24 results on '"Yasushi Yatabe"'
Search Results
2. Real‐world study of next‐generation sequencing diagnostic biomarker testing for patients with lung cancer in Japan
- Author
-
Toshiaki Takahashi, Makoto Nishio, Kazumi Nishino, Yasumasa Yoshiki, Naoko Shiraiwa, Birol Emir, Laura Iadeluca, Yasushi Yatabe, and Kazuto Nishio
- Subjects
Cancer Research ,Oncology ,General Medicine - Published
- 2023
3. MYB mediates downregulation of the colorectal cancer metastasis suppressor heterogeneous nuclear ribonucleoprotein L‐like during epithelial‐mesenchymal transition
- Author
-
Waki Hosoda, Koji Komori, Yasuhiro Shimizu, Yasushi Yatabe, Keiichiro Sakuma, Masahiro Aoki, and Eiichi Sasaki
- Subjects
Cancer Research ,Epithelial-Mesenchymal Transition ,Heterogeneous nuclear ribonucleoprotein ,Transcription, Genetic ,Sp1 Transcription Factor ,Down-Regulation ,colorectal cancer ,MYB ,Transfection ,Heterogeneous-Nuclear Ribonucleoproteins ,Gene Knockout Techniques ,Proto-Oncogene Proteins c-myb ,Cell, Molecular, and Stem Cell Biology ,Downregulation and upregulation ,Humans ,Metastasis suppressor ,Epithelial–mesenchymal transition ,Neoplasm Metastasis ,Promoter Regions, Genetic ,Cell Proliferation ,Gene knockdown ,epithelial‐mesenchymal transition ,Binding Sites ,General transcription factor ,Chemistry ,Original Articles ,Plicamycin ,General Medicine ,HNRNP ,SP1 ,Gene Expression Regulation, Neoplastic ,Oncology ,Gene Knockdown Techniques ,Cancer cell ,Disease Progression ,Cancer research ,Original Article ,Colorectal Neoplasms ,HT29 Cells - Abstract
Heterogeneous nuclear ribonucleoprotein L‐like (HNRNPLL), a suppressor of colorectal cancer (CRC) metastasis, is transcriptionally downregulated when CRC cells undergo epithelial‐mesenchymal transition (EMT). Here we show that decrease of MYB mediates the downregulation of HNRNPLL during EMT. The promoter activity was attributed to a region from −273 to −10 base pairs upstream of the transcription start site identified by 5'‐RACE analysis, and the region contained potential binding sites for MYB and SP1. Luciferase reporter gene assays and knockdown or knockout experiments for genes encoding the MYB family proteins, MYB, MYBL1, and MYBL2, revealed that MYB was responsible for approximately half of the promoter activity. On the other hand, treatment with mithramycin A, an inhibitor for SP1 and SP3, suppressed the promoter activity and their additive contribution was confirmed by knockout experiments. The expression level of MYB was reduced on EMT while that of SP1 and SP3 was unchanged, suggesting that the downregulation of HNRNPLL during EMT was mediated by the decrease of MYB expression while SP1 and SP3 determine the basal transcription level of HNRNPLL. Histopathological analysis confirmed the accumulation of MYB‐downregulated cancer cells at the invasion front of clinical CRC tissues. These results provide an insight into the molecular mechanism underlying CRC progression., Heterogeneous nuclear ribonucleoprotein L‐like (HNRNPLL), a suppressor of colorectal cancer (CRC) metastasis, is transcriptionally downregulated when CRC cells undergo epithelial‐mesenchymal transition (EMT). Here we show that decrease of MYB mediates the downregulation of HNRNPLL during EMT.
