Genomic damage in common (non-familial) colorectal cancer is widespread and begins very early in tumor development. However, understanding how the genomic instability in the common human cancers arises and finding the gene(s) responsible for the instability have been elusive.

Garth R. Anderson, PhD, departments of Cancer Genetics and Surgery, Roswell Park Cancer Institute (RPCI), and colleagues, have shed important light on both issues in their study of intrachromosomal genomic instability in human sporadic (non-familial) colorectal cancer (Cancer Research, November 15, 2001).

"This study focused on determining the origin(s) of genomic instability by locating genes whose loss or defectiveness underlies the instability," according to Dr. Anderson. "These 'instability genes,' whose normal role is to maintain the integrity of the genetic information within the DNA, should provide valuable new prevention targets and be exploitable as prognostic tools.

"It now appears that it is the loss of stability of a cell's genetic information that is the driving force behind the lengthy process of progression to cancer."

Genome-wide allelotyping for loss of heterozygosity (LOH), inter-SSR (simple sequence repeat) polymerase chain reactions [PCR], and microsatellite instability measurements of genomic instability were performed to compare normal tissue DNA with tumor DNA for a set of 59 sporadic colorectal cancers and seven premalignant adenomatous polyps.

The LOH assays enabled the researchers to evaluate whether that form of genomic damage relates to inter-SSR instability, to test if microsatellite instability relates to both these measurements, and to test whether individual loci can be associated with elevated overall degrees of genomic instability in colorectal cancer.

Each method preferentially detected distinct types of instability, and the instability detected by one method was not associated with that detected by another.

"Our results show that intrachromosomal genomic instability can be seen in at least three distinct, independent forms in sporadic colorectal cancer detected as LOH, alterations in inter-SSR PCR electrophoretic band patterns, and microsatellite instability," notes Anderson. "These instabilities combine to generate enormous damage within a tumor cell's genome, and may lead to major differences between cells within a tumor."

The experimental results were analyzed to compare the degree of genetic instability in tumors which had or had not undergone loss of each of 348 markers examined.

Seven principal loci were identified -- chromosomes 3, 8, 11, 13, 14, 18, 20 -- which showed significant association with overall genomic instability.

"We are seeing evidence that the genes preserving integrity are redundant, and two must be independently lost to start the journey to malignancy," according to Daniel L. Stoler, PhD, Division of Experimental Pathology at RPCI and a key contributor to this study. "Candidate genes have been identified for most of these loci, and we are now examining mutations in these candidates to test their role," according to Anderson.

Roswell Park Cancer Institute was founded in 1898, is the nation's first cancer research, treatment and education center and is the only National Cancer Institute-designated comprehensive cancer center in Western New York. - By Deborah Pettibone


[Contact: Deborah Pettibone]

16-Nov-2001