Identification of the Gene Responsible for 
Adenomatous Polyposis 
Raymond L. White, Ph.D. — Investigator 
Dr. White is also Professor of Human Genetics and Adjunct Professor of Cellular, Viral, and Molecular 
Biology at the University of Utah School of Medicine. He received a B.S. degree in microbiology from the 
University of Oregon, Eugene, and a Ph.D. degree in microbiology from the Massachusetts Institute of 
Technology. He did postdoctoral research with David Hogness at Stanford University. Dr. White has held 
various academic appointments at the University of Massachusetts, Worcester, and the University of Utah. 
He was recently named the Thomas D. Dee II Professor of Human Genetics at the University of Utah. Dr. 
White is a corecipient of the National Health Council's National Medical Research Award and was recently 
elected to the National Academy of Sciences. 
FORMATION of a polyp in colonic epithelium 
is an early event in the development of colon 
cancer. In some families a dominantly inherited 
mutation causes familial adenomatous polyposis 
coli (APC), a condition characterized by large 
numbers of polyps and a consequently high risk 
for colon cancer among those who inherit the 
mutant allele. Because colon carcinoma is the 
leading cause of cancer death in the United 
States, identification of the gene that causes poly- 
posis in APC families has been the goal of investi- 
gators seeking to understand cellular mecha- 
nisms that can lead to malignancy. This goal was 
achieved when the gene APC was isolated in 
1991. 
Genetic linkage studies, combined with evi- 
dence from microscopic analysis of altered chro- 
mosomes, had localized the polyposis-causing 
mutation in APC families to a specific region on 
the long arm of chromosome 5 . Molecular tech- 
niques, including physical mapping of large DNA 
fragments, were brought into play to define the 
region more clearly, because numerous genes be- 
sides APC were likely to reside in that portion of 
the chromosome. 
With molecular probes derived from the large 
DNA fragments, small deletions were found in the 
DNA of two unrelated patients with APC. These 
deletions proved to be the key to isolation of 
APC, for they defined a very small region in 
which to search. A nearby gene, MCC, which is 
often mutated in sporadic colonic tumors, had 
been a candidate; but MCC was not interrupted 
by either of the small deletions, and the search 
continued. 
Three other genes were found that did fall 
within the 100-kilobase region deleted in both 
patients, and each of those was investigated for 
the presence of very small ("point") mutations 
in the DNA of other persons with APC. One of 
these genes was subsequently identified as APC 
on the basis of point mutations in several 
patients. 
Although each of these APC-specific genetic al- 
terations had occurred in a different coding re- 
gion of the gene, all were of a kind that could be 
expected to prevent the generation of a normal 
protein product. In one patient the mutation was 
new in his family. His parents' chromosomes 
carried normal copies of APC, but two of his chil- 
dren had inherited his mutant allele. 
APC, like NFl (neurofibromatosis type 1 ) , an- 
other tumor-associated gene cloned recently, ap- 
pears to fall into the growing category of tumor- 
suppressor genes. There were no clues, however, 
to its physiological function, as had come to light 
for NFl with the discovery of similarities in 
amino acid sequence between its predicted prod- 
uct and proteins known to participate in trans- 
duction of growth signals within the cell. The 
only structural motif that could be identified was 
the presence of "heptad repeats," or series of 
seven amino acids in tandem arrays. Heptad re- 
peats often suggest that a protein can interact 
with similar proteins to form coiled helical 
structures. 
The putative product of MCC also contains 
heptad repeats. It is intriguing to speculate upon 
the possibility of interaction between this pro- 
tein and the APC product, in view of the fact that 
alterations in both genes are known to play im- 
portant roles in the pathway to colon cancer. 
Some families exhibit an unusually high inci- 
dence of colon cancer without showing a pattern 
of classical polyposis; that is, affected members 
may develop very few polyps. Inherited muta- 
tions in the APC gene are being sought in these 
families, and colonic tumors in the general popu- 
lation are being tested for mutant APC alleles. 
Characterization of a variety of APC mutations 
may help to explain differences in clinical pro- 
files among people with a genetic predisposition 
to colon cancer. It may also lead to new informa- 
tion about the role of the gene in normal cellular 
processes. 
For many families with APC, discovery of the 
gene has immediate value for presymptomatic, 
even prenatal, diagnosis of carrier status. When a 
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