br SNPs associated with esophagitis in lung
166 SNPs associated with esophagitis in lung cancer
Multivariate analysis using a Cox regression model with a stepwise backward elimination procedure of factors associated with acute and late esophagitis.
Parameter Acute esophagitis
No. of cigarettes per day
No. of packs yearsa
Radiation total dose, Gy
Abbreviations: KPS, Karnofsky Performance Status; V(x), volume of normal esophagus receiving Gy or more radiation.
Bold value indicates a statistically significant difference with a p-value less than 0.05 a Number of pack years = (packs smoked per day) (years as a smoker).
Fig. 1. Kaplan–Meier curve for acute grade 3 and late grade 2 radiation-induced esophagitis in lung cancer patients carrying different rs7459185 and rs11466353 genotypes.
a significantly lower RIET incidence (p < 0.001) compared with patients carrying the CC genotype.
Fig. 2. Kaplan–Meier curve for: (A) the effect of the rs7459185 genotypes in lung cancer patients receiving high (>median) V30 on the cumulative incidence of acute grade 3 radiation-induced esophagitis; and (B) the effect of the rs11466353 genotypes in lung cancer patients receiving high (>median) radiation doses on the cumulative incidence of late grade 2 radiation-induced esophagitis.
Fig. 3. Expression quantitative trait loci analysis of HSPB1 in the presence of the three different rs7459185 genotypes using data from the Genotype-Tissue Expression project.
(2/91) and 3% (2/78), respectively, in patients with rs11466353 GG genotype. For those cases with small-cell carcinoma (N = 57), there was not any statistical significant association. The SNP rs7459185 is a downstream gene variant located in the chromosomal position chr7:76305323 (Supplementary Fig. 1). To provide biologically plausible support to the association and the prediction obtained, rs7459185 different genotypes and HSPB1 mRNA expression patterns were evaluated by expression quantita-tive trait loci analysis using lung tissue and blood GW-311616 expression data from the Genotype-Tissue Expression Database. The results showed a decrease in the HSPB1 mRNA expression levels in the presence of the rs7459185 CC genotype; while there were no evi-dent changes between HSPB1 mRNA expression levels between different genotypes in case of lung tissue (Fig. 3).
Over half of all LC patients are currently treated with RT; how-ever the treatment is sometimes severely limited by the need to constrain the dose to the surrounding normal tissues in order to preserve their function. Esophageal toxicity caused by RT is a real and potentially debilitating toxicity which is estimated to be mainly caused by patient-related factors.
In the present study, half of patients suffered from acute esophagitis grade 2 or 3, which implies a complication that may require invasive treatments and delay the systemic therapies, despite a relatively homogeneous treatment. This common event has been previously explained as a result of the general concomi-tant platinum-based chemotherapy used in LC treatment due to radio-sensitizing nature of these agents [25–27]. Concurrent chemoradiation was associated with grade 2 acute esophagitis in univariate analysis but not for grade 3, much more severe and life-threatening in some cases, requiring enteral or parenteral nutrition. Therefore, concurrent chemoradiotherapy might not answer the more severe cases of toxicity nor explain the variability of the normal tissue response.
Alternatively, dosimetric factors such as the volume of the esophagus in percentage that receives a certain irradiation dose (Gy) as well as esophagus delineation might be suitable predictive dosimetric factors for esophagitis. Escalating the radiation therapy dose seems to increase toxicity risk development, especially when chemotherapy is concomitantly administered. Higher radiation therapy doses with concurrent chemotherapy result in poorer sur-vival, partially due to the high levels of toxicity, which suggests that the optimal radiation dose has yet to be reached .
As a non-invasive alternative for molecular diagnosis and treat-ment monitoring we propose the association study between 7
168 SNPs associated with esophagitis in lung cancer
SNPs, 2 previously described to be linked to RIET risk development (rs1800469 and rs2868371). Firstly, we did not find evidence of associations between the rs1800469, and rs2868371 in our cohort. The connection between the rs1800469 GA/AA genotypes was tested in early-grade RIET in a Chinese population , and next confirmed in an American study which also associated the pres-ence of those genotypes with grade 3 toxicity . Marked differ-ences in cancer occurrence and treatment response may be markers of differences in genetic susceptibility. The SNP distribu-tion is well known to differ among ethnicities and somehow poly-morphic alleles can be under negative or positive selection in a population. The rs1800469 genotyping distribution is substantially different compared to the one found in our population. Relating to rs2868371, a previous American study linked a higher risk of grade 3 RIET with homozygosis for the most common allele C , with a very similar genotyping distribution compared to ours. Neverthe-less, ethnic background should be carefully considered and some bias might affect those previous results owing to the small size and single-institution population analyzed.