Tumor-Suppressor Genes 
Andrew p. Feinberg, M.D., M.P.H. — Associate Investigator 
Dr. Feinberg is also Associate Professor of Internal Medicine and Human Genetics at the University 
of Michigan Medical School. He received his B.A., M.D., and M.P.H. degrees from the Johns Hopkins 
University. He received clinical training at the University of Pennsylvania and Johns Hopkins and did 
postdoctoral research at the University of California, San Diego, and Johns Hopkins. Before moving to the 
University of Michigan, Dr. Feinberg was Assistant Professor of Oncology and Medicine at Johns Hopkins. 
ONE of the most important areas of cancer ge- 
netics is the identification and characteriza- 
tion of tumor-suppressor genes, whose inactiva- 
tion contributes to cancer. Since almost all genes 
are present in two copies in the cell, cancer 
would develop from deletion or inactivation of 
both copies of these suppressor genes. Inactiva- 
tion of one copy could be transmitted in families 
from parent to child. Thus individuals inheriting 
one nonfunctional copy of the gene would be at 
increased cancer risk. 
Wilms' tumor (WT), a childhood kidney 
cancer, was one of the earliest models of suppres- 
sor gene action. Strong and Knudson showed 20 
years ago that WT apparently resulted from two 
mutations, based on two peaks in the age of onset. 
Furthermore, it was discovered in the 1970s that 
some children with WT lack a large portion of 
chromosome 1 1 (in band llpl3), which is visi- 
ble microscopically. Before joining HHMI, I 
observed (with Eric Fearon and Bert Vogelstein) 
that more subtle gene deletions can be detected 
indirectly on chromosome 1 1 in WTs, through 
use of restriction fragment length polymor- 
phisms (RFLPs), which can distinguish the ma- 
ternal and paternal copies of a given gene. 
In collaboration with David Schlessinger 
(Washington University, St. Louis) and Bryan Wil- 
liams (Hospital for Sick Children, Toronto), our 
laboratory has now cloned the 1 1 p 1 3 WT gene 
region in yeast artificial chromosomes (YACs) . In- 
terestingly, we found that this region contains 
multiple genes turned on specifically in develop- 
ing kidney. At least two of these genes showed 
reduced or absent expression in approximately 
half of sporadically occurring WTs, notably those 
of the same histologic type that occur in children 
with 1 lpl3 deletions. One of these genes codes 
for a DNA-binding protein that is mutated in 
some WTs. 
These mutations, however, occur infrequently, 
and the laboratory is investigating whether re- 
duced expression of the gene may be a more 
common mechanism for tumorigenesis and 
whether other genes from this complex may play 
a role. We are also "retrofitting" WT YACs with a 
gene that allows growth in mammalian cells, in 
order to demonstrate directly a tumor-suppressor 
phenotype of the 1 lpl3 WT gene(s) and to de- 
termine by deletion experiments the functional 
role of the multiple genes from this region. 
In addition to the known gene on chromosome 
1 1 that predisposes to WT, we have discovered a 
second predisposing gene at a different location 
on the chromosome (band 11 p 1 5 ) . This gene ap- 
pears to be involved in bladder, breast, and lung 
cancer, as well as WT. Thus WT causation is more 
complex than investigators had previously be- 
lieved, and this second WT gene may turn out to 
be important in common cancers. 
Consistent with this gene being a tumor sup- 
pressor, the laboratory has applied genetic 
linkage analysis to map to the same region 
of 11 pi 5 a cancer-predisposing disorder, Beckwith- 
Wiedemann syndrome (BWS). Using YACs, the 
laboratory has now isolated several DNA break- 
points from BWS patients with germline chromo- 
somal rearrangements. This should enable the lab- 
oratory to determine whether the BWS gene is 
indeed the second WT-suppressor gene on the 
llpl5 band. 
Adding to the complexity of WT is the fact that 
some non-BWS families with hereditary predispo- 
sition to WT do not show linkage of this trait to 
chromosome 1 1 . Recently the laboratory found, 
in collaboration with former sabbatical member 
Anthony Reeve (University of Otago, New Zea- 
land), involvement of chromosome 16. 
The laboratory has recently developed a novel 
approach to isolating tumor-suppressor genes di- 
rectly. Human chromosomes are fragmented into 
2-5 million base pair "superfragments" in a way 
that allows their transfer into any mammalian 
cell. The advantage of this technique is that it 
enables one to transfer the giant DNA pieces into 
a recipient cell and screen directly for a func- 
tional gene. It may thus have immediate ap- 
plication to cloning other chromosome 1 1 
tumor-related genes, or more general application 
to cloning a variety of genes on other chromo- 
somes — genes for which one can currently 
screen but not select, such as those for cellular 
aging. 
For example, one should be able to exploit the 
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