New Technology Pinpoints Genetic Differences Between Cancer and Non-Cancer Patients
Using a custom CGH-like oligonucleotide array to measure the global microsatellite content in the genomes of 72 cancer, cancer-free, and high risk patient and cell line samples (56 germline DNA and 16 in tumor or tumor cell line DNA) we found a unique, reproducible, and statistically significant pattern of 18 motif-specific microsatellite families (out of 962 possible 1-6 mer repeats) in breast cancer patient germline and tumor DNA, but not in germline DNA of cancer-free volunteer controls or in breast cancer patients with BRCA1/2 mutations. These high-similarity A/T rich repetitive motifs were also more pronounced in the germlines and tumors of colon cancer tumor patients (3/6 samples) and microsatellite unstable colon cancer cell lines; however, germline DNA of sporadic breast cancer patients exhibited the largest global content shift for those motifs with extreme AT/GC ratios. These results indicate that global microsatellite variability is complex, suggest the existence of a previously unknown genomic destabilization mechanism in breast cancer patients’ germline DNA, and warrant further testing of such microsatellite variability as a predictor of future breast cancer development.
SUMMARY A group of researchers led by scientists from the Virginia Bioinformatics Institute (VBI) at Virginia Tech have developed a new technology that detects distinct genetic changes differentiating cancer patients from healthy individuals and could serve as a future cancer predisposition test.
The multidisciplinary team, which includes researchers from the University of Texas Southwestern Medical Center, has created a design for a new DNA microarray that allows them to measure the two million microsatellites (short, repetitive DNA sequences) found within the human genome using 300,000 probes.
Microsatellites, which tend to vary greatly among individuals and have traditionally been used in forensics and paternity tests, are also used to uncover information related to a number of other genetic diseases such as Fragile-X or Huntington’s disease. This advancement aided the discovery of a unique pattern of microsatellite variation in breast cancer patients that were not present in the DNA of patients who are cancer-free. Through their evaluation of global changes in the genome, the researchers determined that this pattern change alludes to a new mechanism disrupting the genome in cancer patients and may represent a new breast cancer risk biomarker.
The results of the work will be featured in an upcoming edition of the journal Genes, Chromosomes and Cancer.
“We have now arrived at a new biomarker — an indicator that could be used to evaluate the amount of risk that you have for developing cancer in the future,” explained Harold “Skip” Garner, VBI executive director who leads the institute’s Medical Informatics and Systems Division. “This is part of an effort to understand their (microsatellite) role in the genome and then proceed on directly towards something that is of utility in the clinic. What just came out in our paper is a description of the technology that allows us to very quickly and efficiently and inexpensively measure these two million places using a uniquely designed microarray… It’s the pattern on that microarray that provides us the information we need.”
1. Cristi L. Galindo, Lauren J. McIver, Hongseok Tae, John F. McCormick, Michael A. Skinner, Ina Hoeschele, Cheryl M. Lewis, John D. Minna, David A. Boothman, Harold R. Garner. Sporadic breast cancer patients’ germline DNA exhibit an AT-rich microsatellite signature. Genes, Chromosomes and Cancer, 2011; DOI: 10.1002/gcc.20853