An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors

Chitale, Dhananjay; Gong, Yongxing; Taylor, Barry S.; Broderick, Stephen; Brennan, Cameron; Somwar, Romel; Golas, Ben; Wang, L; Motoi, Noriko; Szőke, János; Reinersman, J. Matthew; Major, John E.; Sander, Chris; Seshan, Venkatraman; Zakowski, Maureen F.; Rusch, Valerie W.; Pao, William; Gerald, William L.; Ladanyi, Marc

doi:10.1038/onc.2009.135

Cited by 202 publications

(246 citation statements)

References 38 publications

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“…S6 C and D). We next carried out a similar analysis in a collection of CRC tumor samples characterized by The Cancer Genome Atlas (the TCGA colorectal tumors) (33) and a combined set of lung tumor samples (the Tomida_Chitale lung tumors) (1,3). We again observed a modest but consistent negative correlation between the ERH and the Singh and Bhattacharjee signature scores in these samples (Fig.…”

Section: Erh Regulates the Expression Of A Subset Of Genes Involved Imentioning

confidence: 71%

“…synthetic lethality | spliceosome T he Ras family of small GTPases is mutated in a significant fraction of human cancers, with high frequencies of mutations in v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) found in colon, lung, and pancreatic cancers (1)(2)(3)(4). Ras proteins are activated by growth factor receptors, and they, in turn, activate a number of downstream effector pathways to coordinate cell proliferation, survival, and migration.…”

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confidence: 99%

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Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells

Weng

Lee

Shu

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Cancers with Ras mutations represent a major therapeutic problem. Recent RNAi screens have uncovered multiple nononcogene addiction pathways that are necessary for the survival of Ras mutant cells. Here, we identify the evolutionarily conserved gene enhancer of rudimentary homolog (ERH), in which depletion causes greater toxicity in cancer cells with mutations in the small GTPase KRAS compared with KRAS WT cells. ERH interacts with the spliceosome protein SNRPD3 and is required for the mRNA splicing of the mitotic motor protein CENP-E. Loss of ERH leads to loss of CENP-E and consequently, chromosome congression defects. Gene expression profiling indicates that ERH is required for the expression of multiple cell cycle genes, and the gene expression signature resulting from ERH down-regulation inversely correlates with KRAS signatures. Clinically, tumor ERH expression is inversely associated with survival of colorectal cancer patients whose tumors harbor KRAS mutations. Together, these findings identify a role of ERH in mRNA splicing and mitosis, and they provide evidence that KRAS mutant cancer cells are dependent on ERH for their survival.synthetic lethality | spliceosome

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Section: Erh Regulates the Expression Of A Subset Of Genes Involved Imentioning

confidence: 71%

mentioning

confidence: 99%

Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells

Weng

Lee

Shu

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…1A and Table S2). The most frequent CNAs observed were gain of chomosome 3q, which harbors PIK3CA and is amplified in many cancers; loss of chromosome 3p, which harbors FHIT, TGFBR2, and FOXP1 and is frequently lost in epithelial cancers; and loss of chromosome 8p, which harbors NKX3 and DUSP4 (30)(31)(32)(33). EGFR/PI3K pathway genes within regions of significant copy number gain included PIK3CA (frequency = 45.2%, q = 7.45 × 10 −7 ), RIC-TOR (frequency = 38.7%, q = 1.12 × 10 −4 ), and EGFR (frequency = 32.3%, q = 3.42 × 10 −5 ).…”

Section: Resultsmentioning

confidence: 99%

“…(D) Clinical outcome by PTPRS expression in lung adenocarcinomas with TKI-sensitive EGFR mutations. Cases treated at Memorial Sloan-Kettering Cancer Center were categorized as low (below median) or normal PTPRS expressors, and recurrence and survival were calculated using the Kaplan-Meier method and a log-rank test (31).…”

