Circulating miR-29a and miR-150 correlate with delivered dose during thoracic radiation therapy for non-small cell lung cancer.
BACKGROUND
Risk of normal tissue toxicity limits the amount of thoracic radiation therapy (RT) that can be routinely prescribed to treat non-small cell lung cancer (NSCLC). An early biomarker of response to thoracic RT may provide a way to predict eventual toxicities-such as radiation pneumonitis-during treatment, thereby enabling dose adjustment before the symptomatic onset of late effects. MicroRNAs (miRNAs) were studied as potential serological biomarkers for thoracic RT. As a first step, we sought to identify miRNAs that correlate with delivered dose and standard dosimetric factors.


METHODS
We performed miRNA profiling of plasma samples obtained from five patients with Stage IIIA NSCLC at five dose-points each during radical thoracic RT. Candidate miRNAs were then assessed in samples from a separate cohort of 21 NSCLC patients receiving radical thoracic RT. To identify a cellular source of circulating miRNAs, we quantified in vitro miRNA expression intracellularly and within secreted exosomes in five NSCLC and stromal cell lines.


RESULTS
miRNA profiling of the discovery cohort identified ten circulating miRNAs that correlated with delivered RT dose as well as other dosimetric parameters such as lung V20. In the validation cohort, miR-29a-3p and miR-150-5p were reproducibly shown to decrease with increasing radiation dose. Expression of miR-29a-3p and miR-150-5p in secreted exosomes decreased with radiation. This was concomitant with an increase in intracellular levels, suggesting that exosomal export of these miRNAs may be downregulated in both NSCLC and stromal cells in response to radiation.


CONCLUSIONS
miR-29a-3p and miR-150-5p were identified as circulating biomarkers that correlated with delivered RT dose. miR-150 has been reported to decrease in the circulation of mammals exposed to radiation while miR-29a has been associated with fibrosis in the human heart, lungs, and kidneys. One may therefore hypothesize that outlier levels of circulating miR-29a-3p and miR-150-5p may eventually help predict unexpected responses to radiation therapy, such as toxicity.
Harvard Medical School, 25 Shattuck St, Boston, MA, 02115, USA.|Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.
Tru-Khang T
TK
Dinh
Department of Biostatistics and Translational Medicine, Medical University of Łódź, Al. Kościuszki 4, 90-419, Łódź, Poland.
Wojciech
W
Fendler
Department of Radiation Oncology, Medical University of Łódź, Al. Kościuszki 4, 90-419, Łódź, Poland.
Justyna
J
Chałubińska-Fendler
Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.
Sanket S
SS
Acharya
Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.
Colin
C
O'Leary
Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.
Peter V
PV
Deraska
Harvard Medical School, 25 Shattuck St, Boston, MA, 02115, USA. alan_dandrea@dfci.harvard.edu.|Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA. alan_dandrea@dfci.harvard.edu.|Center for DNA Damage and Repair, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA. alan_dandrea@dfci.harvard.edu.
Alan D
AD
D'Andrea
Harvard Medical School, 25 Shattuck St, Boston, MA, 02115, USA. dipanjan_chowdhury@dfci.harvard.edu.|Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA. dipanjan_chowdhury@dfci.harvard.edu.
Dipanjan
D
Chowdhury
Harvard Medical School, 25 Shattuck St, Boston, MA, 02115, USA. dkozono@lroc.harvard.edu.|Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA. dkozono@lroc.harvard.edu.|Department of Radiation Oncology, Brigham and Women's Hospital, 75 Francis St, Boston, MA, 02115, USA. dkozono@lroc.harvard.edu.
David
D
Kozono
D015415:Biomarkers / Q000097:blood; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D015331:Cohort Studies; D017077:Culture Media, Conditioned / Q000737:chemistry; D015536:Down-Regulation; D055354:Exosomes / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000097:blood / Q000532:radiotherapy*; D035683:MicroRNAs / Q000097:blood*; D011874:Radiometry / Q000379:methods; D011878:Radiotherapy / Q000379:methods*
D015415:Biomarkers; D017077:Culture Media, Conditioned; D035683:MicroRNAs; C533097:MIR150, human; C532045:MIRN29a microRNA, human
Non-small cell lung cancer; Radiotherapy; Thoracic; microRNAs