1260 - ADH1A rs7654607: A Key Variant for Paclitaxel-Aggravated Radiation Pneumonitis in Esophageal Cancer Chemoradiotherapy

10:55am - 11:00am ET

Room 156

Presenter(s)

Yun Chen, MD - Fudan University Shanghai Cancer Center, Shanghai, Shanghai

Y. Chen¹, R. Zhang², T. Tang¹, and K. Zhao¹; ¹Fudan University Shanghai Cancer Center, Shanghai, China, ²Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China

Purpose/Objective(s):

The ESO-Shanghai 1 Trial demonstrated that paclitaxel-based chemoradiotherapy significantly increases the risk of severe radiation pneumonitis (RP) in esophageal cancer patients compared to cisplatin-based regimens. This underscores the urgent need to uncover the genetic factors driving this susceptibility.

Materials/Methods:

We conducted a two-phase genetic study. In the first phase, a pathway-focused GWAS was performed using samples from the ESO-Shanghai 1 trial cohort. SNPs within drug metabolism pathway genes were extracted from genome-wide chip data (Illumina GSA) and imputed. Associations with severe RP (=Grade 2, CTCAE v4.0) were analyzed in all patients and within chemotherapy subgroups (paclitaxel vs. non-paclitaxel). In the second phase, top SNPs were validated in an independent cohort of esophageal squamous cell carcinoma patients (2012-2015) who received definitive chemoradiotherapy, meeting strict clinical and biospecimen criteria. Mechanistic studies included in silico regulatory analyses (ENCODE, HaploReg, JASPAR), allele-specific dual-luciferase reporter assays, EMSA for transcription factor binding, CRISPR/Cas9-mediated gene overexpression in lung epithelial cells (BEAS-2B, A549) with clonogenic survival assays, and in vivo validation using a transgenic mouse model.

Results:

The pathway-focused GWAS identified rs7654607 as a top candidate SNP, showing a strong association with Grade =2 RP specifically in paclitaxel-treated patients (T allele carriers vs. CC: OR=5.62, p<0.001; no association in non-paclitaxel arm). This SNP maps to an intergenic region near ADH1A. Validation in an independent cohort confirmed the association (T allele carriers vs. CC: OR=2.42, p=0.021; no association in non-paclitaxel arm). Functional studies revealed that the T allele increases enhancer activity and alters HOXA5 binding affinity (confirmed by EMSA). Overexpression of ADH1A synergized with paclitaxel to significantly increase radiation-induced damage in lung epithelial cells. In vivo, ADH1A-overexpressing mice developed exacerbated pulmonary inflammation after combined radiation and paclitaxel treatment.

Conclusion:

Our study identifies rs7654607 as a functional variant predisposing to paclitaxel-aggravated RP by regulating ADH1A, likely via allele-specific HOXA5 regulation. This SNP has significant potential as a predictive biomarker for personalizing chemoradiotherapy, reducing severe pulmonary toxicity in esophageal cancer patients.