Beyond tobacco: genomic disparities in lung cancer between smokers and never-smokers

Tobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10-20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smoke...

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Published in:	BMC cancer Vol. 24; no. 1; pp. 951 - 15
Main Authors:	Garrido, Javiera, Bernal, Yanara, González, Evelin, Blanco, Alejandro, Sepúlveda-Hermosilla, Gonzalo, Freire, Matías, Oróstica, Karen, Rivas, Solange, Marcelain, Katherine, Owen, Gareth, Ibañez, Carolina, Corvalan, Alejandro, Garrido, Marcelo, Assar, Rodrigo, Lizana, Rodrigo, Cáceres-Molina, Javier, Ampuero, Diego, Ramos, Liliana, Pérez, Paola, Aren, Osvaldo, Chernilo, Sara, Fernández, Cristina, Spencer, María Loreto, Aguila, Jacqueline Flores, Dossetto, Giuliano Bernal, Olea, Mónica Ahumada, Rasse, Germán, Sánchez, Carolina, de Amorim, Maria Galli, Bartelli, Thais F, Nunes, Diana Noronha, Dias-Neto, Emmanuel, Freitas, Helano C, Armisén, Ricardo
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 03-08-2024 BioMed Central BMC
Subjects:	Adenocarcinoma Adult Aged Analysis Carcinoma, Non-Small-Cell Lung - epidemiology Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - pathology Chilean Diagnosis EGFR mutation Epidermal growth factor receptors ErbB-2 protein Female Gene frequency Gene mutations Genes Genetic aspects Genetic variation Genomics Genomics - methods Health aspects Humans K-Ras protein KRAS Latin American populations Lung Adenocarcinoma Lung cancer Lung Neoplasms - epidemiology Lung Neoplasms - etiology Lung Neoplasms - genetics Male Malignancy Middle Aged Mortality Mutation Non-small cell lung carcinoma Non-Smokers - statistics & numerical data Passive smoking Risk factors Small cell lung carcinoma Smokers Smokers - statistics & numerical data Smoking Smoking - adverse effects Smoking - epidemiology Smoking - genetics Tobacco Tobacco consumption Tobacco smoke Tumors Chile EGFR mutation Lung Adenocarcinoma MAP2K1 Cancer disparities Chilean KRAS Tobacco consumption Latin American populations
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Summary:	Tobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10-20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smokers and never-smokers. For example, the Lung Adenocarcinoma (LUAD) histological subtype in never-smokers is predominately found in young women of European, North American, and Asian descent. While the clinical presentation and tumor genomic profiles of smokers have been widely examined, never-smokers are usually underrepresented, especially those of a Latin American (LA) background. In this work, we characterize, for the first time, the difference in the genomic profiles between smokers and never-smokers LC patients from Chile. We conduct a comparison by smoking status in the frequencies of genomic alterations (GAs) including somatic mutations and structural variants (fusions) in a total of 10 clinically relevant genes, including the eight most common actionable genes for LC (EGFR, KRAS, ALK, MET, BRAF, RET, ERBB2, and ROS1) and two established driver genes for malignancies other than LC (PIK3CA and MAP2K1). Study participants were grouped as either smokers (current and former, n = 473) or never-smokers (n = 200) according to self-report tobacco use at enrollment. Our findings indicate a higher overall GA frequency for never-smokers compared to smokers (58 vs. 45.7, p-value < 0.01) with the genes EGFR, KRAS, and PIK3CA displaying the highest prevalence while ERBB2, RET, and ROS1 the lowest. Never-smokers present higher frequencies in seven out of the 10 genes; however, smokers harbor a more complex genomic profile. The clearest differences between groups are seen for EGFR (15.6 vs. 21.5, p-value: < 0.01), PIK3CA (6.8 vs 9.5) and ALK (3.2 vs 7.5) in favor of never-smokers, and KRAS (16.3 vs. 11.5) and MAP2K1 (6.6 vs. 3.5) in favor of smokers. Alterations in these genes are comprised almost exclusively by somatic mutations in EGFR and mainly by fusions in ALK, and only by mutations in PIK3CA, KRAS and MAP2K1. We found clear differences in the genomic landscape by smoking status in LUAD patients from Chile, with potential implications for clinical management in these limited-resource settings.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1471-2407 1471-2407
DOI:	10.1186/s12885-024-12737-1