br Regarding the non previously described SNP analyzed
Regarding the non-previously described SNP analyzed, the results obtained showed that patients carrying the rs7459185 CC Ethylmalonyl Coenzyme A located in HSPB1 sequence present a significantly higher risk of acute RIET while LC patient’s harboring the rs11466353 TT/ TG genotypes are associated with a higher susceptibility for late RIET development. The association between these genotypes and higher esophagitis risk resulted independent of other clinical– pathological and treatment factors although the SNP rs11466353 association did not retained statistical significance after Bonferroni correction. Interestingly, only the rs7459185 SNP showed a signif-icant association with RIET when analyzing adenocarcinoma cases and only the rs11466353 SNP showed an association with RIET for patients with squamous cell carcinoma. We acknowledge that the distribution of cases across histological subtypes in our series is not representative in the clinical setting, where there is usually much more adenocarcinoma than squamous cell carcinomas. These SNPs are within the TGFB1 and HSPB1 sequences, which are widely-known for their role in RT clinical response and have been previously subjected as radiation tolerance biomarkers [29– 31].
On one hand, TGFB1 has been well-established to be associated with radiation induced inflammation as a master switch for fibro-sis development and persistence [17,32,33]. Moreover, ionizing radiation induces TGFB1 release, and overall the literature suggests plasma TGFB1 levels for its potential value to predict toxicities in LC [34,35]. However, TGFB1 plasma measurement is challenging because of its reproducibility, whereas DNA is more stable and easily testable, giving the opportunity to individualize treatment. Thus the use of associated TGFB1 SNPs as biomarkers is notably convenient. The significant statistical association between the rs11466353 TT genotype and late esophagitis merely might be a prognostic biomarker and play an important role in the clinical outcomes of LC patients. Nonetheless, to test the rs11466353 intro-nic variant regulatory potential role in silico resulted in a struggle due to the little data available, thus the molecular mechanisms for the observed connection should be further investigated.
On the other hand, the rise of the rs7459185 CC genotype within HSPB1 gene was linked to the risk of acute grade 3 esophagitis in LC patients. Bioinformatics’ analysis showed a decrease in HSPB1 mRNA expression levels in the presence of the rs7459185 CC risk genotype. HSPB1 is also well-known for its func-tion in stress-induced cellular damage prevention and protein sta-bility, being strongly induced by different stressors, including ionizing radiation [36–38]. In this regard, high HSPB1 expression levels enhance the antioxidant capacity of ionizing radiation. Therefore, a HSPB1 down-regulation triggered by the rs7459185 C risk allele may increase cell sensitivity to RT, promoting RIET,
which may partly explain the underlying biological mechanisms of the observed associations, although this hypothesis needs to be confirmed.
In conclusion, we were able to identify genetic variants associ-ated with the development of short- and long-term side effects of RT. To our knowledge, this is the first evidence that the presence of different genotypes of both SNPs (rs7459185/rs11466353) associ-ate with acute or late RIET risk, respectively. Together with radia-tion dosimetric and other risk factors, the genetic test performed in the current analysis might be useful as biomarker in the prescrip-tion of personalized RT.
This work was supported by grants from Instituto de Salud Carlos
Conflicts of interest
Appendix A. Supplementary data
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