Gene expression profiling of epidermal growth factor receptor/KRAS pathway activation in lung adenocarcinoma

Shibata, Tatsuhiro; Hanada, Satoko; Kokubu, Akiko; Matsuno, Yoshihiro; Asamura, Hisao; Ohta, Tsutomu; Sakamoto, Michiie; Hirohashi, Setsuo

doi:10.1111/j.1349-7006.2007.00483.x

Cited by 30 publications

(35 citation statements)

References 27 publications

(35 reference statements)

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“…The possibility of a genetic classification of lung adenocarcinomas based on oncogene mutations has already been considered. In fact, one-third to nearly half of Japanese adenocarcinomas harbor EGFR mutations, 4,20 about 10% have KRAS mutations [21][22][23] and about 4% have EML4-ALK translocations, implying that two-thirds of adenocarcinomas feature mutually exclusive oncogenic mutations. The mutation rate of TP53 (1/11 ¼ 9.1%) was also low compared with that of lung adenocarcinomas in general (41%), 18 and the single mutation found was G to A transition, which was not related to smoking.…”

Section: Discussionmentioning

confidence: 99%

EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset

et al. 2009

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A subset of lung cancers harbors a small inversion within chromosome 2p, giving rise to a transforming fusion gene, EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene), which encodes an activated tyrosine kinase. We have earlier examined the presence of EML4-ALK by multiplex reverse transcription-polymerase chain reaction in 363 specimens of lung cancer, identifying 11 adenocarcinoma cases featuring the fusion gene. In this study, we clinicopathologically examined the characteristics of the EML4-ALK-positive cases, including the mutation status of EGFR, KRAS, and TP53, and whether they were of thyroid transcription factor-1 (TTF-1) cell lineage or not. Of 11 patients, 4 (36%) with EML4-ALK-positive lung adenocarcinomas who were below 50 years of age were affected by these diseases, as compared with 12 of 242 patients (5.0%) with EML4-ALK-negative lung adenocarcinomas (P ¼ 0.00038). EML4-ALK-positive lung adenocarcinomas were characterized by less-differentiated grade (P ¼ 0.0082) and acinar-predominant structure (Po0.0001) in histology. Furthermore, the presence of EML4-ALK appears to be mutually exclusive for EGFR and KRAS mutations (P ¼ 0.00018), whereas coexisting with TP53 mutations at a low frequency (1/11 ¼ 9.1%), and correlating with non-or light smoking (P ¼ 0.040), in line with the TTF-1 immunoreactivity. Thus, EML4-ALK-positive tumors may form a distinct entity among lung adenocarcinomas, characterized by young onset, acinar histology, no or rare mutations in EGFR, KRAS, and TP53, and a TTF-1 cell lineage, all in agreement with the prevalence in non-or light smokers.

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Section: Discussionmentioning

confidence: 99%

EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset

et al. 2009

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“…36), a TRU-like signature (25), an alveolar/bronchial signature (28), and a distal airway stem cell (DASC)-like subtype (37) as described (Supplementary Methods).…”

Section: Gene Expression Analysesmentioning

confidence: 99%

“…For instance, in the Wilkerson and colleagues (26) meta-analysis, 60% of all never-smokers were classified as bronchioid, representing 30% of this subgroup. However, unsupervised analyses of genome-wide expression patterns in adenocarcinomas have not yet identified never-smokers as a separate and distinct transcriptional entity without notable inclusion of smokers, challenging the hypothesis of a separate disease entity (13,17,22,25,27,28). Thus, further investigations are warranted for improved understanding of the molecular pathogenesis, especially into whether specific CNAs or transcriptional differences are actually acquired depending on smoking status in otherwise clinically and pathologically similar tumors.…”

Section: Introductionmentioning

confidence: 99%

Genomic and Transcriptional Alterations in Lung Adenocarcinoma in Relation to Smoking History