- Published
- 2021
4. Appropriate use of cancer comprehensive genome profiling assay using circulating tumor DNA
- Author
-
Kuniko Sunami, Tetsu Hayashida, Kazuto Nishio, Shinji Kohsaka, Ichiro Kinoshita, Hiroyuki Uetake, Kenji Tamura, Koshi Mimori, Hideaki Takahashi, Shinichi Toyooka, Noboru Yamamoto, Hideaki Bando, Masayuki Takeda, Keigo Komine, Katsuya Tsuchihara, Yoichi Naito, and Yasushi Yatabe
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,cancer comprehensive genome profiling assay ,Guidelines as Topic ,Appropriate use ,Japan ,Report ,Neoplasms ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Liquid biopsy ,plasma ,circulating tumor DNA ,Blood Specimen Collection ,liquid biopsy ,Universal health insurance ,business.industry ,Task force ,Gene Expression Profiling ,High-Throughput Nucleotide Sequencing ,Cancer ,General Medicine ,medicine.disease ,Advice (programming) ,next‐generation sequencer ,Circulating tumor DNA ,Mutation ,Genome profiling ,sense organs ,Transcriptome ,business ,Reports - Abstract
Comprehensive genomic profiling (CGP) is being increasingly used for the routine clinical management of solid cancers. In July 2018, the use of tumor tissue‐based CGP assays became available for all solid cancers under the universal health insurance system in Japan. Several restrictions presently exist, such as patient eligibility and limitations on the opportunities to perform such assays. The clinical implementation of CGP based on plasma circulating tumor DNA (ctDNA) is also expected to raise issues regarding the selection and use of tissue DNA and ctDNA CGP. A Joint Task Force for the Promotion of Cancer Genome Medicine comprised of three Japanese cancer‐related societies has formulated a policy proposal for the appropriate use of plasma CGP (in Japanese), available at https://www.jca.gr.jp/researcher/topics/2021/files/20210120.pdf, http://www.jsco.or.jp/jpn/user_data/upload/File/20210120.pdf, and https://www.jsmo.or.jp/file/dl/newsj/2765.pdf. Based on these recommendations, the working group has summarized the respective advantages and cautions regarding the use of tissue DNA CGP and ctDNA CGP with reference to the advice of a multidisciplinary expert panel, the preferred use of plasma specimens over tissue, and multiple ctDNA testing. These recommendations have been prepared to maximize the benefits of performing CGP assays and might be applicable in other countries and regions.
- Published
- 2021
5. Characterization of the large-scale Japanese patient-derived xenograft (J-PDX) library
- Author
-
Ken Kato, Yasushi Yatabe, Akinobu Hamada, Takeshi Kuwata, Atsushi Ohtsu, Toshio Imai, Mikiko Suzuki, Kazuaki Shimada, Mami Takahashi, Hiroyuki Mano, Shigehiro Yagishita, Toshirou Nishida, and Atsushi Ochiai
- Subjects
0301 basic medicine ,Oncology ,Adult ,Male ,Patient-Specific Modeling ,Cancer Research ,medicine.medical_specialty ,patient‐derived xenograft ,Adolescent ,Colorectal cancer ,Tumor heterogeneity ,03 medical and health sciences ,Mice ,Young Adult ,0302 clinical medicine ,Japan ,Internal medicine ,Neoplasms ,medicine ,Animals ,Humans ,Clinical efficacy ,Stage (cooking) ,Lung cancer ,Child ,Tumor xenograft ,Aged ,Neoplasm Staging ,Aged, 80 and over ,J‐PDX ,business.industry ,Cancer type ,Cancer ,General Medicine ,Original Articles ,Middle Aged ,medicine.disease ,030104 developmental biology ,Drug Discovery and Delivery ,Organ Specificity ,030220 oncology & carcinogenesis ,Child, Preschool ,coclinical trial ,Female ,Original Article ,business ,Neoplasm Transplantation - Abstract
The use of patient‐derived xenografts (PDXs) has recently attracted attention as a drug discovery platform with a high predictive clinical efficacy and a preserved tumor heterogeneity. Given the racial differences in genetic variations, it would be desirable to establish a PDX library from Japanese cancer patients on a large scale. We thus tried to construct the Japanese PDX (J‐PDX) library with a detailed clinical information for further clinical utilization. Between August 2018 and May 2020, a total of 1126 cancer specimens from 1079 patients were obtained at the National Cancer Center Hospital and National Cancer Center Hospital East, Japan, and were immediately transplanted to immunodeficient mice at the National Cancer Center Research Institute. A total of 298 cross‐cancer PDXs were successfully established. The time to engraftment varied greatly by cancer subtypes, especially in the first passage. The engraftment rate was strongly affected by the clinical stage and survival time of the original patients. Approximately 1 year was needed from tumor collection to the time when coclinical trials were conducted to test the clinical utility. The 1‐year survival rates of the patients who were involved in establishing the PDX differed significantly, from 95.6% for colorectal cancer to 56.3% for lung cancer. The J‐PDX library consisting of a wide range of cancer subtypes has been successfully established as a platform for drug discovery and development in Japan. When conducting coclinical trials, it is necessary to consider the target cancer type, stage, and engraftment rate in light of this report., We have successfully established a PDX library derived from Japanese cancer patients. In less than 2 years, we have registered more than 1000 specimens and established nearly 300 PDXs. We will further enrich the library and use it as a platform to accelerate drug discovery in Japan.
