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ABSTRACT: Podoplanin, a small type I integral membrane mucin-type sialoglycoprotein, serves as a useful marker for diagnosing malignant pleural mesothelioma (MPM); however, the physiological function of podoplanin in mesothelioma cells is not known. To elucidate the role of podoplanin in the pathogenesis of MPM, we generated two mesothelioma cell lines (PODO1 and PODO2) that stably express high levels of podoplanin. Although PODO1 cells proliferated to the same extent in culture or in nude mice, the survival rate of the mice was significantly reduced compared with that of the controls. We demonstrated that PODO1 and PODO2 cells had increased invasive ability in in vitro assays and induced upregulation of matrix metalloproteinase-1. PODO1 and PODO2 cultures could not be induced to undergo apoptosis when starved or treated with cis-diamminedichloroplatinum(II) (CDDP) compared with the controls. Moreover, silencing of podoplanin expression using RNA interference restored the ability of CDDP to induce apoptosis. Consistent with their growth properties, we detected constitutive activation of extracellular signal-regulated kinase in PODO1 and PODO2 cultures. These findings suggest that constitutive expression of podoplanin contributes to the invasive growth properties of mesothelioma cells and their resistance to apoptosis. Moreover, our data suggest that podoplanin or components of its signaling pathway, or both, may serve as important targets for developing novel treatments for MPM.
Oncology Reports 01/2013; · 1.84 Impact Factor
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ABSTRACT: A 35-year-old female presented with multiple bilateral pulmonary nodules on a chest X-ray during a regular health checkup. Chest computed tomography revealed multiple well-defined nodular shadows in the lung. She had undergone a myomectomy 7 years previously for leiomyoma of the uterus. Thoracoscopic resection of one of the nodules was performed to establish a pathological diagnosis. Pathological findings were consistent with benign metastasizing leiomyoma. Estrogen and progesterone receptors showed strong positives by immunohistostaining of the tumor. The patient is currently receiving outpatient treatment for a benign metastasizing leiomyoma by administration of a GnRH analog drug.
General Thoracic and Cardiovascular Surgery 11/2012;
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ABSTRACT: Giant cell tumors (GCTs) are rare neoplasms, most commonly arising in the metaphysis/epiphysis of long bones. They consist of multinucleated giant cells with surrounding spindle-shaped mononuclear stromal cells. GCTs rarely appear in the ribs. We report a case of a GCT originating from the anterior arc of the fourth rib in a 31-year-old man who presented with a progressively growing thoracic mass in the left anterior chest wall. Thoracotomy involving en bloc resection of the chest wall and tumor and a reconstruction of the chest wall were performed.
General Thoracic and Cardiovascular Surgery 04/2012; 60(4):233-6.
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ABSTRACT: A 31-year old female with anorexia nervosa was referred to the Department of General Surgical Science at Gunma University for a surgical resection of a pulmonary aspergilloma. The patient had received treatment for anorexia nervosa at the Department of Psychiatry of the Hospital of Gunma University Graduate School of Medicine. A chest radiograph showed an infiltrative shadow with apical pleural thickening in the left upper lung field. A contrast enhanced computed tomography showed an irregular mass shadow with cavity formation that involved spherical clusters in the left upper lobe. The patient was diagnosed with pulmonary aspergilloma by serological studies and radiological features. A pulmonary segmentectomy of the left apical segment (S1 + 2) through a lateral thoracotomy was successfully performed. She had an uneventful postoperative recovery, and the final histopathological examination confirmed the diagnosis of pulmonary aspergilloma. This is a rare case study of a young female patient with anorexia nervosa who developed pulmonary aspergilloma.
Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia. 02/2012; 18(5):465-7.
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ABSTRACT: Here, we report a rare case of a 39-year-old male who presented with left forearm pain and swelling as the initial manifestation of non-small cell lung cancer (NSCLC). The patient underwent chemoradiotherapy followed by surgical resection of the primary lesion as a salvage treatment. Four years and 7 months after his first presentation, the patient is alive with no symptoms of recurrence or metastasis. Although the optimal treatment for skeletal muscle metastasis from NSCLC has not been determined, aggressive treatment for the primary and the solitary metastatic lesion could be considered as a potentially successful treatment option.
Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia. 02/2012; 18(5):468-71.
