Matteo Canale, Alessandra Virga, Davide Angeli, Eugenio Fonzi, Letizia Gnetti, Alessandra Dubini, Gianluca Tedaldi, Milena Urbini, Giovanni Bocchialini, Elisabetta Petracci, Alberto Verlicchi, Paola Cravero, Fabrizio Citarella, Chiara Bennati, Kalliopi Andrikou, Angelo Delmonte, Lucio Crinò, Paolo Carbognani, Paola Ulivi, Luca Ampollini
{"title":"吸烟者和非吸烟者肺鳞状细胞癌患者的基因组和转录组学特征。","authors":"Matteo Canale, Alessandra Virga, Davide Angeli, Eugenio Fonzi, Letizia Gnetti, Alessandra Dubini, Gianluca Tedaldi, Milena Urbini, Giovanni Bocchialini, Elisabetta Petracci, Alberto Verlicchi, Paola Cravero, Fabrizio Citarella, Chiara Bennati, Kalliopi Andrikou, Angelo Delmonte, Lucio Crinò, Paolo Carbognani, Paola Ulivi, Luca Ampollini","doi":"10.2147/LCTT.S517580","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Lung Squamous Cell Carcinoma (SCC) is a Non-Small Cell Lung Cancer (NSCLC) subtype with a strong clinical association with smoking habits and a very low incidence in never-smokers. Molecular profiling of SCC in never-smokers could unveil tumor vulnerabilities and new treatment strategies.</p><p><strong>Patients and methods: </strong>We considered a patient cohort of 17 former or current smokers (51.5%) and 16 never-smoker SCC patients (48.5%). TruSight Oncology<sup>®</sup> 500, investigating hotspots in 523 cancer-related genes, Tumor mutation burden (TMB) and microsatellite instability (MSI), and RNA sequencing was performed on tumor tissue. Genomic and transcriptomic profiles were compared between smokers and never-smoker patients.</p><p><strong>Results: </strong>The most frequently altered genes were <i>TP53</i> (67%), <i>CDKN2A</i> (20%) and <i>PIK3CA</i> (17%), with no substantial differences between groups, except for <i>TP53</i> which was more frequently mutated in smokers (86.7% vs 46.7%, p = 0.05), who also showed a higher TMB with respect to non-smokers (median 11 mut/Mb vs 5.5 mut/Mb, p = 0.028); all patients were stable for MSI score (median 1.87 vs 1.82, p = 0.87). Activating mutations in <i>EGFR</i> and <i>MET</i> were found in one and two never-smokers, respectively. Three smoker patients had simultaneous amplifications in <i>FGF3, FGF19</i> and <i>FGF4</i>. Enrichment analyses showed that cyclin-dependent protein Ser/Thr kinase activity and PI3K signaling pathways were affected in both groups, while cellular damage response was exclusively altered in never-smokers. Unsupervised hierarchical clustering on transcriptomes effectively identified different specific transcriptional subtypes between smokers and never-smokers. Gene set enrichment analysis highlighted that tumors from never-smokers are characterized by dysregulation in cell membrane potential and ion homeostasis across cell membrane pathways.</p><p><strong>Conclusion: </strong>Genomic and transcriptomic profiles deeply differentiate SCC occurring in never-smokers with respect to SCC in smoker patients. Moreover, SCC could carry canonical NSCLC) activating mutations. Our data suggest that deep molecular analyses resolve tumor heterogeneity and may help with new algorithm-based treatment strategies for SCC.</p>","PeriodicalId":18066,"journal":{"name":"Lung Cancer: Targets and Therapy","volume":"16 ","pages":"85-96"},"PeriodicalIF":3.3000,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12223270/pdf/","citationCount":"0","resultStr":"{\"title\":\"Genomic and Transcriptomic Profiles in Smokers and Never-Smokers Lung Squamous Cell Carcinoma Patients.\",\"authors\":\"Matteo Canale, Alessandra Virga, Davide Angeli, Eugenio Fonzi, Letizia Gnetti, Alessandra Dubini, Gianluca Tedaldi, Milena Urbini, Giovanni Bocchialini, Elisabetta Petracci, Alberto Verlicchi, Paola Cravero, Fabrizio Citarella, Chiara Bennati, Kalliopi Andrikou, Angelo Delmonte, Lucio Crinò, Paolo Carbognani, Paola Ulivi, Luca Ampollini\",\"doi\":\"10.2147/LCTT.S517580\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>Lung Squamous Cell Carcinoma (SCC) is a Non-Small Cell Lung Cancer (NSCLC) subtype with a strong clinical association with smoking habits and a very low incidence in never-smokers. Molecular profiling of SCC in never-smokers could unveil tumor vulnerabilities and new treatment strategies.</p><p><strong>Patients and methods: </strong>We considered a patient cohort of 17 former or current smokers (51.5%) and 16 never-smoker SCC patients (48.5%). TruSight Oncology<sup>®</sup> 500, investigating hotspots in 523 cancer-related genes, Tumor mutation burden (TMB) and microsatellite instability (MSI), and RNA sequencing was performed on tumor tissue. Genomic and transcriptomic profiles were compared between smokers and never-smoker patients.