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Radiation Response Score Developed With Mouse Genetic Data

NEW YORK – With the help of medulloblastoma patient data and genetic analyses in recombinant inbred mouse strains, a research team from the US and China has identified genetic contributors to the variable immune system responses documented after radiation treatment, using the data to develop a radiation resistance score related to medulloblastoma patient outcomes.

As they reported in Cell Genomics on Friday, researchers from the Lawrence Berkeley National Laboratory (LBNL), the University of California at Berkeley, and elsewhere started with blood count data for 99 children and young adults receiving head- and spine-focused irradiation treatments for medulloblastoma.

Although the team uncovered recurrent dips in immune-related white blood cell (WBC) counts and other blood cell measures a week after the patients' initial radiotherapy treatment, the extent of those changes varied from one individual to the next, as did sensitivity to the radiation treatment.

To explore such patterns further, the investigators turned to a mouse model of radiation exposure, using a genome-wide association study to look for genetic variants associated with short- and longer-term responses to radiation exposure in 1,720 mice spanning almost three dozen strains in the Collaborative Cross mouse resource collection.

"We present a community resource of immune parameters and genome-wide association analyses before and after radiation exposure for future investigations of the contributions of host genetics on radiosensitivity," the authors wrote.

Based on genetic associations involving 22 immune parameters measured 24 hours or four weeks after radiation exposure, the researchers were able to identify and distinguish between genetic variants linked to acute hematologic toxicity patterns and more lingering, "persistent" hematologic toxicity-related changes relative to a pre-treatment baseline.

Those risk variants, together with RNA sequencing profiles on blood samples from pre- and post-radiation exposure mice, provided insights into the quantitative trait loci and targeted genes contributing to these processes, the team reported, pointing to genes that resembled those involved in human immune responses in prior studies.

"We observed significant overlap between the genes identified in our mouse GWAS and genes identified in human GWAS of immune-related conditions and parameters," co-senior and co-corresponding authors Antoine Snijders, chair of LBNL's bioengineering and biomedical sciences department and a comparative biochemistry researcher at UC Berkeley, and Jian-Hua Mao, a biological systems and engineering researcher affiliated with LBNL and UC Berkeley, said in an email.

Together, these patterns made it possible to put together a radiation sensitivity score in the mouse model that showed promise for predicting radiation responses in human patients, Snijders and Mao explained, noting that the radiation sensitivity scoring system developed in mice showed significant associations with relapse-free survival in patients with known radiation responses, hematologic toxicity patterns, and clinical outcomes.

"Our study provides a resource for investigators interested in determining risks associated with radiation exposure from a variety of sources," Snijders and Mao said. "We also identified a number of genes associated with radiation sensitivity which could be developed into a biomarker panel to help identify patients at increased risk for hematologic toxicity."