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ABSTRACT: Meningiomas are common neoplasms arising from the central nervous system meninges. On the other hand, primary ectopic meningiomas are extremely rare and usually limited to the head and neck region or to the paravertebral soft tissues. Their occurrence in the mediastinum is even rarer. Until now, only 4 cases of primary mediastinal meningioma have been reported in the literature searched on Medline. Because of its rarity and intriguing pathogenesis, we report here a case of primary mediastinal meningioma that was treated by surgical resection. The clinical features, treatment, pathological findings, and prognosis are analyzed, and the literature on ectopic meningioma is reviewed.
World Journal of Surgical Oncology 01/2012; 10:17. · 1.12 Impact Factor
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ABSTRACT: Extracutaneous glomus tumors are uncommon, and their occurrence in the trachea is rare. We present a case of a surgically resected glomus tumor of the trachea in a 56-year-old woman who presented with worsening dyspnea and cough. Bronchoscopy and computed tomography showed a polypoid tumor arising from the posterior membrane of the lower trachea just above the carina; the tracheal lumen was approximately 80% occluded. The patient underwent successful tracheal sleeve resection with primary reconstruction. The histological characteristics and immunohistochemical profile were typical for this tumor. The clinicopathological features of this unusual neoplasm are discussed, and the literature is reviewed.
General Thoracic and Cardiovascular Surgery 12/2011; 59(12):815-8.
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ABSTRACT: Mesenchymal cystic hamartomas are uncommon tumors originating from nodules of primitive mesenchymal cells, and their occurrence in the lung is extremely rare. We present a case of surgically resected mesenchymal cystic hamartoma of the lung in a 49-year old woman who presented without any symptoms. Chest computed tomography showed a solitary cystic lesion in the right lower lobe. The patient underwent preoperative marking by 0.2 ml lipiodol 4 days before surgery. Thoracoscopic partial resection of the right lower lobe was performed. The histological picture and immunohistochemical profile were compatible with this tumor.
General Thoracic and Cardiovascular Surgery 09/2011; 59(9):619-22.
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ABSTRACT: Activating mutation in the kinase domain of the human EGF receptor 2 (HER2) gene (also known as ERBB2 or neu) is reported to be present in a small fraction of lung adenocarcinomas. However its prognostic and predictive implications are not yet established.
We examined 504 Japanese lung cancer patients who underwent pulmonary resection for HER2 mutations by direct sequencing and evaluated their prognostic and predictive implications. Updated prognostic data of 14 Japanese patients with HER2 mutation from previous two reports were also gathered.
HER2 mutations were identified in 13 of 504 cases (2.6%). Patients with HER2 mutations were common in female, nonsmokers and adenocarcinomas as those with EGFR mutations. When confined to the subgroup of nonsmokers with adenocarcinoma or adenosquamous cell carcinoma without EGFR mutations, the frequency of HER2 mutations was 14.1% (11/78). There was no difference in the overall survival of patients with HER2 mutations, compared with patients harboring EGFR mutations and patients harboring wild types for both EGFR and HER2. Within the patients with HER2 mutation, two of three with TP53 mutation and one of 13 without TP53 mutation died of the disease, suggesting negative prognostic role of the TP53 mutation. Three patients with HER2 mutations did not respond to platinum-based chemotherapy and EGFR-TKIs. Of note, one patient with the most common HER2 mutations, YVMA776-779ins, responded to trastuzumab plus vinorelbine after failure of multiple round of platinum-based chemotherapy and gefitinib.
HER2 mutations are present in a subset of patients with lung cancer having distinct clinical features. HER2 mutations were not associated with the prognosis of patients with lung cancers. Patients with HER2 mutations might benefit from anti-HER2 therapy.
Lung cancer (Amsterdam, Netherlands) 02/2011; 74(1):139-44. · 3.14 Impact Factor
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ABSTRACT: Gefitinib and erlotinib, which are epidermal growth factor receptor- (EGFR-) specific tyrosine kinase inhibitors (TKIs), are widely used as molecularly targeted drugs for non-small-cell lung cancer (NSCLC). Currently, the search for EGFR gene mutations is becoming essential for the treatment of NSCLC since these have been identified as predictive factors for drug sensitivity. On the other hand, in almost all patients responsive to EGFR-TKIs, acquired resistance is a major clinical problem. Mechanisms of acquired resistance reported in the past few years include secondary mutation of the EGFR gene, amplification of the MET gene, and overexpression of HGF; novel pharmaceutical agents are currently being developed to overcome resistance. This review focuses on these mechanisms of acquired resistance to EGFR-TKIs and discusses how they can be overcome.