</p><p><strong>Results: </strong>The most frequently altered genes were <i>TP53</i> (67%), <i>CDKN2A</i> (20%) and <i>PIK3CA</i> (17%), with no substantial differences between groups, except for <i>TP53</i> which was more frequently mutated in smokers (86.7% vs 46.7%, p = 0.05), who also showed a higher TMB with respect to non-smokers (median 11 mut/Mb vs 5.5 mut/Mb, p = 0.028); all patients were stable for MSI score (median 1.87 vs 1.82, p = 0.87). Activating mutations in <i>EGFR</i> and <i>MET</i> were found in one and two never-smokers, respectively. Three smoker patients had simultaneous amplifications in <i>FGF3, FGF19</i> and <i>FGF4</i>. Enrichment analyses showed that cyclin-dependent protein Ser/Thr kinase activity and PI3K signaling pathways were affected in both groups, while cellular damage response was exclusively altered in never-smokers. Unsupervised hierarchical clustering on transcriptomes effectively identified different specific transcriptional subtypes between smokers and never-smokers. Gene set enrichment analysis highlighted that tumors from never-smokers are characterized by dysregulation in cell membrane potential and ion homeostasis across cell membrane pathways.</p><p><strong>Conclusion: </strong>Genomic and transcriptomic profiles deeply differentiate SCC occurring in never-smokers with respect to SCC in smoker patients. Moreover, SCC could carry canonical NSCLC) activating mutations. Our data suggest that deep molecular analyses resolve tumor heterogeneity and may help with new algorithm-based treatment strategies for SCC.</p>\",\"PeriodicalId\":18066,\"journal\":{\"name\":\"Lung Cancer: Targets and Therapy\",\"volume\":\"16 \",\"pages\":\"85-96\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2025-06-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12223270/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Lung Cancer: Targets and Therapy\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.2147/LCTT.S517580\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Lung Cancer: Targets and Therapy","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2147/LCTT.S517580","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
目的:肺鳞状细胞癌(SCC)是一种非小细胞肺癌(NSCLC)亚型,临床与吸烟习惯密切相关,在不吸烟者中发病率极低。从不吸烟的SCC分子谱分析可以揭示肿瘤的脆弱性和新的治疗策略。患者和方法:我们纳入了17例既往或当前吸烟者(51.5%)和16例从不吸烟者(48.5%)的患者队列。TruSight Oncology®500,研究523个癌症相关基因的热点,肿瘤突变负荷(Tumor mutation burden, TMB)和微卫星不稳定性(microsatellite instability, MSI),并对肿瘤组织进行RNA测序。比较了吸烟者和不吸烟者的基因组和转录组谱。结果:TP53(67%)、CDKN2A(20%)和PIK3CA(17%)是最常发生突变的基因,两组间无显著差异,除了TP53在吸烟者中更常发生突变(86.7% vs 46.7%, p = 0.05), TP53在非吸烟者中也表现出更高的TMB(中位数11 mut/Mb vs 5.5 mut/Mb, p = 0.028);所有患者的MSI评分均稳定(中位数1.87 vs 1.82, p = 0.87)。在一名和两名不吸烟者中分别发现了EGFR和MET的激活突变。3例吸烟者同时出现FGF3、FGF19和FGF4基因扩增。富集分析显示,两组细胞周期蛋白依赖蛋白Ser/Thr激酶活性和PI3K信号通路均受到影响,而细胞损伤反应仅在不吸烟者中发生改变。转录组的无监督分层聚类有效地识别了吸烟者和不吸烟者之间不同的特定转录亚型。基因集富集分析强调,从不吸烟者的肿瘤具有细胞膜电位和跨细胞膜途径离子稳态失调的特征。结论:相对于吸烟者的SCC,不吸烟者的SCC在基因组和转录组学上有很大的区别。此外,SCC可能携带典型NSCLC激活突变。我们的数据表明,深入的分子分析可以解决肿瘤的异质性,并可能有助于新的基于算法的SCC治疗策略。
Genomic and Transcriptomic Profiles in Smokers and Never-Smokers Lung Squamous Cell Carcinoma Patients.
Purpose: Lung Squamous Cell Carcinoma (SCC) is a Non-Small Cell Lung Cancer (NSCLC) subtype with a strong clinical association with smoking habits and a very low incidence in never-smokers. Molecular profiling of SCC in never-smokers could unveil tumor vulnerabilities and new treatment strategies.
Patients and methods: We considered a patient cohort of 17 former or current smokers (51.5%) and 16 never-smoker SCC patients (48.5%). TruSight Oncology® 500, investigating hotspots in 523 cancer-related genes, Tumor mutation burden (TMB) and microsatellite instability (MSI), and RNA sequencing was performed on tumor tissue. Genomic and transcriptomic profiles were compared between smokers and never-smoker patients.
Results: The most frequently altered genes were TP53 (67%), CDKN2A (20%) and PIK3CA (17%), with no substantial differences between groups, except for TP53 which was more frequently mutated in smokers (86.7% vs 46.7%, p = 0.05), who also showed a higher TMB with respect to non-smokers (median 11 mut/Mb vs 5.5 mut/Mb, p = 0.028); all patients were stable for MSI score (median 1.87 vs 1.82, p = 0.87). Activating mutations in EGFR and MET were found in one and two never-smokers, respectively. Three smoker patients had simultaneous amplifications in FGF3, FGF19 and FGF4. Enrichment analyses showed that cyclin-dependent protein Ser/Thr kinase activity and PI3K signaling pathways were affected in both groups, while cellular damage response was exclusively altered in never-smokers. Unsupervised hierarchical clustering on transcriptomes effectively identified different specific transcriptional subtypes between smokers and never-smokers. Gene set enrichment analysis highlighted that tumors from never-smokers are characterized by dysregulation in cell membrane potential and ion homeostasis across cell membrane pathways.
Conclusion: Genomic and transcriptomic profiles deeply differentiate SCC occurring in never-smokers with respect to SCC in smoker patients. Moreover, SCC could carry canonical NSCLC) activating mutations. Our data suggest that deep molecular analyses resolve tumor heterogeneity and may help with new algorithm-based treatment strategies for SCC.