PurposeOne possible way to quantify each individual's response or damage from ionizing radiation is to estimate their accelerated biological age following exposure. Since there is currently no definitive way to know if biological age estimations are accurate, we aim to establish a rad-age association using genomics as its foundation.MethodsTwo datasets were combined and used to empirically find the age cutoff between young and old patients. With age as both a categorical and continuous variable, two other datasets that included radiation exposure are used to test the interaction between radiation and age. The gene lists are oriented in preranked lists for both pathway and diseases analysis. Finally, these genes are used to evaluate another dataset on the clinical relevance in differentiating lung disease given ethnicity and sex using both pairwise t-tests and linear models.ResultsUsing 12 well-known genes associated with aging, a threshold of 29-years-old was found to be the difference between young and old patients. The two interaction tests yielded 234 unique genes such that pathway analysis flagged IL-1 signaling and PRPP biosynthesis as significant with high cell proliferation diseases and carcinomas being a common trend. LAPTM4B was the only gene with significant interaction among lung disease, ethnicity, and sex, with fold change greater than two.ConclusionThe results corroborate an initial association between radiation and age, given inflammation and metabolic pathways and multiple genes emphasizing mitochondrial function, oxidation, and histone modification. Being able to tie rad-age genes to lung disease supplements future work for risk assessment following radiation exposure.

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The human kidney is known to possess renal progenitor cells (RPCs) that can assist in the repair of acute tubular injury. The RPCs are sparsely located as single cells throughout the kidney. We recently generated an immortalized human renal progenitor cell line (HRTPT) that co-expresses PROM1/CD24 and expresses features expected on RPCs. This included the ability to form nephrospheres, differentiate on the surface of Matrigel, and undergo adipogenic, neurogenic, and osteogenic differentiation. These cells were used in the present study to determine how the cells would respond when exposed to nephrotoxin. Inorganic arsenite (iAs) was chosen as the nephrotoxin since the kidney is susceptible to this toxin and there is evidence of its involvement in renal disease. Gene expression profiles when the cells were exposed to iAs for 3, 8, and 10 passages (subcultured at 1:3 ratio) identified a shift from the control unexposed cells. The cells exposed to iAs for eight passages were then referred with growth media containing no iAs and within two passages the cells returned to an epithelial morphology with strong agreement in differential gene expression between control and cells recovered from iAs exposure. Results show within three serial passages of the cells exposed to iAs there was a shift in morphology from an epithelial to a mesenchymal phenotype. EMT was suggested based on an increase in known mesenchymal markers. We found RPCs can undergo EMT when exposed to a nephrotoxin and undergo MET when the agent is removed from the growth media.

Purpose: Ionizing radiation may serve as a reference variable to estimating biological age since it mirrors cumulative DNA damage similar to aging processes. To do this, we aim to establish a rad-age association using genomics as its foundation and clinical applicability with lung disease as an overlapping health concern. Methods: Two datasets were combined and used to empirically find the age cutoff between young and old patients: GSE42488 (Data-A1) and GSE53351 (Data-A2). With age as both a categorical and continuous variable, two other datasets that include radiation exposure are used to test the interaction between radiation and age: GSE21240 (Data-B1) and GSE23515 (Data-B2). A radiation only data was also used in conjunction to evaluate trend analysis with increasing exposure levels: GSE20173 (Data-R1). The gene lists are oriented in preranked lists for both pathway and diseases functional analysis. Finally, these genes are used to evaluate another dataset via GSE42834 (Data-D1) on the clinical relevance in differentiating lung diseases given ethnicity and sex using both pairwise t-tests and linear models including pneumonic, tuberculosis, active and non-active sarcoidosis, lung cancer, and healthy controls. Results: Using 12 well-known genes associated with aging, a threshold of 29 years old was found to be the difference between young and old patients. The two interaction tests (rad and age as continuous plus rad and age as categorical) yielded 234 unique genes such that pathway analysis flagged IL-1 signaling and PRPP biosynthesis as significant with high cell proliferation diseases and carcinomas being a common trend. From the radiation only t-tests, we see a trend of continued upregulation in gene expression as radiation levels increase in 15 of the 17 common genes. When looking at pairwise comparison of disease, ethnicity, or sex, 10 genes were statistically significant, 3 of which had a combination of pairwise significance and fold-change, while LAPTM4B (probe identifier ILMN1680196) was the only gene with significant interaction (p-value=0.004) between lung disease, ethnicity, and sex and fold change greater than two. Conclusion: The results corroborate an initial association between radiation and age given inflammation and metabolic pathways and multiple genes emphasizing mitochondrial function, oxidation, and histone modification. Being able to tie rad-age genes to lung disease supplements a geroscience approach in future work. Citation Format: Nathan A. Ruprecht, Sonalika Singhal, Kalli Schaefer, Jappreet S. Gill, Benu Bansal, Sandeep K. Singhal. Using a genomic only approach to a radiation-age association for supplementing differentiation amongst lung diseases and cancer using PMBCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB064.