- Published
- 2021
6. <scp>HNRNPLL</scp> stabilizes <scp>mRNA</scp> for <scp>DNA</scp> replication proteins and promotes cell cycle progression in colorectal cancer cells
- Author
-
Koji Komori, Eiichi Sasaki, Masahiro Aoki, Yasushi Yatabe, Keiichiro Sakuma, Kenya Kimura, and Yasuhiro Shimizu
- Subjects
DNA Replication ,0301 basic medicine ,Cancer Research ,Heterogeneous nuclear ribonucleoprotein ,Down-Regulation ,colorectal cancer ,Heterogeneous-Nuclear Ribonucleoproteins ,03 medical and health sciences ,0302 clinical medicine ,Cell, Molecular, and Stem Cell Biology ,Downregulation and upregulation ,Cell Line, Tumor ,Humans ,Immunoprecipitation ,RNA, Messenger ,mRNA stability ,Gene ,Cell Proliferation ,Gene knockdown ,biology ,Cell growth ,Cell Cycle ,DNA replication ,Cell Differentiation ,Original Articles ,General Medicine ,Cell cycle ,Up-Regulation ,Cell biology ,Proliferating cell nuclear antigen ,Gene Expression Regulation, Neoplastic ,HNRNPLL ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Original Article ,Colorectal Neoplasms ,HT29 Cells - Abstract
Heterogeneous nuclear ribonucleoprotein L-like (HNRNPLL), an RNA-binding protein that regulates alternative splicing of pre-mRNA, has been shown to regulate differentiation of lymphocytes, as well as metastasis of colorectal cancer cells. Here, we show that HNRNPLL promotes cell cycle progression and, hence, proliferation of colorectal cancer cells. Functional annotation analysis of those genes whose expression levels were changed threefold or more in RNA sequencing analysis between SW480 cells overexpressing HNRNPLL and those knocked down for HNRNPLL revealed enrichment of DNA replication-related genes by HNRNPLL overexpression. Among 13 genes detected in the DNA replication pathway, PCNA, RFC3 and FEN1 showed reproducible upregulation by HNRNPLL overexpression both at mRNA and at protein levels in SW480 and HT29 cells. Importantly, knockdown of any of these genes alone suppressed the proliferation-promoting effect induced by HNRNPLL overexpression. RNA-immunoprecipitation assay presented a binding of FLAG-tagged HNRNPLL to mRNA of these genes, and HNRNPLL overexpression significantly suppressed the downregulation of these genes during 12 h of actinomycin D treatment, suggesting a role of HNRNPLL in mRNA stability. Finally, analysis of a public RNA sequencing dataset of clinical samples suggested a link between overexpression of HNRNPLL and that of PCNA, RFC3 and FEN1. This link was further supported by immunohistochemistry of colorectal cancer clinical samples, whereas expression of CDKN1A, which is known to inhibit the cooperative function of PCNA, RFC3 and FEN1, was negatively associated with HNRNPLL expression. These results indicate that HNRNPLL stabilizes mRNA encoding regulators of DNA replication and promotes colorectal cancer cell proliferation.
- Published
- 2018
7. Japanese Society of Medical Oncology Clinical Guidelines: Molecular Testing for Colorectal Cancer Treatment, Third Edition
- Author
-
Kentaro Yamazaki, Hiroya Taniguchi, Takayuki Yoshino, Kiwamu Akagi, Hideyuki Ishida, Hiromichi Ebi, Kaname Nakatani, Kei Muro, Yasushi Yatabe, Kensei Yamaguchi, and Katsuya Tsuchihara
- Subjects
0301 basic medicine ,Proto-Oncogene Proteins B-raf ,Cancer Research ,Membrane Proteins ,General Medicine ,Medical Oncology ,DNA Mismatch Repair ,GTP Phosphohydrolases ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Japan ,030220 oncology & carcinogenesis ,Mutation ,Practice Guidelines as Topic ,Humans ,Genetic Testing ,Colorectal Neoplasms ,Societies, Medical - Abstract
The Japanese Society of Medical Oncology (JSMO) previously published 2 editions of the clinical guidelines: "Japanese guidelines for testing of KRAS gene mutation in colorectal cancer" in 2008 and "Japanese Society of Medical Oncology Clinical Guidelines: RAS (KRAS/NRAS) mutation testing in colorectal cancer patients" in 2014. These guidelines have contributed to the proper use of KRAS and RAS mutation testing, respectively. Recently, clinical utility, particularly for colorectal cancer (CRC) patients with BRAF V600E mutation or DNA mismatch-repair (MMR) deficiency, has been established. Therefore, the guideline members decided these genetic alterations should also be involved. The aim of this revision is to properly carry out testing for BRAF V600E mutation and MMR deficiency in addition to RAS mutation. The revised guidelines include the basic requirements for testing for these genetic alterations based on recent scientific evidence. Furthermore, because clinical utility of comprehensive genetic testing using next-generation sequencing and somatic gene testing of analyzing circulating tumor DNA has increasingly evolved with recent advancements in testing technology, we noted the current situation and prospects for these testing technologies and their clinical implementation in the revised guidelines.
