Characterizing the cancer genome in lung adenocarcinoma.

Abstract

Somatic alterations in cellular DNA underlie almost all human cancers. The prospect of targeted therapies and the development of high-resolution, genome-wide approaches are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in approximately 12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.

• Authors: Barbara A Weir, Michele S Woo, Gad Getz, Sven Perner, Li Ding, Rameen Beroukhim, William M Lin, Michael A Province, Aldi Kraja, Laura A Johnson, Kinjal Shah, Mitsuo Sato, Roman K Thomas, Justine A Barletta, Ingrid B Borecki, Stephen Broderick, Andrew C Chang, Derek Y Chiang, Lucian R Chirieac, Jeonghee Cho, Yoshitaka Fujii, Adi F Gazdar, Thomas Giordano, Heidi Greulich, Megan Hanna, Bruce E Johnson, Mark G Kris, Alex Lash, Ling Lin, Neal Lindeman, Elaine R Mardis, John D McPherson, John D Minna, Margaret B Morgan, Mark Nadel, Mark B Orringer, John R Osborne, Brad Ozenberger, Alex H Ramos, James Robinson, Jack A Roth, Valerie Rusch, Hidefumi Sasaki, Frances Shepherd, Carrie Sougnez, Margaret R Spitz, Ming-Sound Tsao, David Twomey, Roel G W Verhaak, George M Weinstock, David A Wheeler, Wendy Winckler, Akihiko Yoshizawa, Soyoung Yu, Maureen F Zakowski, Qunyuan Zhang, David G Beer, Ignacio I Wistuba, Mark A Watson, Levi A Garraway, Marc Ladanyi, William D Travis, William Pao, Mark A Rubin, Stacey B Gabriel, Richard A Gibbs, Harold E Varmus, Richard K Wilson, Eric S Lander, Matthew Meyerson
• Journal: Nature (Nature) Vol. 450 Issue 7171 Pg. 893-8 (Dec 06 2007) ISSN: 1476-4687 [Electronic] England
• PMID: 17982442 (Publication Type: Journal Article)

Chemical References

• Intracellular Signaling Peptides and Proteins
• MAS1 protein, human
• MBIP protein, human
• NKX2-1 protein, human
• Nuclear Proteins
• Proto-Oncogene Mas
• Thyroid Nuclear Factor 1
• Transcription Factors

Topics

• Adenocarcinoma (genetics)
• Cell Line, Tumor
• Chromosome Deletion
• Chromosomes, Human, Pair 14 (genetics)
• Gene Amplification (genetics)
• Genome, Human (genetics)
• Genomics
• Genotype
• Humans
• Intracellular Signaling Peptides and Proteins (genetics)
• Loss of Heterozygosity (genetics)
• Lung Neoplasms (genetics)
• Neoplasms (genetics)
• Nuclear Proteins (genetics)
• Polymorphism, Single Nucleotide (genetics)
• Proto-Oncogene Mas
• RNA Interference
• Thyroid Nuclear Factor 1
• Transcription Factors (genetics)