Background/Objectives: Lung cancer (LC) remains one of the most lethal malignancies worldwide, with both environmental and occupational exposures contributing to its incidence. While oncogene-addicted tumors—defined by single driver mutations—have garnered attention due to their therapeutic implications, less is known about the mutational landscape of tumors potentially arising from occupational exposure to carcinogens. This real-life observational study aimed to assess whether previous occupational exposure to lung carcinogens correlates with distinct LC phenotypes, particularly non-oncogene-addicted (nOA) profiles.Methods: A total of 199 LC patients were enrolled across two specialized oncology centers in Northern Italy between 2021 and 2023. Each participant underwent detailed occupational history taking and molecular characterization using next-generation sequencing. Patients were stratified into nonexposed (NE), low exposed (LE), and high exposed (HE) to carcinogens for lung based on standardized questionnaires and sector-specific assessments.Results: No significant differences were found in histological subtypes across exposure groups. However, people with adenocarcinoma and high occupational exposure to lung carcinogens were more frequently characterized by a nOA phenotype compared to those with low occupational exposure. Logistic regression models—adjusted for age, sex, and smoking habits—confirmed that HE patients had a significantly higher likelihood of developing nOA tumors (OR = 3.07; 95% CI: 1.16–8.11;p= 0.023). This association persisted after adjusting for smoking habits Exposures occurring 5–10 years before diagnosis seemed to be associated with an increased nOA profile.Conclusions: These findings suggest that high levels of exposure to occupational carcinogens impact LC phenotypes. Indeed, these phenotypes are more complex to treat and show the worst prognosis. Assessing the occupational exposure to lung carcinogens during work may offer prognostic insights and support the request for more adequate compensation for the patients. Further studies are warranted to validate these results and to explain the mechanisms that produce the differences observed in LC phenotypes in people with high exposure to occupational carcinogens.
**背景/目的：** 肺癌仍是全球致死率最高的恶性肿瘤之一，其发病与环境及职业暴露均有关联。尽管由单一驱动基因突变定义的"癌基因成瘾性"肿瘤因其治疗意义而备受关注，但对于可能由职业性致癌物暴露引发的肿瘤，其突变谱特征尚不明确。本项真实世界观察性研究旨在评估既往职业性肺癌致癌物暴露是否与特定的肺癌表型相关，尤其是非癌基因成瘾性表型。 **方法：** 2021年至2023年间，在意大利北部的两家肿瘤专科中心共纳入199名肺癌患者。每位参与者均接受了详细的职业史采集，并使用二代测序技术进行分子特征分析。根据标准化问卷和特定行业评估，将患者按肺癌致癌物暴露程度分为无暴露组、低暴露组和高暴露组。 **结果：** 不同暴露组间的组织学亚型未见显著差异。然而，与低职业暴露者相比，患有腺癌且职业性肺癌致癌物高暴露的患者更频繁地表现为非癌基因成瘾性表型。经年龄、性别和吸烟习惯校正后的逻辑回归模型证实，高暴露患者发生非癌基因成瘾性肿瘤的可能性显著更高（比值比 = 3.07；95% 置信区间：1.16–8.11；p = 0.023）。即使在调整吸烟习惯后，此关联依然存在。诊断前5-10年发生的暴露似乎与非癌基因成瘾性表型增加相关。 **结论：** 这些发现表明，高水平的职业性致癌物暴露会影响肺癌表型。事实上，这些表型治疗更为复杂，且预后最差。评估工作期间肺癌致癌物的职业暴露情况，可提供预后信息，并支持为患者争取更合理的补偿。需要进一步的研究来验证这些结果，并解释职业致癌物高暴露人群肺癌表型差异的产生机制。
肿瘤(癌症)患者之家