Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events

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 three 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.

Sanguinarine inhibits Rac1b-rendered cell survival enhancement by promoting apoptosis and blocking proliferation

“…However, tumor cells with up-regulated Rac1b may partially survive this situation and thus greatly aggravate the process of the diseases. Our results support previous reports showing that up-regulated Rac1b can contribute to the tumor progression and metastasis [6,[16][17][18] .…”

“…Apart from its constitutive activity, significantly upregulated Rac1b expression has been reported to be deeply involved in tumorigenesis and the metastasis of colorectal, breast, lung, and thyroid cancers [6,[16][17][18] . Transient overexpression of Rac1b in cultured cells was able to promote cell proliferation [19] .…”

Phosphorylation of SRSF1 by SRPK1 regulates alternative splicing of tumor-related Rac1b in colorectal cells

“…One particular example is the tumor-related splicing variant Rac1b, an isoform of the signaling GTPase Rac1 (Matos et al 2003), in which a usually skipped exon 3b is retained. The resulting protein isoform Rac1b is overexpressed in a specific subtype of colorectal tumors and required to sustain tumor cell survival (Jordan et al 1999;) but was also reported in breast, lung, and thyroid tumors (Schnelzer et al 2000;Radisky et al 2005;Liu et al 2012;Stallings-Mann et al 2012;Silva et al 2013;Zhou et al 2013). Interestingly, Rac1b was found to be predominantly in the signaling-competent GTP-bound conformation (Schnelzer et al 2000;Matos et al 2003;Fiegen et al 2004;Radisky et al 2005), so that small changes in its expression level yield significant cellular responses.…”

Structural Integrity of Centromeric Chromatin and Faithful Chromosome Segregation Requires Pat1

“…Although the role of the human ortholog of Pat1 (Pat1b) in kinetochore function has not been defined, nuclear localization of Pat1b has been observed in humans (Marnef et al 2012). Furthermore, mutations and misregulation of Pat1b have been observed in several human cancers (Araujo et al 2012;Liu et al 2012;Dulak et al 2013). Hence, future studies aimed at understanding the role of the human homolog of Pat1 in the structure and function of the kinetochore may help us identify potential therapeutic targets for cancer therapy.…”