“The effect sizes associated with any SNP were too small to have any clinical relevance individually,” said West. “The work highlights the need for large cooperative studies, which are required to detect exactly which SNPs are important. It also highlights the need to move to genome-wide association studies, where there is no assumption about the genes that are important.”


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TIME TO CAST A WIDER NET

“This is not the ‘end’ of radiogenomics,” Matthew Parliament, MD, Director of Radiation Oncology at the Cross Cancer Institute at the University of Alberta in Edmonton, Canada, told Oncology Nurse Advisor. “To paraphrase Churchill, it is the end of the beginning. The model we thought we knew, upon which the choice of candidate genes in pathways such as DNA damage repair, is probably not totally sufficient to explain the phenomenon of radiation injury at the tissue level. A genome-wide gene sequencing approach, as in other population-based studies of complex chronic diseases, is much more likely to discover highly significant, heretofore unknown variants, which may in fact be causative.”

Several years ago, Rosenstein’s team initiated genome-wide searches for SNPs associated with adverse urinary, sexual function, and rectal effects among prostate cancer patients treated with radiotherapy. Using genetic data for patients from the United States, England, the Netherlands, and Japan, he hopes to narrow down a list of thousands of preliminary associations to a small pool of powerfully predictive SNPs.

“We’ve taken SNPs with the strongest (preliminary) associations with these three major complications and have created our own customized gene array with 5,000 SNPs,” Rosenstein explained. “We’ve just concluded screening 1,100 prostate cancer patients, using a case/control study approach. Within the next few months, we’re hoping to see that of the 5,000 SNPs, there are a much smaller number, 10, 50, or 100 SNPs, that have much stronger associations with the complications we’re looking at. We’re hoping we can carve it down to a reasonable number of genetic markers that can be used as a predictive assay, not one or a few but a group of markers.”

GOING FORWARD

The Radiogenomics Consortium applied for National Institutes of Health (NIH)funding in March 2012. It plans to prospectively enroll 16,000 radiotherapy patients at 12 institutions in the United States and Europe in a study that will use uniform measures of toxicity and establish a radiogenomics data and biobank with blood specimens and detailed information about treatment, dosimetric measurements, and clinical outcomes. “We’ll follow them, hopefully for the remainder of their lives,” Rosenstein said. “If the funding comes through, we’ll start January 1, 2013.”

Five years from now, Rosenstein predicts, patients may have their entire genomes sequenced for the cost of a CT scan, with which oncologists can use SNP analysis algorithms to identify a patient’s risk of radiation toxicities. “I predict there will be some important discoveries made in this area in the next couple of years,” Parliament agreed; “assuming, of course, that researchers share their data with the Radiogenomics Consortium so that large, statistically powerful datasets can address the question.” ONA


Bryant Furlow is a medical journalist based in Albuquerque, New Mexico.


REFERENCES

1. Rosenstein BS. Identification of SNPs associated with susceptibility for development of adverse reactions to radiotherapy. Pharmacogenomics. 2011;12(2):267-275.

2. Andreassen CN. Searching for genetic determinants of normal tissue radiosensitivity: are we on the right track? Radiother Oncol. 2010;97:1-8.

3. West C, Rosenstein BS. Establishment of a radiogenomics consortium. Radiother Oncol. 2010;94:117-124.

4. Barnett GC, Coles CE, Elliott RM, et al. Independent validation of genes and polymorphisms reported to be associated with radiation toxicity: a prospective analysis study. Lancet Oncol. 2012;13:65-77.