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Genomic and evolutionary classification of lung cancer in never smokers.

ABSTRACT: Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but its genomic landscape is poorly characterized. Here high-coverage whole-genome sequencing of 232 LCINS showed 3 subtypes defined by copy number aberrations. The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and slow growth, as suggested by the occurrence of cancer drivers' progenitor cells many years before tumor diagnosis. The other subtypes are characterized by specific amplifications and EGFR mutations (mezzo-forte) and whole-genome doubling (forte). No strong tobacco smoking signatures were detected, even in cases with exposure to secondhand tobacco smoke. Genes within the receptor tyrosine kinase-Ras pathway had distinct impacts on survival; five genomic alterations independently doubled mortality. These findings create avenues for personalized treatment in LCINS.

SUBMITTER: Zhang T

PROVIDER: S-EPMC8432745 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Genomic and evolutionary classification of lung cancer in never smokers.

Zhang Tongwu T Joubert Philippe P Ansari-Pour Naser N Zhao Wei W Hoang Phuc H PH Lokanga Rachel R Moye Aaron L AL Rosenbaum Jennifer J Gonzalez-Perez Abel A Martínez-Jiménez Francisco F Castro Andrea A Muscarella Lucia Anna LA Hofman Paul P Consonni Dario D Pesatori Angela C AC Kebede Michael M Li Mengying M Gould Rothberg Bonnie E BE Peneva Iliana I Schabath Matthew B MB Poeta Maria Luana ML Costantini Manuela M Hirsch Daniela D Heselmeyer-Haddad Kerstin K Hutchinson Amy A Olanich Mary M Lawrence Scott M SM Lenz Petra P Duggan Maire M Bhawsar Praphulla M S PMS Sang Jian J Sang Jian J Kim Jung J Mendoza Laura L Saini Natalie N Klimczak Leszek J LJ Islam S M Ashiqul SMA Otlu Burcak B Khandekar Azhar A Cole Nathan N Stewart Douglas R DR Choi Jiyeon J Brown Kevin M KM Caporaso Neil E NE Wilson Samuel H SH Pommier Yves Y Lan Qing Q Rothman Nathaniel N Almeida Jonas S JS Carter Hannah H Ried Thomas T Kim Carla F CF Lopez-Bigas Nuria N Garcia-Closas Montserrat M Shi Jianxin J Bossé Yohan Y Zhu Bin B Gordenin Dmitry A DA Alexandrov Ludmil B LB Chanock Stephen J SJ Wedge David C DC Landi Maria Teresa MT

Nature genetics 20210906 9

Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but its genomic landscape is poorly characterized. Here high-coverage whole-genome sequencing of 232 LCINS showed 3 subtypes defined by copy number aberrations. The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and ...[more]

PMID: 34493867

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Project description:BackgroundTobacco 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.MethodsWe 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.ResultsOur 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.ConclusionsWe 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.

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Genomic and evolutionary classification of lung cancer in never smokers.

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Genomic and evolutionary classification of lung cancer in never smokers.

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