- Published
- 2018
8. Japanese Society of Medical Oncology Clinical Guidelines: <scp>RAS</scp> ( <scp>KRAS</scp> / <scp>NRAS</scp> ) mutation testing in colorectal cancer patients
- Author
-
Eishi Baba, Toshiaki Watanabe, Atsushi Ochiai, Takayuki Yoshino, Yasushi Yatabe, Katsuya Tsuchihara, Hiroya Taniguchi, Hiromichi Ebi, Kei Muro, and Kentaro Yamazaki
- Subjects
Oncology ,Neuroblastoma RAS viral oncogene homolog ,Cancer Research ,medicine.medical_specialty ,Mutation ,medicine.diagnostic_test ,Cetuximab ,Colorectal cancer ,business.industry ,General Medicine ,medicine.disease ,medicine.disease_cause ,Proto-Oncogene Proteins p21(ras) ,Internal medicine ,medicine ,Mutation testing ,KRAS ,business ,Genetic testing ,medicine.drug - Abstract
The Japanese guidelines for the testing of KRAS mutations in colorectal cancer have been used for the past 5 years. However, new findings of RAS (KRAS/NRAS) mutations that can further predict the therapeutic effects of anti-epidermal growth factor receptor (EGFR) antibody therapy necessitated a revision of the guidelines. The revised guidelines included the following five basic requirements for RAS mutation testing to highlight a patient group in which anti-EGFR antibody therapy may be ineffective: First, anti-EGFR antibody therapy may not offer survival benefit and/or tumor shrinkage to patients with expanded RAS mutations. Thus, current methods to detect KRAS exon 2 (codons 12 and 13) mutations are insufficient for selecting appropriate candidates for this therapy. Additional testing of extended KRAS/NRAS mutations is recommended. Second, repeated tests are not required for the detection; tissue materials of either primary or metastatic lesions are applicable for RAS mutation testing. Evaluating RAS mutations prior to anti-EGFR antibody therapy is recommended. Third, direct sequencing with manual dissection or allele-specific PCR-based methods is currently applicable for RAS mutation testing. Fourth, thinly sliced sections of formalin-fixed, paraffin-embedded tissue blocks are applicable for RAS mutation testing. One section stained with H&E should be provided to histologically determine whether the tissue contains sufficient amount of tumor cells for testing. Finally, RAS mutation testing must be performed in laboratories with appropriate testing procedures and specimen management practices.
- Published
- 2015
9. Association between insulin-like growth factor-1 polymorphisms and stomach cancer risk in a Japanese population
- Author
-
Hidemi Ito, Hideo Tanaka, Daisuke Ennishi, Satoyo Hosono, Kenji Yamao, Miki Watanabe, Nobuyuki Hamajima, Kazuo Tajima, Keitaro Matsuo, Kohei Shitara, Yasushi Yatabe, Seiji Ito, Mitsune Tanimoto, and Akira Sawaki
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,Genotype ,medicine.medical_treatment ,Polymorphism, Single Nucleotide ,Insulin-like growth factor ,Japan ,Risk Factors ,Stomach Neoplasms ,Diabetes mellitus ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Insulin-Like Growth Factor I ,Family history ,Allele ,Stomach cancer ,Aged ,Aged, 80 and over ,business.industry ,Confounding ,Cancer ,General Medicine ,Odds ratio ,Middle Aged ,medicine.disease ,Case-Control Studies ,Female ,business ,Signal Transduction - Abstract
