Genomic and evolutionary classification of lung cancer in never smokers

Zhang, Tongwu
Joubert, Philippe
Ansari-Pour, Naser
Zhao, Wei
Hoang, Phuc H.
Lokanga, Rachel
Moye, Aaron L.
Rosenbaum, Jennifer
Gonzalez-Perez, Abel
Martinez-Jimenez, Francisco
Castro, Andrea
Muscarella, Lucia Anna
Hofman, Paul
Consonni, Dario
Pesatori, Angela C.
Kebede, Michael
Li, Mengying
Rothberg, Bonnie E. Gould
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 Sarıtaş, Burçak
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
Bosse, Yohan
Zhu, Bin
Gordenin, Dmitry A.
Alexandrov, Ludmil B.
Chanock, Stephen J.
Wedge, David C.
Landi, Maria Teresa
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.


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Citation Formats
T. Zhang et al., “Genomic and evolutionary classification of lung cancer in never smokers,” NATURE GENETICS, vol. 53, no. 9, pp. 1348–1375, 2021, Accessed: 00, 2022. [Online]. Available: