Mapping the Hallmarks of Lung Adenocarcinoma with Massively Parallel Sequencing

Imieliński, Marcin; Berger, Alice H.; Hammerman, Peter S.; Hernandez, Bryan; Pugh, Trevor J.; Hodis, Eran; Cho, Jeonghee; Suh, James; Capelletti, Marzia; Sivachenko, Andrey; Sougnez, Carrie; Auclair, Daniel; Lawrence, Michael S.; Stojanov, Petar; Cibulskis, Kristian; Choi, Kae Won; Waal, Luc de; Sharifnia, Tanaz; Brooks, Angela N.; Greulich, Heidi; Banerji, Shantanu; Zander, Thomas; Seidel, Danila; Leenders, Frauke; Ansén, Sascha; Ludwig, Corinna; Engel-Riedel, Walburga; Stoelben, Erich; Wolf, Jürgen; Goparju, Chandra; Thompson, Kristin M.; Winckler, Wendy; Kwiatkowski, David J.; Johnson, Bruce E.; Jänne, Pasi A.; Miller, Vincent A.; Pao, William; Travis, William D.; Pass, Harvey I.; Gabriel, Stacey; Lander, Eric S.; Thomas, Roman K.; Garraway, Levi A.; Getz, Gad; Meyerson, Matthew

doi:10.1016/j.cell.2012.08.029

Cited by 1,637 publications

(1,630 citation statements)

References 71 publications

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“…The genetic features of these mutations and mouse model studies suggest that U2AF1, SF3B1 and SRSF2 promote cancer formation by gain of function or altered function mechanisms and therefore are potentially proto-oncogenes [64]. Recurrent mutations in U2AF1 and the RBM5 paralog RBM10 were also associated with lung adenocarcinomas [23]. In addition, 220 somatic mutations in RBM5 have been identified in various cancers as annotated in the Cancer Genome Atlas (TCGA) (www.cancergenome.nih.gov).…”

Section: Discussionmentioning

confidence: 99%

“…RBM5 and its paralog RBM6 are located in the human chromosome 3p21.3 region and were identified as candidate tumor suppressors of lung cancers and other solid tumors [16–22]. RBM10 , another paralog of RBM5 , is also frequently mutated in lung adenocarcinoma samples [23]. In mice and human, RBM5 can reduce lung cancer progression [24,25].…”

Section: Introductionmentioning

confidence: 99%

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RBM-5 modulates U2AF large subunit-dependent alternative splicing inC. elegans

Zhou

Gao

et al. 2018

RNA Biology

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A key step in pre-mRNA splicing is the recognition of 3ʹ splicing sites by the U2AF large and small subunits, a process regulated by numerous trans-acting splicing factors. How these trans-acting factors interact with U2AF in vivo is unclear. From a screen for suppressors of the temperature-sensitive (ts) lethality of the C. elegans U2AF large subunit gene uaf-1(n4588) mutants, we identified mutations in the RNA binding motif gene rbm-5, a homolog of the tumor suppressor gene RBM5. rbm-5 mutations can suppress uaf-1(n4588) ts-lethality by loss of function and neuronal expression of rbm-5 was sufficient to rescue the suppression. Transcriptome analyses indicate that uaf-1(n4588) affected the expression of numerous genes and rbm-5 mutations can partially reverse the abnormal gene expression to levels similar to that of wild type. Though rbm-5 mutations did not obviously affect alternative splicing per se, they can suppress or enhance, in a gene-specific manner, the altered splicing of genes in uaf-1(n4588) mutants. Specifically, the recognition of a weak 3ʹ splice site was more susceptible to the effect of rbm-5. Our findings provide novel in vivo evidence that RBM-5 can modulate UAF-1-dependent RNA splicing and suggest that RBM5 might interact with U2AF large subunit to affect tumor formation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

RBM-5 modulates U2AF large subunit-dependent alternative splicing inC. elegans

Zhou

Gao

et al. 2018

RNA Biology

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“…These genomic events include somatic EGFR mutations within regions of either the extracellular domain, in glioblastoma, or the kinase domain in lung adenocarcinoma,3, 4 as well as through gene amplification as observed in many other types of solid tumors 5, 6. In addition, several intragenic deletions within either the extracellular or C‐terminal domain of EGFR have also been reported to be oncogenic in a subset of glioblastoma and lung adenocarcinoma 7, 8, 9…”

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confidence: 99%

“…Furthermore, accumulating data suggest that the downstream signaling pathways activated by oncogenic mutant EGFR differ from those activated by ligand stimulated wild‐type EGFR 17, 18, 19. Notably, C‐terminal deletion EGFR mutants, lacking some or all of the autophosphorylation sites that have been identified in GBM and lung adenocarcinoma, are able to induce cellular transformation 8, 9, 20. These observations have raised the question whether autophosphorylation of oncogenic mutant EGFR, which is a consequence of constitutive receptor dimerization, is required for oncogenic activation and induction of cellular transformation by cancer‐derived EGFR mutants.…”

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confidence: 99%

Autophosphorylation of the carboxyl‐terminal domain is not required for oncogenic transformation by lung‐cancer derived EGFR mutants

Cho

Kim

et al. 2018

Intl Journal of Cancer

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Aberrant activation of cancer‐derived mutants of the epidermal growth factor receptor (EGFR) is closely associated with cancer pathogenesis and is thought to be mediated through multiple tyrosine phosphorylations within the C‐terminal domain. Here, we examined the consequences of the loss of these C‐terminal phosphorylation sites on cellular transformation in the context of lung‐cancer‐derived L858R, exon 19 deletion and exon 20 insertion mutant EGFR. Oncogenic EGFR mutants with substitution of the 10 potential C‐terminal tyrosine autophosphorylation sites for phenylalanine (CYF10) were still able to promote anchorage‐independent growth in soft agar at levels comparable to the parental L858R or exon19 deletion or exon 20 insertion mutants with intact autophosphorylation sites. Furthermore, these CYF10 mutants retained the ability to transform Ba/F3 cells in the absence of IL‐3. Bead‐based phosphorylation and immunoprecipitation analyses demonstrated that key EGFR‐associated proteins—including Grb2 and PLC‐γ—are neither phosphorylated nor bound to CYF10 mutants in transformed cells. Taken together, we conclude that tyrosine phosphorylation is not required for oncogenic activity of lung‐cancer‐derived mutant EGFR, suggesting these mutants can lead to cellular transformation by an alternative mechanism independent of EGFR phosphorylation.

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“…16 Recently, CCDC6-RET fusions and CCDC6 inactivating mutations (N394Y, T462A, S351Y, E227K; www.sanger.ac.uk/genetics/ CGP/cosmic) have been reported in NSCLC. 21,22 In this study, we examined CCDC6 protein and mRNA levels in a group of NSCLC cell lines along with DNA repair proficiency, DNA damage response and platinum-based therapy as a single agent or in combination with PARP inhibitors. We further analyzed CCDC6 expression in a wide range of early resectable or locally advanced NSCL primary tumors to establish the predictive power of CCDC6 expression in the clinics.…”

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confidence: 99%

New therapeutic perspectives in CCDC6 deficient lung cancer cells

Morra

Luise

Visconti

et al. 2014

Intl Journal of Cancer

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Non-small cell lung cancer (NSCLC) is the main cause of cancer-related death worldwide and new therapeutic strategies are urgently needed. In this study, we have characterized a panel of NSC lung cancer cell lines for the expression of coiled-coildomain containing 6 (CCDC6), a tumor suppressor gene involved in apoptosis and DNA damage response. We show that low CCDC6 protein levels are associated with a weak response to DNA damage and a low number of Rad51 positive foci. Moreover, CCDC6 deficient lung cancer cells show defects in DNA repair via homologous recombination. In accordance with its role in the DNA damage response, CCDC6 attenuation confers resistance to cisplatinum, the current treatment of choice for NSCLC, but sensitizes the cells to olaparib, a small molecule inhibitor of the repair enzymes PARP1/2. Remarkably, the combination of the two drugs is more effective than each agent individually, as demonstrated by a combination index <1. Finally, CCDC6 is expressed at low levels in about 30% of the NSCL tumors we analyzed by TMA immunostaining. The weak CCDC6 protein staining is significatively correlated with the presence of lymph node metastasis (p 0.02) and negatively correlated to the disease free survival (p 0.01) and the overall survival (p 0.05). Collectively, the data indicate that CCDC6 levels provide valuable insight for OS. CCDC6 could represent a predictive biomarker of resistance to conventional single mode therapy and yield insight on tumor sensitivity to PARP inhibitors in NSCLC.

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Mapping the Hallmarks of Lung Adenocarcinoma with Massively Parallel Sequencing

Cited by 1,637 publications

References 71 publications

RBM-5 modulates U2AF large subunit-dependent alternative splicing inC. elegans

RBM-5 modulates U2AF large subunit-dependent alternative splicing inC. elegans

Autophosphorylation of the carboxyl‐terminal domain is not required for oncogenic transformation by lung‐cancer derived EGFR mutants

New therapeutic perspectives in CCDC6 deficient lung cancer cells

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