The insulin-like growth factor (IGF) signaling system plays a central role in cellular growth, differentiation and proliferation. Although the association between IGF1 gene polymorphisms and cancer risk has been evaluated for several carcinomas, this association has not yet been examined for stomach cancer. We investigated the association between IGF1 polymorphisms and the risk of stomach cancer in a Japanese population. A total of 703 patients with stomach cancer and 1462 non-cancer control subjects were enrolled in this case–control study. Associations between polymorphisms of 10 IGF1 loci and the risk of stomach cancer were evaluated using odds ratios (OR) and 95% confidence intervals (CI) in multiple logistic regression models. We observed that the C allele in rs1520220 and the G allele in rs4764887 were significantly associated with stomach cancer risk in the per-allele model after adjusting for other risk factors (OR: 1.14 [95% CI: 1.00–1.30] and OR: 1.18 [95% CI: 1.02-1.36], respectively). We also observed a positive and dose-dependent association between the number of risk alleles and stomach cancer risk (P-trend: 0.019) when examining the two loci in the same model. These associations were still seen after adjusting for potential confounders, including sex, age, smoking status, history of diabetes and family history of stomach cancer. We did not find any significant interaction between these factors and the number of risk alleles. In conclusion, we observed a significant association between IGF1 polymorphisms and stomach cancer risk among a Japanese population. Examination of the biological significance of IGF1 is warranted. (Cancer Sci 2011; 102: 2231–2235)
- Published
- 2011
10. Comparison between self-reported facial flushing after alcohol consumption and ALDH2 Glu504Lys polymorphism for risk of upper aerodigestive tract cancer in a Japanese population
- Author
-
Satoyo Hosono, Yasushi Yatabe, Hideo Tanaka, Hidemi Ito, Kazuo Tajima, Keitaro Matsuo, Shunzo Hatooka, Masayuki Shinoda, Takakazu Kawase, Takeshi Suzuki, Yasuhisa Hasegawa, Isao Oze, and Miki Watanabe
- Subjects
Adult ,Male ,Risk ,Cancer Research ,medicine.medical_specialty ,Pathology ,Alcohol Drinking ,Esophageal Neoplasms ,Gastroenterology ,Internal medicine ,Genotype ,Flushing ,medicine ,Humans ,Genetic Predisposition to Disease ,Laryngeal Neoplasms ,Genotyping ,Aged ,ALDH2 ,Polymorphism, Genetic ,Surrogate endpoint ,business.industry ,Aldehyde Dehydrogenase, Mitochondrial ,digestive, oral, and skin physiology ,Head and neck cancer ,Cancer ,Pharyngeal Neoplasms ,General Medicine ,Odds ratio ,Aldehyde Dehydrogenase ,Middle Aged ,medicine.disease ,Confidence interval ,Oncology ,Female ,Mouth Neoplasms ,business - Abstract
Some Japanese exhibit facial flushing after drinking alcohol. Facial flushing was considered to be caused by acetaldehydemia. The concentration of blood acetaldehyde was concerned with the catalytic activity of acetaldehyde dehydrogenase (ALDH). Acetaldehyde dehydrogenase (ALDH)-2 polymorphism (rs671, Glu504Lys) was known to be associated with upper aerodigestive tract (UAT) cancer due to modulation of ALDH2 enzyme activity. It remains controversial whether facial flushing is useful in predicting UAT cancer risk as a surrogate marker of ALDH2 polymorphism. We conducted a case-control study to assess the risk of UAT cancer and facial flushing and ALDH2 polymorphism. Cases and controls were 585 UAT cancer patients and matched 1170 noncancer outpatients of Aichi Cancer Center Hospital. Information on facial flushing and other lifestyle factors was collected via a self-administered questionnaire. Association between facial flushing, polymorphism, and UAT cancer was assessed by odds ratios and 95% confidence intervals by using conditional logistic regression models. The facial flushing had no significant association with UAT cancer, although ALDH2 Lys allele was significantly associated with UAT cancer. No significant interaction between facial flushing and alcohol consumption was observed in this study, whereas ALDH2 Lys allele had significant association with UAT cancer. The misclassification between facial flushing and ALDH2 genotype was observed in 18% of controls with ALDH2 Glu/Glu genotype and in 16% of controls with ALDH2 Glu/Lys genotype. Facial flushing was less useful to predict UAT cancer risk than genotyping ALDH2 polymorphism.
