Genomic and evolutionary classification of lung cancer in never smokers

• Published in: Nature genetics Vol. 53; no. 9; pp. 1348 - 1359
• Main Authors: Zhang, Tongwu, Joubert, Philippe, Ansari-Pour, Naser, Zhao, Wei, Hoang, Phuc H., Lokanga, Rachel, Moye, Aaron L., Rosenbaum, Jennifer, Gonzalez-Perez, Abel, Martínez-Jiménez, Francisco, Castro, Andrea, Muscarella, Lucia Anna, Hofman, Paul, Consonni, Dario, Pesatori, Angela C., Kebede, Michael, Li, Mengying, Gould Rothberg, Bonnie E., Peneva, Iliana, Schabath, Matthew B., Poeta, Maria Luana, Costantini, Manuela, Hirsch, Daniela, Heselmeyer-Haddad, Kerstin, Hutchinson, Amy, Olanich, Mary, Lawrence, Scott M., Lenz, Petra, Duggan, Maire, Bhawsar, Praphulla M. S., Sang, Jian, Kim, Jung, Mendoza, Laura, Saini, Natalie, Klimczak, Leszek J., Islam, S. M. Ashiqul, Otlu, Burcak, Khandekar, Azhar, Cole, Nathan, Stewart, Douglas R., Choi, Jiyeon, Brown, Kevin M., Caporaso, Neil E., Wilson, Samuel H., Pommier, Yves, Lan, Qing, Rothman, Nathaniel, Almeida, Jonas S., Carter, Hannah, Ried, Thomas, Kim, Carla F., Lopez-Bigas, Nuria, Garcia-Closas, Montserrat, Shi, Jianxin, Bossé, Yohan, Zhu, Bin, Gordenin, Dmitry A., Alexandrov, Ludmil B., Chanock, Stephen J., Wedge, David C., Landi, Maria Teresa
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2021; Nature Publishing Group
• Subjects: 631/208/212; 631/67/1612/1350; 692/699/67/1612/1350; Adult; Aged; Aged, 80 and over; Agriculture; Animal Genetics and Genomics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Care and treatment; Copy number; Copy number variations; Development and progression; DNA Copy Number Variations - genetics; Enzymes; ErbB Receptors - genetics; Female; Gene expression; Gene Function; Gene sequencing; Genes; Genetic aspects; Genome - genetics; Genome-Wide Association Study; Genomes; Genomics; Health aspects; Heterogeneity; Human Genetics; Humans; Kinases; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; Middle Aged; Mitochondrial DNA; Mortality; Mutation; Neoplastic Stem Cells - pathology; Non-Smokers - statistics & numerical data; Passive smoking; Piano; Progenitor cells; Protein-tyrosine kinase receptors; Proto-Oncogene Proteins p21(ras) - genetics; Receptors, Androgen - genetics; Risk Factors; Smokers; Smoking; Smoking - genetics; Stem cells; Telomeres; Tobacco; Tobacco smoking; Tumors; Tyrosine; Ubiquitin-Activating Enzymes - genetics; Whole Genome Sequencing; Young Adult; United States
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-021-00920-0

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. Whole-genome sequencing of lung cancer in never smokers identifies different copy number subtypes and shows a lack of tobacco smoking signatures, even in cases exposed to secondhand smoke.