TY - JOUR
T1 - Genomic and evolutionary classification of lung cancer in never smokers
AU - Zhang, Tongwu
AU - Joubert, Philippe
AU - Ansari-Pour, Naser
AU - Zhao, Wei
AU - Hoang, Phuc H.
AU - Lokanga, Rachel
AU - Moye, Aaron L.
AU - Rosenbaum, Jennifer
AU - Gonzalez-Perez, Abel
AU - Martínez-Jiménez, Francisco
AU - Castro, Andrea
AU - Muscarella, Lucia Anna
AU - Hofman, Paul
AU - Consonni, Dario
AU - Pesatori, Angela C.
AU - Kebede, Michael
AU - Li, Mengying
AU - Gould Rothberg, Bonnie E.
AU - Peneva, Iliana
AU - Schabath, Matthew B.
AU - Poeta, Maria Luana
AU - Costantini, Manuela
AU - Hirsch, Daniela
AU - Heselmeyer-Haddad, Kerstin
AU - Hutchinson, Amy
AU - Olanich, Mary
AU - Lawrence, Scott M.
AU - Lenz, Petra
AU - Duggan, Maire
AU - Bhawsar, Praphulla M.S.
AU - Sang, Jian
AU - Kim, Jung
AU - Mendoza, Laura
AU - Saini, Natalie
AU - Klimczak, Leszek J.
AU - Islam, S. M.Ashiqul
AU - Otlu, Burcak
AU - Khandekar, Azhar
AU - Cole, Nathan
AU - Stewart, Douglas R.
AU - Choi, Jiyeon
AU - Brown, Kevin M.
AU - Caporaso, Neil E.
AU - Wilson, Samuel H.
AU - Pommier, Yves
AU - Lan, Qing
AU - Rothman, Nathaniel
AU - Almeida, Jonas S.
AU - Carter, Hannah
AU - Ried, Thomas
N1 - Funding Information:
This work has been supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, and the Intramural Research Program of the National Institute of Environmental Health Sciences (project nos. Z01 ES050159 to S.H.W. and Z1AES103266 to D.A.G.), National Institutes of Health (NIH). This project was funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract nos. 75N91019D00024 and HHSN261201800001I. The content of this publication does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. The research was supported by the Wellcome Trust Core Award, grant no. 203141/Z/16/Z with funding from the National Institute for Health Research Oxford Biomedical Research Centre. L.B.A. is an Abeloff V scholar and he is personally supported by an Alfred P. Sloan Research Fellowship and a Packard Fellowship for Science and Engineering. Research at the L.B.A. laboratory was supported by a National Institute of Environmental Health Sciences grant no. R01ES032547. The views expressed are those of the authors and not necessarily those of the National Health Service, National Institute for Health Research or Department of Health. The collection of samples from the Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Université Laval was supported by the IUCPQ Foundation. The GR Program 2010-2316264 supported L.A.M. for sample collection by the Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Casa Sollievo della Sofferenza. A.L.M. is supported by a Damon Runyon Cancer Research Foundation postdoctoral fellowship (no. DRG:2368-19) and a Postdoctoral Enrichment Program Award from the Burroughs Wellcome Fund (no. 1019903). C.F.K. is supported in part by grant no. R35HL150876-01, the Thoracic Foundation, Ellison Foundation, American Lung Association (no. LCD-619492) and the Harvard Stem Cell Institute. N.L-B. acknowledges funding from the European Research Council (consolidator grant no. 682398). P.H. is supported in part by the Association pour la Recherche contre le Cancer (CANC’AIR GENExposomics project). This work has been supported in part by the Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, a comprehensive cancer center designated by the National Cancer Institute and funded in part by a Moffitt Cancer Center Support Grant (no. P30-CA076292). B.E.G.R. is supported by NIH grant nos. 1P50 CA196530-01 and NIH 1K08 CA151645-01. We thank the Sherlock-Lung study scientific advisory board (M. Meyerson, J. Samet, M. Spitz, R. Summers, M. Thun and W. Travis) for their support. We also thank Y. Rubanova from Toronto University for her help with the TrackSig analysis. We thank the staff at the IUCPQ Université Laval Biobank, Nice Biobank Centre de Ressources Biologiques, Yale University and Moffitt Cancer Center & Research Institute for their valuable assistance in collecting samples and corresponding clinical data. This work utilized the computational resources of the NIH high-performance computational capabilities Biowulf cluster (http://hpc.nih.gov).
Publisher Copyright:
© 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85114594641&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85114594641&partnerID=8YFLogxK
U2 - 10.1038/s41588-021-00920-0
DO - 10.1038/s41588-021-00920-0
M3 - Article
AN - SCOPUS:85114594641
VL - 53
SP - 1348
EP - 1359
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 9
ER -