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Clinical Outcome-Related Cancer Pathways and Mutational Signatures in Patients With Unresectable Esophageal Squamous Cell Carcinoma Treated With Chemoradiotherapy

医学 危险系数 放化疗 肿瘤科 内科学 食管癌 癌症研究 置信区间 癌症
作者
Li Li,Jujie Sun,Ning Liu,Ruoying Yu,Junli Zhang,Jiaohui Pang,Qiuxiang Ou,Ying Yin,Jinfeng Cui,Xuling Yao,Ranran Zhao,Yang Shao,Shuanghu Yuan,Jin-Ming Yu
出处
期刊:International Journal of Radiation Oncology Biology Physics [Elsevier]
卷期号:115 (2): 382-394 被引量:8
标识
DOI:10.1016/j.ijrobp.2022.07.1835
摘要

Definitive chemoradiotherapy (dCRT) is a standard-of-care for locally advanced unresectable esophageal squamous cell carcinoma (ESCC). However, even in individuals treated with the same dCRT regimen, differences in the local control rate and radiation-induced thoracic toxicity exist (radiation-induced esophagitis [RIE]).Here, we describe a comprehensive genomic evaluation of pretreatment tumor tissue samples from 183 patients with ESCC using targeted sequencing of 474 cancer-related genes. The association between endpoints (progression-free survival [PFS], overall survival, locoregional relapse-free survival, distant metastasis-free survival), toxicity (RIE) and genomic features, including altered pathways and the mutational signature, was analyzed. An independent cohort of 84 stage II-III patients with ESCC was used for validation.Gene alterations in the cell cycle pathway were identified in 87% of cases. Other frequently altered pathways included PI3K-AKT (45.9%), NOTCH (38.3%), NRF2 (36.6%), RKT-RAS (28.4%), and homologous recombination repair (HRR; 20.2%). HRR pathway alterations correlated with shortened PFS (mutation vs wild-type: 9.00 vs 14.40 months, hazard ratio, 2.10; 95% confidence interval, 1.29-3.44), while altered RTK-RAS pathways were correlated with worse overall survival in patients with ESCC treated with chemoradiotherapy (mutation vs wild-type: 23.70 vs 33.50 months; hazard ratio, 1.65; 95% confidence interval, 1.01-2.69). Furthermore, enrichment of apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) signatures (signatures 2 and 13) was identified in ESCC tumors with altered HRR pathways. High APOBEC signatures and an altered HRR pathway were correlated with poor prognoses in dCRT-treated ESCC. Moreover, the APOBEC signature and/or the presence of HRR pathway alterations were associated with poor PFS and overall survival, which was validated in an independent whole exome sequence cohort. Notably, the altered HRR pathway was also associated with high-grade RIE toxicity in patients with ESCC.Collectively, our results support the use of comprehensive genomic profiling to guide treatment and minimize RIE in patients with ESCC.
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