Journal of Biomedicine and Biotechnology 01/2011; 2011:165214. · 2.44 Impact Factor
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ABSTRACT: Patients with lung adenocarcinoma who carry epidermal growth factor receptor (EGFR) gene mutations respond remarkably well to EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib, or erlotinib. However, the effect of EGFR-TKI treatment on the prolongation of overall survival (OS) of these patients remains uncertain, although several recent studies have shown prolongation of progression free survival compared with cytotoxic chemotherapy.
A total of 304 patients with lung adenocarcinoma who had postoperative recurrent disease were studied. To eliminate potential biases as possible, the matching of four potential predictive factors of responsiveness to EGFR-TKI led to the identification of 81 pairs of patients (those who were treated with gefitinib and those who were not). A deletion mutation in exon 19 and a point mutation (L858R) in exon 21 of the EGFR gene were also analyzed. We compared the OS between the two groups.
OS in the gefitinib group was significantly longer than in the control group (median, 63 vs. 41 months; p = 0.015). EGFR mutations were detected in 65 out of 129 patients (50%) in the whole sample. EGFR mutational status was not an independent prognostic factor of gefitinib benefit; rather, it was a predictive factor.
This study strongly suggested that gefitinib treatment improved OS of lung adenocarcinoma patients who had postoperative recurrence, especially those carrying EGFR mutations.
Surgical Oncology 12/2010; 19(4):e144-9. · 2.44 Impact Factor
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Marileila Varella-Garcia,
Tetsuya Mitsudomi,
Yashushi Yatabe, Takayuki Kosaka,
Eiji Nakajima,
Ana Carolina Xavier,
Margaret Skokan,
Chan Zeng,
Wilbur A Franklin,
Paul A Bunn,
Fred R Hirsch
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ABSTRACT: Sensitivity to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and frequency of activation mutations in EGFR is lower in Caucasian than Asian non small-cell lung cancer (NSCLC) patients. Increased EGFR gene copy numbers evaluated by fluorescence in situ hybridization (FISH) has been reported as predictor of clinical benefit from EGFR-TKIs in Caucasian NSCLC patients. This study was carried out to verify whether EGFR FISH had similar performance in Japanese patients.
A cohort of 44 Japanese patients with recurrent NSCLC after surgery was treated with gefitinib 250 mg daily. The cohort included 48% females and 52% never-smokers; 73% had prior chemotherapy and 57% had stage III-IV at the time of surgery. Adenocarcinoma was the most common histology (86%). FISH was performed using the EGFR/Chromosome Enumeration Probe 7 and PathVysion DNA probes (Abbott Molecular). Specimens were classified as FISH positive when showing gene amplification or high polysomy (> or = 4 copies of the gene in > or = 40% of tumor cells). Tumor response to gefitinib was assessed by RECIST for 33 patients with measurable diseases.
Twenty-nine tumors (66%) were EGFR FISH+ and 23 (53%) were HER2 FISH+. Overall response rate was 52%, representing 65% of EGFR FISH+ patients and 29% of EGFR FISH- patients (p = 0.0777). Survival was not impacted by the EGFR FISH (p = 0.9395) or the HER2 FISH (p = 0.0671) status. EGFR FISH+ was significantly associated with HER2 FISH+ (p = 0.015) and presence of EGFR mutation (p = 0.0060). EGFR mutation significantly correlated with response (p < 0.0001) and survival after gefitinib (p = 0.0204). EGFR and HER2 FISH status were not associated with KRAS mutation.
Frequency of EGFR FISH+ status was higher and its predictive power for TKI sensitivity was lower in this Japanese cohort than in Western NSCLC cohorts. These findings support differences in the mechanisms of EGFR pathway activation in NSCLC between Asian and Caucasian populations. Confirmation of these results in larger cohorts is warranted.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 03/2009; 4(3):318-25. · 4.55 Impact Factor
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ABSTRACT: MET (Met proto-oncogene) activation either by gene amplification or mutation is implicated in various types of human cancers. For lung cancer, MET gene amplification is reported to occur in a subset of adenocarcinomas. Although somatic mutations of MET in lung adenocarcinomas are rare, all but one of those reported so far entail a splice mutation deleting the juxtamembrane domain for binding the c-Cbl E3-ligase; normally such binding leads to ubiquitination and receptor degradation, and loss of this domain leads to MET activation. The purpose of this study was to clarify in the role of MET activation in lung carcinogenesis.