- Published
- 2010
11. Usefulness of cumulative smoking dose for identifying theEGFRmutation and patients with non-small-cell lung cancer for gefitinib treatment
- Author
-
Hiroshi Date, Hiromasa Yamamoto, Katsuyuki Kiura, Takafumi Kubo, Masaomi Yamane, Shinichi Toyooka, Yuichiro Ohe, Keitaro Matsuo, Toshimi Takano, Yoshifumi Sano, Takahiro Oto, Kazunori Tsukuda, Yasushi Yatabe, Masaru Jida, Tetsuya Mitsudomi, Shinichiro Miyoshi, and Katsuyuki Hotta
- Subjects
Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.drug_class ,DNA Mutational Analysis ,Antineoplastic Agents ,Kaplan-Meier Estimate ,Sensitivity and Specificity ,Disease-Free Survival ,Tyrosine-kinase inhibitor ,Gefitinib ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,medicine ,Humans ,Epidermal growth factor receptor ,Lung cancer ,biology ,business.industry ,Smoking ,Hazard ratio ,Respiratory disease ,Cancer ,General Medicine ,medicine.disease ,Confidence interval ,ErbB Receptors ,Endocrinology ,ROC Curve ,Drug Resistance, Neoplasm ,Area Under Curve ,Mutation ,Quinazolines ,biology.protein ,Female ,business ,medicine.drug - Abstract
We examined the diagnostic accuracy of the cumulative smoking dose for identifying the epidermal growth factor receptor (EGFR) exon 19 deletion and L858R mutation among Japanese patients with non-small-cell lung cancer (NSCLC). EGFR mutations in exon 19 and exon 21 were determined in 1001 NSCLC patients. A receiver–operating characteristic (ROC) curve methodology was applied to estimate the diagnostic accuracy. EGFR mutations were detected in 314 patients (31.4%). A cumulative smoking dose of less than 13 pack-years (PY) was the optimal cut-off point for predicting a positive EGFR mutation status, producing a balance between the sensitivity (73.5%) and the specificity (77%). The area under the ROC curve was 0.77, indicating that the smoking dose had a moderate diagnostic accuracy. The median survival time or the median progression-free survival time of patients who had smoked less than 13 pack-years (PY) were 18.6 and 6.3 months, respectively, while those of patients with equal to or more than 13 PY were 9.6 and 2.4 months, respectively. The overall survival (OS) and progression-free survival (PFS) rates were significantly different between the two groups (OS: hazard ratio [HR] = 0.64, 95% confidence interval [CI] = 0.51–0.80, P = 0.0001) (PFS: HR = 0.58, 95% CI = 0.47–0.71, P
- Published
- 2009
12. Risk factors differ for non-small-cell lung cancers with and without EGFR mutation: assessment of smoking and sex by a case-control study in Japanese
- Author
-
Hidemi Ito, Takeshi Suzuki, Takayuki Kosaka, Keitaro Matsuo, Kazuo Tajima, Yasushi Yatabe, Akio Hiraki, Tetsuya Mitsudomi, Kenji Wakai, and Kaoru Hirose
- Subjects
Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Sex Factors ,Asian People ,Risk Factors ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Epidemiology ,medicine ,Carcinoma ,Humans ,Epidermal growth factor receptor ,Risk factor ,Lung cancer ,Aged ,biology ,business.industry ,Smoking ,Case-control study ,General Medicine ,Odds ratio ,Middle Aged ,medicine.disease ,Confidence interval ,respiratory tract diseases ,ErbB Receptors ,Endocrinology ,Case-Control Studies ,Mutation ,biology.protein ,Female ,business - Abstract
The present study aimed to assess the impact of smoking and sex for the risk of non-small-cell lung cancer (NSCLC) with or without epidermal growth factor receptor (EGFR) mutation. We conducted a case-control study using 152 patients with EGFR-mutated (EGFRmut) NSCLC, 283 with EGFR-wild-type (EGFRwt) NSCLC and 2175 age- and sex-frequency-matched controls. Smoking was a significant risk factor for EGFRwt NSCLC (odds ratio [OR] for ever-smokers, 4.05; 95% confidence interval [CI], 2.79-5.88) but not for EGFRmut NSCLC (OR, 0.73; CI, 0.46-1.14). Sex did not affect this association. The association was observed consistently with other smoking-related parameters including pack-years. Sex was the sole risk factor for EGFRmut NSCLC (OR for women relative to men, 2.19; CI, 1.41-3.39) and there was no significant interaction between women and smoking. In contrast, sex, smoking and their interaction were significant in EGFRwt NSCLC. The impact of sex on EGFR mutation status was assessed by several indicators of reproductive history among women. Total fertile years showed a significant positive association with EGFRmut NSCLC but not with EGFRwt NSCLC. Other indicators showed similar trends and this result may partly explain the sexual difference in the acquisition of EGFR mutation. In conclusion, our case-control study clearly demonstrated that the impacts of smoking and sex on the risk of EGFRmut NSCLC are different from those for EGFRwt NSCLC. Further epidemiological evaluation is warranted.
