faced with unemployment and the loss of their home. Their aspirations were crushed, and shifted to thoughts of a brighter future for themselves and their children. My sister and I learned not to want unattainable material things. I also developed a life-long consciousness of, and sympathy for, the underprivileged of the world.
We were fortunate to have excellent schools, and parents who found underpaid employment that spared us from poverty. We had a humble home for my musically talented sister and myself, but one where the importance of hard work, education, and ethical living were emphasized. I became interested in art and inspired by literature. The teachers in my public schools revealed the scientific glories of Euclid, Mendeleev, and Newton which prepared me for the California Institute of Technology, and the privilege of studying genetics in the department of Morgan, the first Nobelist in genetics.
World War II began as I was making the transition to college, and affected all of us. It was my good fortune to be sent to Medical School while in the U.S. Navy. Genetics and embryology both fascinated me and led naturally to an interest in Pediatrics. I became fascinated with the thought of combining scientific inquiry with caring for sick people. World War II ended, and I continued my training, inspired especially by my teachers in pediatrics. I found there was nothing I could imagine that surpasses the feeling of curing a child with a deadly disease like meningitis. All barriers of race, religion, or social status disappear. During my pediatric training I first encountered children with cancer, a subject of central interest for me ever since.