MET gene copy number was determined by real-time quantitative polymerase chain reaction in 187 of the patients with lung cancer and the MET gene splice mutation deleting the juxtamembrane domain was examined by direct sequencing in 262. The results were correlated with various clinical and pathologic features including mutations of the epidermal growth factor receptor, KRAS, and HER2 genes.
All the instances of MET activation occurred in patients with adenocarcinomas. The prevalences of MET gene amplification and splice mutations were 1.4% (2 of 148) and 3.3% (7 of 211), respectively. We identified four different intronic mutations that disrupted a splice consensus sequence in genomic DNA. Activation of MET and mutations of the epidermal growth factor receptor, KRAS, and HER2 genes had strict mutual exclusionary relationships.
About 5% of pulmonary adenocarcinomas in this cohort of Japanese patients were driven by activated MET by gene amplification or splice mutations. Such patients would be candidates for targeted therapy against MET.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2009; 4(1):5-11. · 4.55 Impact Factor
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ABSTRACT: Although mutation of the epidermal growth factor receptor (EGFR) gene is predictive for the response to EGFR-tyrosine kinase inhibitor, its prognostic impact for patients without EGFR-tyrosine kinase inhibitor treatment remains controversial. We examined for EGFR, KRAS or TP53 mutations in a consecutive large cohort of patients with lung adenocarcinoma, and evaluated their prognostic impact.
We analyzed 397 patients with lung adenocarcinoma who underwent potentially curative pulmonary resection. Total ribonucleic acid was extracted and direct sequencing of each gene was performed after reverse transcription-polymerase chain reaction.
We found that 196 patients (49%) had EGFR mutations. Of these, 83 were exon 19 deletions (42%) and 92 were L858R (47%). Univariate analysis showed that patients with EGFR mutations survived for a longer period than those without mutations (p = 0.0046). However, there was no difference in overall survival between the patients with exon 19 deletion and those with L858R (p = 0.4144). Patients with KRAS mutations or TP53 mutations tended to survive for a shorter period (p = 0.2183 and 0.0230, respectively). Multivariate analysis using the Cox proportional hazards model revealed that smoking status (p = 0.0310) and disease stage (p < 0.0001) were independent prognostic factors. However, none of the gene mutations was independent prognostic factors (EGFR, p = 0.3225; KRAS, p = 0.8500; TP53, p = 0.3191).
EGFR, KRAS, and TP53 gene mutations were not independently associated with the prognosis for Japanese patients with surgically treated lung adenocarcinoma.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2009; 4(1):22-9. · 4.55 Impact Factor
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ABSTRACT: Epidermal growth factor receptor (EGFR) mutations play substantial roles in genesis and proliferation of non-small-cell lung cancers (NSCLCs). We recently found that reproductive factors have a substantial impact on risk of development of NSCLCs featuring such EGFR mutations. Therefore, we explored the influence of dietary habits on NSCLC risk with reference to the EGFR mutational status. We conducted a case-control study using 353 patients with NSCLCs (122 EGFR mutated and 231 EGFR wild-type) and 1765 age-sex matched non-cancer control subjects. Dietary exposure was based on a semiquantitative food frequency questionnaire and impact of major food items, like meats, seafoods, vegetables and soybean products was assessed by multivariate logistic regression. Soybean products demonstrated a protective association with EGFR mutated, but not EGFR wild-type NSCLCs, with multivariate-adjusted odds ratios and 95% confidence intervals for the 2nd and 3rd tertile of soybean product consumption of 0.79 (0.50-1.27) and 0.56 (0.34-0.93) relative to those in the lowest tertile (trend P = 0.023). In conclusion, soy consumption may exert a protective association against the development of NSCLCs with EGFR mutations, providing possible insights into mechanisms of their genesis.
Cancer Science 07/2008; 99(6):1202-8. · 3.33 Impact Factor
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Hideki Endoh,
Yasunori Ishibashi,
Ei Yamaki,
Takeshi Yoshida,
Toshiki Yajima,
Hitoshi Kimura, Takayuki Kosaka,
Ryoichi Onozato,
Shigebumi Tanaka,
Tetsuya Mitsudomi,
Hiroyuki Kuwano
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ABSTRACT: Overexpression of EGFR is found in several malignancies including lung cancers. Recently, EGFR mutation has been shown to correlate with responsiveness to tyrosine kinase inhibitors (TKI). Although antibodies against phophorylated EGFR have been used in vitro, phosphorylated EGFR has yet not been examined well in resected non-small cell lung cancers (NSCLCs).
