Helicos’ True Single Molecule Sequencing platform was used to study mice and human cell lines.
Researchers at Massachusetts General Hospital (MGH) Cancer Center discovered that tumor cells demonstrate an over-expression of satellite repeats, or DNA sequences that do not code for proteins. Previously, satellite repeats had been studied for their role in chromosomal structure but had not been suspected of having any role in cancer.
The research appears online in Science, and the paper is titled, “Aberrant Overexpression of Satellite Repeats in Pancreatic and Other Epithelial Cancers.”
Satellite repeats in heterochromatin are transcribed into noncoding RNAs that have been linked to gene silencing and maintenance of chromosomal integrity. Previously available tools for analyzing the transcription of DNA into RNA were designed to focus on sequences that are eventually translated into proteins. They thus excluded segments present in multiple-repeat copies that do not produce proteins, like satellite repeats.
The MGH team set out to provide a more comprehensive picture of the transcriptome of primary tumors. They tapped Helicos BioSciences’ True Single Molecule Sequencing (tSMS™) platform for their research. The scientists found satellite repeat transcripts overexpressed in mouse as well as human epithelial cancers.
In 8 of 10 mouse pancreatic ductal adenocarcinomas (PDAC), pericentromeric satellites accounted for a mean 12% of all cellular transcripts, a mean 40-fold increase over normal tissue. In 15/15 human PDACs, alpha satellite transcripts were most abundant, and HSATII transcripts were highly specific for cancer. Similar patterns were observed in cancers of lung, kidney, ovary, colon, and prostate. Derepression of satellite transcripts correlated with overexpression of the LINE-1 retrotransposon and with aberrant expression of neuroendocrine-associated genes proximal to LINE-1 insertions.
Increased satellite expression in lower-grade tumors suggests that over-expression of the DNA sequence occurs early in tumor development. It may also reflect global alterations in heterochromatin silencing and could potentially be useful as a biomarker for cancer detection, the MGH team concludes.
“In a few of the analyzed samples, our team demonstrated that pancreatic cancer cells were correctly identified based on satellite RNA expression, which was appreciably higher than in nonmalignant cells,” says David Ting, M.D., of the MGH Cancer Center and co-lead author of the Science paper. “If confirmed in large prospective clinical trials, satellite RNA expression may provide a new and highly specific biomarker relevant to multiple types of epithelial cancers.”