Section: Methodsmentioning

confidence: 99%

Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers

Morris¹,

Taylor²,

Bivona³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Activation of the PI3K and epidermal growth factor receptor (EGFR) pathway is able to drive oncogenesis in multiple human cancers, including head and neck squamous cell carcinoma. Targeted agents such as cetuximab and erlotinib are currently used in patients with head and neck squamous cell carcinoma, but, in this disease, the genomic alterations that cause pathway activation and determine response to pharmacologic inhibition remain ill-defined. Here, we present a detailed dissection of the EGFR/PI3K pathway, composed of sequencing of the core pathway components, and high-resolution genomic copy number assessment. Mutations were found in PIK3CA (6%), but no point mutations were observed in other pathway genes such as PTEN and EGFR . In contrast, we observed frequent copy number alterations of genes in the pathway, including PIK3CA , EGFR , protein tyrosine phosphatase receptor S ( PTPRS ), and RICTOR . In total, activating genetic pathway alterations were identified in 74% of head and neck tumors. Importantly, intragenic microdeletions of the EGFR phosphatase PTPRS were frequent (26%), identifying this gene as a target of 19p13 loss. PTPRS loss promoted EGFR/PI3K pathway activation, modulated resistance to EGFR inhibition, and strongly determined survival in lung cancer patients with activating EGFR mutations. These findings have important implications for our understanding of head and neck cancer tumorigenesis and for the use of targeted agents for this malignancy.

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“…Other studies have examined LCINS for multiple mutations, including EGFR and KRAS mutations, but did not include ALK rearrangements. 41,45 More recently, Sun et al reported multiple genetic alterations in lung adenocarcinoma samples from never-smokers. However, those authors did not examine survival outcomes after chemotherapy or EGFR TKI treatment and only investigated a small patient cohort.…”

Section: Discussionmentioning

confidence: 99%

Distinct clinical features and outcomes in never‐smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement

Kim

Shim

Chung

et al. 2011

Cancer

135

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BACKGROUND:The objectives of this study were to determine the proportions of major oncogenic alterations and to examine survival in genotype-specific subsets of never-smokers with nonsmall cell lung cancer (NSCLC). METHODS:The authors concurrently analyzed mutations in the epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genes and investigated anaplastic lymphoma kinase (ALK) gene rearrangements in samples from 229 never-smokers with NSCLC. ALK rearrangements were identified by fluorescent in situ hybridization and were confirmed by immunohistochemistry. Mutations in EGFR (exons 18 to 21) and KRAS (codons 12 and 13) were determined by direct sequencing. RESULTS: Of 229 tumors, the frequency of EGFR mutations, ALK rearrangements, KRAS mutations, and no mutations (wild type [WT]) in any of the 3 genes (WT/WT/WT) was 48%, 8.3%, 3.5%, and 40.2%, respectively. All genetic alterations were mutually exclusive. The median progression-free survival after treatment with EGFR tyrosine kinase inhibitors (TKIs) was 12.8 months, 6.3 months, 2.1 months, and 1.6 months in patients with EGFR mutations, the WT/WT/WT genotype, KRAS mutations, and ALK rearrangements, respectively. In a Cox regression model, the adjusted hazard ratio for the risk of disease progression after treatment with EGFR TKIs was 0.59 (95% confidence interval [CI], 0.40-0.87; P ¼ .008) for patients with EGFR mutations, 4.58 (95% CI, 2.07-10.15; P < .001) for patients with ALK rearrangements, and 4.23 (95% CI, 1.65-10.8; P ¼ .003) for patients with KRAS mutations. Overall survival also differed significantly among genotypes. CONCLUSIONS: To the authors' knowledge, this was the largest comprehensive and concurrent analysis to date of 3 major oncogenic alterations in a cohort of East Asian never-smokers with NSCLC. Because survival outcomes differed among genotypes, and drugs that target specific alterations currently are available, genetic profiling to identify genotype-specific subsets can lead to successful treatment with appropriate kinase inhibitors. Cancer 2012;118:729

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An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors

Cited by 202 publications

References 38 publications

Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells

Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells

Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers

Distinct clinical features and outcomes in never‐smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement

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