We studied the immunohistochemistry of anti-EGFR and phosphorylated EGFR in 97 resected NSCLCs, examined the relationship with EGFR mutation, and performed quantitative RT-PCR of the EGFR gene in the TaqMan assay.
EGFR mutation was seen in 27% of 97 NSCLCs and 37% of 70 adenocarcinomas. EGFR was stained in 60% of 97 NSCLCs. Phosphorylation of tyrosine 845 (pY845) and 1068 (pY1068) was positive in 49% and 48%, respectively. The observed correlation with EGFR mutation and pY845 or pY1068 was statistically significant (P=0.0001 for pY845, P<0.0001 for pY1068, chi square test), although phospho-EGFR status was not associated with a particular mutation type. pY1068-positive tumors also correlated with female, light smoker, and adenocarcinoma histology, but not with mRNA expression. Moreover, patients with pY1068-positive tumors showed prolonged survival (P=0.0093, log-rank test).
It is possible that immunohistochemistry of phosphorylated EGFR can substitute for EGFR mutation analysis. Further investigation is necessary to determine whether phospho-EGFR immunohistochemistry predicts response to TKIs and survival benefit.
Lung Cancer 06/2008; 63(2):241-6. · 3.43 Impact Factor
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Shinichi Toyooka,
Toshimi Takano, Takayuki Kosaka,
Katsuyuki Hotta,
Keitaro Matsuo,
Shuji Ichihara,
Yoshiro Fujiwara,
Junichi Soh,
Hiroki Otani,
Katsuyuki Kiura,
Keisuke Aoe,
Yasushi Yatabe,
Yuichiro Ohe,
Tetsuya Mitsudomi,
Hiroshi Date
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ABSTRACT: Epidermal growth factor receptor (EGFR) mutations have been reported as a predictive factor for favorable prognosis of gefitinib-treated patients with lung adenocarcinoma. However, its confounding with sex and smoking makes it unclear whether the EGFR mutation is independently associated with prolonged patient survival. In this study, we analyzed a large-scale database to discriminate the survival impact of EGFR mutations against those of sex and smoking after gefitinib therapy. EGFR mutations in exon19 and exon21 named drug-sensitive EGFR mutations were examined to investigate the impact of EGFR mutation, sex, and smoking status on survival of 362 gefitinib-treated patients with lung adenocarcinoma. Drug-sensitive EGFR mutations were detected in 169 patients (46.7%). The multivariate analysis including EGFR, sex, and smoking status showed that drug-sensitive EGFR mutations were significantly related to longer overall survival (OS) (P < 0.001) and progression-free survival (PFS) (P < 0.001). In addition, we investigated the impact of sex and smoking status according to EGFR mutation status, and the impact of EGFR mutation status according to sex and smoking status on survival. Sex and smoking status were not significantly associated with longer OS and PFS according to EGFR mutation status. Drug-sensitive EGFR mutations were significantly associated with longer OS and PFS according to sex or smoking status. Our results indicated that drug-sensitive EGFR mutations were the only independent factor for longer survival of patients treated with gefitinib, suggesting that patient selection based on EGFR mutation status for gefitinib therapy will lead to a better outcome for patients with lung adenocarcinoma.
Cancer Science 02/2008; 99(2):303-8. · 3.33 Impact Factor
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ABSTRACT: Mutation of the LKB1 gene (also known as STK11) is regarded as a cause of Peutz-Jeghers syndrome. In Caucasian patients, LKB1 somatic mutations occur in approximately one-third of lung adenocarcinomas. The aim of the present study was to examine the LKB1 gene in Japanese patients with lung cancer and to evaluate its clinical and pathological implications. We sequenced the LKB1 gene in 22 lung cancer cell lines and 100 Japanese patients with lung cancer (including 81 adenocarcinomas, 14 squamous cell carcinomas and five other histological types) who had undergone curative pulmonary resection. We also determined expression levels of the LKB1 gene by quantitative real-time reverse transcription-polymerase chain reaction and correlated these results with the clinical and pathological features of patients. Among the 22 cell lines, four had mutations and three of these were in adenocarcinoma cells. Of 100 primary lung cancers, only three had LKB1 gene mutations (3%). All of them were male smokers with adenocarcinomas. Hence, when confined to this subset of patients, the mutation frequency was 9% (3/33). No significant correlation was observed between the expression level of LKB1 and patient clinicopathological features. In conclusion, LKB1 gene mutations were relatively rare in Japanese patients with lung cancer compared with Caucasian patients. LKB1 gene mutations appear to be frequent in male, smoking patients of Caucasian origin, in contrast to EGFR or HER2 mutations that are frequent in non-smoking, female patients of Asian origin.
