Counting
Alleles Leads to Better Prognosis of Colorectal Cancer
A study by researchers
at Emory University's Winship Cancer Institute (WCI) and The Sidney
Kimmel Comprehensive Cancer Center at Johns Hopkins University identifies
chromosomal imbalances as an accurate marker to predict recurrences
of colorectal cancer. The study, "Counting Alleles to Predict Recurrence
of Early Stage Colorectal Cancers," will be published in the January
19, 2002, issue of The Lancet.
Wei Zhou, Ph.D., of WCI,
and Bert Vogelstein, Ph.D., of Johns Hopkins and Investigator, Howard
Hughes Medical Institute, have developed a technique called Digital
SNP (Single-Nucleotide Polymorphism), which accurately measures chromosomal
imbalances by directly counting alleles in sample chromosomes. This
is the first study to apply measurement of chromosomal imbalance to
the prediction of which patients are likely to suffer a recurrence of
colorectal cancer.
Colorectal Cancer is a common
malignancy in the U.S., with an annual incidence of 135,000 cases, responsible
for 55,000 deaths each year. Patients with advanced colorectal cancer
typically have a poor prognosis for recovery. Patients with early stage
colorectal cancer typically have a good prognosis, however, 10 to 30
percent of these patients develop recurrences and die from the disease.
The ability to predict which of these patients might develop a recurrence
would greatly benefit the patient and physician in planning for future
treatment.
Previous studies have shown
that when regions of certain chromosomes are lost, an imbalance results.
If the lost region of the chromosome contains a tumor suppressor gene,
those cells may acquire a competitive growth advantage and play an important
role in the recurrence of colorectal tumors.
Accurately measuring chromosomal
imbalances is extremely difficult. Dr. Zhou, Dr. Vogelstein and their
team developed the Digital SNP, in which each allele in the chromosomal
sample is counted, one by one, providing an unprecedented degree of
accuracy to the analysis.
The study focused on two
specific chromosomes (8 and 18) in which the inactivation of tumor suppressor
genes indicates an important role in subsequent tumor progression. Researchers
studied 180 colorectal cancer patients from four different hospitals
in the U.S. and Europe over the course of five years. Using Digital
SNP, a strong connection between specific chromosomal imbalances and
disease recurrence emerged, providing valuable information for the prognosis
and treatment of this cancer.
In addition, Digital SNP
has enabled researchers to reach more definitive conclusions than previously
possible. For example, microdissection is essential to obtain tumor
cells, however, the amount of usable DNA recovered from microdissected
cells is limited. Sampling errors based on analysis of only a few DNA
molecules could lead to erroneous conclusions. This is the first study
to count the number of alleles actually analyzed in each sample, which
eliminates possible errors based on limited data.
Dr. Zhou and Dr. Vogelstein
believe the approaches and results of allele imbalance in colorectal
cancer may be applicable to other cancers. Previous studies have shown
evidence of allele imbalance in at least nine different chromosomes
with some relation to colorectal cancer development. It is possible
then, that allele imbalance within chromosomes in general indicates
greater chances of metastasis, possibly due to increased instability.
If this is true, then using Digital SNP to study the allele imbalance
of any chromosome that is lost during tumor progression should provide
useful prognostic information.
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