| 摘要: |
| ［摘要］ 目的 基于基因组图谱筛选与非小细胞肺癌（NSCLC）放化疗（CRT）疗效和胸部放射性毒性相关的生物标志物。方法 招募2022年3月至2024年3月在湖北省肿瘤医院接受CRT的NSCLC患者55例。于根治性CRT（dCRT）前后采集血清样本，提取细胞游离DNAs（cfDNAs）进行全外显子组测序（WES）。计算肿瘤突变负荷（TMB）和肿瘤分数（TF）。采用液滴数字聚合酶链反应（ddPCR）评估突变等位基因频率。对患者进行随访，记录放射性损伤和疾病进展情况。结果 共有110个cfDNAs配对样本接受了WES。患者dCRT前后平均TF分别为36.30%和50.30%。体细胞单核苷酸变异数与TF、肿瘤直径呈正相关（r=0.257，P=0.033；r=0.274，P=0.025）。WES与ddPCR的变异等位基因频率相关性良好（r=0.971，P<0.001）。本组28例患者接受同步dCRT，其余27例接受序贯dCRT。治疗期间有21例（38.18%）患者出现≥2级毒性反应，包括17例放射性肺炎、6例放射性食管炎。截至2025年1月2日，本组病例中位随访时间为19.6个月（9.0～36.5个月），剔除5例放弃原方案治疗或失访患者后共有50例患者纳入预后分析。38例患者出现疾病进展，最终18例（36.00%）患者因癌症死亡。多因素Cox回归分析结果显示，有吸烟史［HR（95%CI）=2.265（1.019～4.601），P=0.036］、ATM基因突变［HR（95%CI）=2.074（1.004～4.351），P=0.042］、KEAP1基因突变［HR（95%CI）=2.585（1.083～5.425），P=0.014］和MLL2基因突变［HR（95%CI）=3.202（1.272～9.851），P=0.011］是影响NSCLC患者dCRT后无疾病生存期的独立危险因素。ZNF217基因扩增［HR（95%CI）=5.325（1.098～25.827），P=0.038］和POLD1基因突变［HR（95%CI）=9.756（1.670～57.008），P=0.011］是≥2级胸部放射性损伤发生的独立危险因素。结论 ATM基因、KEAP1基因和MLL2基因突变是影响NSCLC患者dCRT后无进展生存期的遗传特征，而ZNF217基因扩增和POLD1基因突变与放射学毒性具有关联性。 |
| 关键词: 非小细胞肺癌 基因组图谱 放化疗 放射性毒性 疗效 |
| DOI：10.3969/j.issn.1674-3806.2026.04.08 |
| 分类号:R 734.2 |
| 基金项目:湖北省自然科学基金面上项目（编号：2022CFB078） |
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| Screening biomarkers related to the efficacy and thoracic radiological toxicity of chemoradiotherapy in non-small cell lung cancer based on genomic maps |
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LIU Yuanxiang1, WANG Huabin1, LIANG Gai2, XIANG Zhengkai1
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1.Department of Thoracic Surgery/Bone and Soft Tissue Surgery, Hubei Cancer Hospital, Wuhan 430079, China; 2.Radiotherapy Center, Hubei Cancer Hospital, Wuhan 430079, China
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| Abstract: |
| ［Abstract］ Objective To screen biomarkers related to the efficacy and thoracic radiological toxicity of chemoradiotherapy(CRT) in non-small cell lung cancer(NSCLC) based on genomic maps. Methods A total of 55 patients with NSCLC who received CRT in Hubei Cancer Hospital from March 2022 to March 2024 were recruited. The serum samples of the patients were collected before and after definitive CRT(dCRT), and cell-free deoxyribonucleic acids(cfDNAs) were extracted for whole exome sequencing(WES). Tumor mutational burden(TMB) and tumor fraction(TF) were calculated. Droplet digital polymerase chain reaction(ddPCR) was used to evaluate the frequencies of mutant alleles. The patients were followed up and their radiation injuries and disease progression were recorded. Results WES was performed on a total of 110 paired cfDNAs samples in the NSCLC patients, with an average TF of 36.30% before dCRT and 50.30% after dCRT. Somatic single nucleotide variations were positively correlated with TF and tumor diameter(r=0.257, P=0.033; r=0.274, P=0.025). WES showed a strong correlation with variant allele frequencies measured by ddPCR(r=0.971, P<0.001).There were 28 patients receiving concurrent dCRT and 27 patients receiving sequential dCRT in this study. During the treatment, 21 patients(38.18%) experienced toxic reactions ≥grade 2, including 17 cases of radiation pneumonitis and 6 cases of radiation esophagitis. Up to January 2, 2025, the median follow-up time for the patients in this study was 19.6 months(9.0-36.5 months). After excluding 5 patients who abandoned the original treatment plan or were lost to follow-up, a total of 50 patients were included in the prognosis analysis. Thirty-eight patients experienced disease progression, and ultimately 18 patients(36.00%) died due to cancer. The multivariate Cox regression analysis showed that smoking history［HR(95%CI)=2.265(1.019-4.601), P=0.036］, ATM gene mutation［HR(95%CI)=2.074(1.004-4.351), P=0.042］, KEAP1 gene mutation［HR(95%CI)=2.585(1.083-5.425), P=0.014］, and MLL2 gene mutation［HR(95%CI)=3.202(1.272-9.851), P=0.011］ were independent risk factors affecting the disease-free survival of NSCLC patients after dCRT. ZNF217 gene amplification［HR(95%CI)=5.325(1.098-25.827), P=0.038］ and POLD1 gene mutation［HR(95%CI)=9.756(1.670-57.008), P=0.011］ were the independent risk factors of developing chest radiation injuries ≥grade 2. Conclusion ATM, KEAP1 and MLL2 gene mutations are the genetic features that affect progression-free survival in NSCLC patients after dCRT, while ZNF217 gene amplification and POLD1 gene mutation are associated with radiological toxicity. |
| Key words: Non-small cell lung cancer(NSCLC) Genomic maps Chemoradiotherapy Radiological toxicity Efficacy |