Cancer Science 12/2007; 98(11):1747-51. · 3.33 Impact Factor
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Shinichi Toyooka,
Keitaro Matsuo,
Hisayuki Shigematsu, Takayuki Kosaka,
Masaki Tokumo,
Yasushi Yatabe,
Syuji Ichihara,
Michio Inukai,
Hiroshi Suehisa,
Junichi Soh,
Katsuyuki Kiura,
Kwun M Fong,
Huei Lee,
Ignacio I Wistuba,
Adi F Gazdar,
Tetsuya Mitsudomi,
Hiroshi Date
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ABSTRACT: Mutation of epidermal growth factor receptor (EGFR) gene has been reported to be present in non-small cell lung cancer (NSCLC) and significantly associated with female sex and never-smoking status. In this study, we extensively investigated the impact of sex and smoking on the EGFR mutation.
We examined EGFR exons 18 to 21 status in 1,467 NSCLC patients by direct sequencing to study the impact of sex and smoking status on the EGFR mutational spectrum.
Among 1,467 patients, 197 mutations were found at exon 19, 176 at exon 21, 21 at exon 18, and 24 at exon 20. To examine the independent effect of sex and smoking, the mutational status of each exon was compared between smokers and never smokers in each sex and between males and females stratified by smoking status. In females, exon 19 (P = 0.001) and exon 21 (P < 0.001) mutations were significantly less frequent in ever smokers compared with never smokers. In males, exon 19 (P < 0.001), exon 21 (P < 0.001), and exon 18 (P = 0.003) mutations were significantly less frequent in ever smokers compared with never smokers. In analysis stratified by smoking, there was no difference in sex among never smokers. However, exon 19 mutations were significantly less frequent in males compared with females among ever smokers (P = 0.003). In addition, the interactive effect of male sex and ever smoking status significantly decreased the frequency of exon 19 mutations (P = 0.047) when female never smoker was set as a reference.
Both sex and smoking status could influence the EGFR mutational spectrum. Our findings suggest that individual EGFR exons may have differing susceptibilities for mutagenesis.
Clinical Cancer Research 11/2007; 13(19):5763-8. · 7.74 Impact Factor
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Hisaaki Tanaka,
Kiyoshi Yanagisawa,
Keiko Shinjo,
Ayumu Taguchi,
Ken Maeno,
Shuta Tomida,
Yukako Shimada,
Hirotaka Osada, Takayuki Kosaka,
Hideo Matsubara,
Tetsuya Mitsudomi,
Yoshitaka Sekido,
Mitsune Tanimoto,
Yasushi Yatabe,
Takashi Takahashi
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ABSTRACT: Emerging evidence, although currently very sparse, suggests the presence of "lineage-specific dependency" in the survival mechanisms of certain cancers. TTF-1 has a decisive role as a master regulatory transcription factor in lung development and in the maintenance of the functions of terminal respiratory unit (TRU) cells. We show that a subset of lung adenocarcinoma cell lines expressing TTF-1, which presumably represent those derived from the TRU lineage, exhibit marked dependence on the persistent expression of TTF-1. The inhibition of TTF-1 by RNA interference (RNAi) significantly and specifically induced growth inhibition and apoptosis in these adenocarcinoma cell lines. Furthermore, a fraction of TTF-1-expressing tumors and cell lines displayed an increase in the gene dosage of TTF-1 in the analysis of 214 patients with non-small-cell lung cancer, including 174 adenocarcinomas, showing a tendency of higher frequency of increased gene copies at metastatic sites than at primary sites (P=0.07, by two-sided Fisher's exact test). These findings strongly suggest that in addition to the development and maintenance of TRU lineages in normal lung, sustained TTF-1 expression may be crucial for the survival of a subset of adenocarcinomas that express TTF-1, providing credence for the lineage-specific dependency model.
Cancer Research 08/2007; 67(13):6007-11. · 7.86 Impact Factor