Karlsson

Ringnér

Lauss

et al. 2014

Clinical Cancer Research

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Purpose: Cigarette smoking is the major pathogenic factor for lung cancer. The precise mechanisms of tobacco-related carcinogenesis and its effect on the genomic and transcriptional landscape in lung cancer are not fully understood.Experimental Design: A total of 1,398 (277 never-smokers and 1,121 smokers) genomic and 1,449 (370 never-smokers and 1,079 smokers) transcriptional profiles were assembled from public lung adenocarcinoma cohorts, including matched next-generation DNA-sequencing data (n ¼ 423). Unsupervised and supervised methods were used to identify smoking-related copy-number alterations (CNAs), predictors of smoking status, and molecular subgroups.Results: Genomic meta-analyses showed that never-smokers and smokers harbored a similar frequency of total CNAs, although specific regions (5q, 8q, 16p, 19p, and 22q) displayed a 20% to 30% frequency difference between the two groups. Importantly, supervised classification analyses based on CNAs or gene expression could not accurately predict smoking status (balanced accuracies 60% to 80%). However, unsupervised multicohort transcriptional profiling stratified adenocarcinomas into distinct molecular subgroups with specific patterns of CNAs, oncogenic mutations, and mutation transversion frequencies that were independent of the smoking status. One subgroup included approximately 55% to 90% of neversmokers and approximately 20% to 40% of smokers (both current and former) with molecular and clinical features of a less aggressive and smoking-unrelated disease. Given the considerable intragroup heterogeneity in smoking-defined subgroups, especially among former smokers, our results emphasize the clinical importance of accurate molecular characterization of lung adenocarcinoma.Conclusions: The landscape of smoking-related CNAs and transcriptional alterations in adenocarcinomas is complex, heterogeneous, and with moderate differences. Our results support a molecularly distinct less aggressive adenocarcinoma entity, arising in never-smokers and a subset of smokers. Clin Cancer Res; 20(18); 4912-24. Ó2014 AACR.

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“…The present study investigated the association between certain factors and the effect of BaP on lung cancer progression. Table I shows the background of the cell lines used in the present study (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). A previous study using CD-1 mice indicated that female mice are more susceptible to the carcinogenic effects of BaP compared with males (29).…”

Section: Discussionmentioning

confidence: 99%

Laricitrin suppresses increased benzo(a)pyrene-induced lung tumor-associated monocyte-derived dendritic cell cancer progression

et al. 2016

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Abstract. Benzo(a)pyrene (BaP) stimulates lung cancer cells, promoting monocyte-derived dendritic cells to secrete soluble factors, including heparin binding-epidermal growth factor and C-X-C motif chemokine 5. The secretions from monocyte-derived dendritic cells stimulate the progression of lung cancer cells, including the migration and invasion of cells. To the best of our knowledge, these secretions remain unknown, and require additional study. The present study identified that treatment with BaP-H1395-tumor-associated dendritic cell-conditioned medium had the most marked effect on cell migration and invasion. This result may be associated with the female gender, stage 2 adenocarcinoma or mutation of the proto-oncogene B-Raf (BRAF), according to the cell line background. Laricitrin, a dietary flavonoid derivative present in grapes and red wine, suppresses certain factors and decreases the progression of lung cancer cells that are promoted by BaP in the lung cancer tumor microenvironment. The results of the present study suggest that prolonged exposure to BaP exacerbates lung cancer, particularly in female lung cancer patients with the BRAF mutation, but that laricitrin may ameliorate this effect.

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Gene expression profiling of epidermal growth factor receptor/KRAS pathway activation in lung adenocarcinoma

Cited by 30 publications

References 27 publications

EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset

EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset

Genomic and Transcriptional Alterations in Lung Adenocarcinoma in Relation to Smoking History

Laricitrin suppresses increased benzo(a)pyrene-induced lung tumor-associated monocyte-derived dendritic cell cancer progression

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