Abstract
Lung cancer is a highly
heterogeneous disease in terms of both underlying genetic lesions and response
to therapeutic treatments. We performed deep whole genome sequencing and
transcriptome sequencing on 19 lung cancer cell lines and 3 lung tumor/normal
pairs. Overall, our data show that cell line models exhibit similar mutation
spectra to human tumor samples. Smoker and never-smoker cancer samples exhibit
distinguishable patterns of mutations. A number of epigenetic regulators,
including KDM6A, ASH1L, SMARCA4 and ATAD2, are frequently altered by mutations
or copy number changes. A systematic survey of splice-site mutations identified
106 splice site mutations associated with cancer specific aberrant splicing,
including mutations in several known cancer-related genes. RAC1b, an isoform of
the RAC1 GTPase that includes one additional exon, was found to be
preferentially up-regulated in lung cancer. We further show that its expression
is significantly associated with sensitivity to a MAP2K (MEK) inhibitor
PD-0325901. Taken together, these data present a comprehensive genomic
landscape of a large number of lung cancer samples and further demonstrate that
cancer-specific alternative splicing is a widespread phenomenon that has
potential utility as therapeutic biomarkers. The detailed characterizations of
the lung cancer cell lines also provide genomic context to the vast amount of
experimental data gathered for these lines over the decades, and represent
highly valuable resources for cancer biology.
Source: Genome
and transcriptome sequencing of lung cancers reveal diverse mutational and
splicing events. Liu J, Lee W, Jiang Z, Chen Z, Jhunjhunwala S, Haverty PM,
Gnad F, Guan Y, Gilbert H, Stinson J, Klijn C, Guillory J, Bhatt D, Vartanian
S, Walter K, Chan J, Holcomb T, Dijkgraaf P, Johnson S, Koeman J, Minna JD,
Gazdar AF, Stern HM, Hoeflich KP, Wu TD, Settleman J, de Sauvage FJ, Gentleman
RC, Neve RM, Stokoe D, Modrusan Z, Seshagiri S, Shames DS, Zhang Z (zhang.zemin@gene.com). Genome Res. 2012
Oct 2.
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