- Published
- 2007
13. Japanese Society of Medical Oncology Clinical Guidelines: RAS (KRAS/NRAS) mutation testing in colorectal cancer patients
- Author
-
Hiroya, Taniguchi, Kentaro, Yamazaki, Takayuki, Yoshino, Kei, Muro, Yasushi, Yatabe, Toshiaki, Watanabe, Hiromichi, Ebi, Atsushi, Ochiai, Eishi, Baba, and Katsuya, Tsuchihara
- Subjects
N-ras genes ,Paraffin Embedding ,Staining and Labeling ,Panitumumab ,Antibodies, Monoclonal ,Cetuximab ,Membrane Proteins ,Antineoplastic Agents ,colorectal cancer ,Sequence Analysis, DNA ,Antibodies, Monoclonal, Humanized ,GTP Phosphohydrolases ,ErbB Receptors ,Proto-Oncogene Proteins p21(ras) ,Japan ,Proto-Oncogene Proteins ,Report ,Mutation ,Anti-EGFR antibodies ,ras Proteins ,Humans ,Genetic Testing ,K-ras genes ,Colorectal Neoplasms ,guideline - Abstract
The Japanese guidelines for the testing of KRAS mutations in colorectal cancer have been used for the past 5 years. However, new findings of RAS (KRAS/NRAS) mutations that can further predict the therapeutic effects of anti-epidermal growth factor receptor (EGFR) antibody therapy necessitated a revision of the guidelines. The revised guidelines included the following five basic requirements for RAS mutation testing to highlight a patient group in which anti-EGFR antibody therapy may be ineffective: First, anti-EGFR antibody therapy may not offer survival benefit and/or tumor shrinkage to patients with expanded RAS mutations. Thus, current methods to detect KRAS exon 2 (codons 12 and 13) mutations are insufficient for selecting appropriate candidates for this therapy. Additional testing of extended KRAS/NRAS mutations is recommended. Second, repeated tests are not required for the detection; tissue materials of either primary or metastatic lesions are applicable for RAS mutation testing. Evaluating RAS mutations prior to anti-EGFR antibody therapy is recommended. Third, direct sequencing with manual dissection or allele-specific PCR-based methods is currently applicable for RAS mutation testing. Fourth, thinly sliced sections of formalin-fixed, paraffin-embedded tissue blocks are applicable for RAS mutation testing. One section stained with H&E should be provided to histologically determine whether the tissue contains sufficient amount of tumor cells for testing. Finally, RAS mutation testing must be performed in laboratories with appropriate testing procedures and specimen management practices.
- Published
- 2014
14. Throwing new light on lung cancer pathogenesis: Updates on three recent topics
- Author
-
Shuta Tomida, Kiyoshi Yanagisawa, Yasushi Yatabe, Tetsuya Mitsudomi, and Takashi Takahashi
- Subjects
Cancer Research ,Lung Neoplasms ,Proteome ,Colorectal cancer ,Adenocarcinoma ,Bioinformatics ,medicine.disease_cause ,Pathogenesis ,Chromosomal Instability ,Chromosome instability ,medicine ,Humans ,Genes, Tumor Suppressor ,Lung cancer ,business.industry ,Gene Expression Profiling ,Cancer ,Genes, erbB-1 ,General Medicine ,medicine.disease ,Review article ,Genes, cdc ,Genes, ras ,Oncology ,Mutation ,Immunology ,business ,Carcinogenesis - Abstract
Lung cancers have become the leading cause of cancer deaths in Japan, claiming more than 55 000 lives annually. Unfortunately, substantial improvement in terms of cure rates has not been achieved over the last two decades, although during the same period of time in-depth basic knowledge of the molecular mechanisms, which underlies carcinogenesis and progression of this deadly group of neoplasms, has accumulated at an amazing pace. It has consequently become evident that they have many shared but also distinct features, when comparisons are made not only with other common epithelial cancers of adults, such as colon cancer, but also within the various histologic types of lung cancers themselves. This review article provides an up-date on cutting-edge research into the following three different topics, from which important new insights have been obtained. The first concerns genetic instability, especially chromosome instability, and checkpoint failure in lung cancers. Second, we deal with EGFR mutations, which shows revealing specificities in various aspects. Finally, advances in the expression profiling analysis of both transcriptomes and proteomes of lung cancers are summarized.
