K-ras gene mutations in non-small cell lung cancer in Japanese

Noda, Naotaka; Matsuzoe, Daisuke; Konno, Toshikazu; Kawahara, Katsunobu; Yamashita, Yuichi; Shirakusa, Takayuki

doi:10.3892/or.8.4.889

Cited by 17 publications

(20 citation statements)

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“…We detected the EGFR gene mutations at similar frequency as reported (31,32,40) and the presence of somatic mutations was significantly associated with never-smoking history as previous studies reported (8 -10, 31, 32, 40). We detected K-ras mutations relatively less frequent than previously reported (41) but comparatively to other study (42) probably because our analyzed cases contained more female and nonsmokers. We found that EGFR mutation and K-ras mutation were mutually exclusive as reported (31,32,40) and this finding is consistent with the notion that activation of both EGFR and K-ras stimulates the same downstream pathway (43).…”

Section: Imaging Diagnosis Prognosiscontrasting

confidence: 52%

Genetic Classification of Lung Adenocarcinoma Based on Array-Based Comparative Genomic Hybridization Analysis: Its Association with Clinicopathologic Features

Shibata¹,

Uryu

Kokubu³

et al. 2005

Clinical Cancer Research

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The array-based comparative genomic hybridization using microarrayed bacterial artificial chromosome clones allows high-resolution analysis of genome-wide copy number changes in tumors. To analyze the genetic alterations of primary lung adenocarcinoma in a high-throughput way, we used laser-capture microdissection of cancer cells and array comparative genomic hybridization focusing on 800 chromosomal loci containing cancer-related genes.We identified a large number of chromosomal numerical alterations, including frequent amplifications on 7p12, 11q13,12q14-15, and 17q21, and two homozygous deletions on 9p21 and one on 8p23. Unsupervised hierarchical clustering analysis of multiple alterations revealed three subgroups of lung adenocarcinoma that were characterized by the accumulation of distinct genetic alterations and associated with smoking history and gender. The mutation status of the epidermal growth factor receptor (EGFR) gene was significantly associated with specific genetic alterations and supervised clustering analysis based on EGFR gene mutations elucidated a subgroup including all EGFR gene mutated tumors, which showed significantly shorter disease-free survival. Our results suggest that there exist multiple molecular carcinogenesis pathways in lung adenocarcinoma that may associate with smoking habits and gender, and that genetic cancer profiling will reveal previously uncharacterized genetic heterogeneity of cancer and be beneficial in estimating patient prognosis and discovering novel cancer-related genes including therapeutic targets.

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Section: Imaging Diagnosis Prognosiscontrasting

confidence: 52%

Genetic Classification of Lung Adenocarcinoma Based on Array-Based Comparative Genomic Hybridization Analysis: Its Association with Clinicopathologic Features

Shibata¹,

Uryu

Kokubu³

et al. 2005

Clinical Cancer Research

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“…Both K-ras and EGFR are important molecules that are responsible to the regulation of the mitogen-activated protein kinase pathway. But K-ras mutations are linked to the development of adenocarcinomas (Ahrendt et al, 2001), and are rarely observed in adenocarcinomas in nonsmokers (Noda et al, 2001). This is in marked contrast to EGFR mutations, which occur more frequently in nonsmokers.…”

Section: Discussionmentioning

confidence: 50%

“…However, lung cancer also develops in nonsmokers, and 30 -40% of the lung cancer patients in Japan have never smoked history are female, and their major histological tumour type is adenocarcinoma (Sobue et al, 1994;Akazawa et al, 2003). While several reports have shown that the adenocarcinomas that occurred in nonsmokers were distinct from those that developed in smokers in terms of their histological subclassification, prognosis, gene expression pattern, and gene alterations (Tsuchiya et al, 1988;Hashimoto et al, 2000;Ahrendt et al, 2001;Bhattacharjee et al, 2001;Koga et al, 2001;Noda et al, 2001;Vahakangas et al, 2001;Yang et al, 2002), few significant genetic alterations have been reported in adenocarcinomas that developed in nonsmokers.…”

mentioning

confidence: 99%

Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma

et al. 2005

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Epidermal growth factor receptor (EGFR) mutations are a potential predictor of the effectiveness of EGFR inhibitors for the treatment of lung cancer. Although EGFR mutations were reported to occur with high frequency in nonsmoking Japanese adenocarcinoma patients, the exact nature has not been fully elucidated. We examined EGFR gene mutations within exons 18 -21 and their correlations to clinico-pathological factors and other genetic alterations in tumour specimens from 154 patients who underwent resection for lung cancer at Kyoto University Hospital. Epidermal growth factor receptor mutations were observed in 60 tumours (39.0%), all of which were adenocarcinoma. Among the patients with adenocarcinoma (n ¼ 108), EGFR mutations were more frequently observed in nonsmokers than former smokers or current smokers (83.0, 50.0, 15.2%, respectively), in women than men (76.3 vs 34.0%), in tumours with bronchio-alveolar component than those without bronchio-alveolar component (78.9 vs 42.9%), and in well or moderately differentiated tumours than poorly differentiated tumours (72.0, 64.4, 34.2%). No tumours with EGFR mutations had any K-ras codon 12 mutations, which were well-known smoking-related gene mutations. In conclusion, adenocarcinomas with EGFR mutation had a distinctive clinico-pathological feature unrelated to smoking. Epidermal growth factor receptor mutations may play a key role in the development of smoking-independent adenocarcinoma.

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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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K-ras gene mutations in non-small cell lung cancer in Japanese

Cited by 17 publications

References 0 publications

Genetic Classification of Lung Adenocarcinoma Based on Array-Based Comparative Genomic Hybridization Analysis: Its Association with Clinicopathologic Features

Genetic Classification of Lung Adenocarcinoma Based on Array-Based Comparative Genomic Hybridization Analysis: Its Association with Clinicopathologic Features

Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma

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

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