- Published
- 2005
15. Reduced expression of Dicer associated with poor prognosis in lung cancer patients
- Author
-
Shinichiro Miyoshi, Takahashi Takahashi, Kiyoshi Yanagisawa, Yoko Karube, Yoshio Tatematsu, Tetsuya Mitsudomi, Hirotaka Osada, Yasushi Yatabe, Shuta Tomida, Hisaaki Tanaka, and Junichi Takamizawa
- Subjects
Adult ,Male ,Ribonuclease III ,Cancer Research ,Lung Neoplasms ,XPO5 ,Pathogenesis ,Carcinoma, Non-Small-Cell Lung ,microRNA ,medicine ,Humans ,Lung cancer ,Survival analysis ,Drosha ,Aged ,biology ,Smoking ,Cancer ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,MicroRNAs ,Oncology ,Immunology ,biology.protein ,Cancer research ,Female ,Dicer - Abstract
Emerging evidence suggests that microRNA, which are well-conserved, abundant and small regulatory RNA, may be involved in the pathogenesis of human cancers. We recently reported that expression of let-7 was frequently reduced in lung cancers, and that reduced let-7 expression was significantly associated with shorter patient survival. Two members of the double-stranded RNA-specific endonuclease family, Dicer and Drosha, convert precursor forms of microRNA into their mature forms using a stepwise process. In the present study, we examined expression levels of these genes in 67 non-small cell lung cancer cases, and found for the first time that Dicer expression levels were reduced in a fraction of lung cancers with a significant prognostic impact on the survival of surgically treated cases. It should be noted that multivariate COX regression analysis showed that the prognostic impact of Dicer (P=0.001) appears to be independent of disease stage (P=0.001), while logistic regression analysis demonstrated that the higher incidence of reduced Dicer expression in poorly differentiated tumors remained significant even after correction for other parameters (P=0.02). Given the fundamental and multiple biological roles of Dicer in various cellular processes, our results suggest the involvement of reduced Dicer expression in the development of lung cancers, thus warranting further investigations of the underlying mechanisms, which can be expected to enhance understanding of the molecular pathogenesis of this fatal cancer.
- Published
- 2005
16. Gene expression profiling of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly reveals alterations of characteristic oncogenetic pathways
- Author
-
Masataka Okamoto, Yasuo Morishima, Shigeo Nakamura, Kenji Ishitsuka, Masao Seto, Teru Kanda, Yasushi Yatabe, Kazuhito Yamamoto, Harumi Kato, Shinobu Tsuzuki, Miyuki Katayama, Koichi Ohshima, Yukiyasu Ozawa, Kennosuke Karube, Jun Takizawa, and Tomohiro Kinoshita
- Subjects
Adult ,Male ,STAT3 Transcription Factor ,Cancer Research ,Aging ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Electrophoretic Mobility Shift Assay ,lymphoma ,medicine.disease_cause ,NF-κB ,Epstein–Barr virus ,STAT3 ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Biomarkers, Tumor ,Humans ,Epstein–Barr virus infection ,neoplasms ,Aged ,Janus Kinases ,Oligonucleotide Array Sequence Analysis ,biology ,Activator (genetics) ,Gene Expression Profiling ,NF-kappa B ,General Medicine ,Original Articles ,Middle Aged ,medicine.disease ,Lymphoma ,Gene expression profiling ,Enzyme Activation ,Oncology ,Cancer research ,biology.protein ,STAT protein ,Female ,Lymphoma, Large B-Cell, Diffuse ,Diffuse large B-cell lymphoma - Abstract
Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly (EBV[+]DLBCL-E) is classified as a subtype of DLBCL. Until now, its molecular pathogenesis has remained unknown. To identify pathways characteristic of EBV(+)DLBCL-E, gene expression profiling of five EBV(+)DLBCL-E and seven EBV-negative DLBCL (EBV[-]DLBCL) cases was undertaken using human oligonucleotide microarray analysis. Gene set enrichment analysis and gene ontology analysis showed that gene sets of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and nuclear factor kappa B (NF-κB) pathways were enriched in EBV(+)DLBCL-E cases. To confirm the results of the expression profiles, in vitro analysis was performed. Expression profiling analysis showed that high activation of the JAK-STAT and NF-κB pathways was induced by EBV infection into DLBCL cell lines. Activation of the NF-κB pathway was confirmed in EBV-infected cell lines using an electrophoretic mobility shift assay. Western blot analysis revealed an increased protein expression level of phosphorylated signal transducer and activator of transcription 3 (STAT3) in an EBV-infected cell line. Protein expression of phosphorylated STAT3 was frequently observed in lymphoma cells of EBV(+)DLBCL-E clinical samples using immunohistochemistry (EBV[+]DLBCL-E: 80.0% [n = 20/25] versus EBV[-]DLBCL: 38.9% [n = 14/36]; P = 0.001). The results of the present study suggest that activation of the JAK-STAT and NF-κB pathways was characteristic of EBV(+)DLBCL-E, which may reflect the nature of EBV-positive tumor cells. Targeting these pathways as therapies might improve clinical outcomes of EBV(+)DLBCL-E.
- Published
- 2013
17. ABO blood group alleles and the risk of pancreatic cancer in a Japanese population
- Author
-
Satoyo Hosono, Miki Watanabe, Shinsuke Iida, Hidemi Ito, Hideo Tanaka, Saeko Ogata, Kazuo Tajima, Keitaro Matsuo, Nobumasa Mizuno, Yasushi Yatabe, Makoto Nakao, Kenji Yamao, Shigeki Sato, and Ryuzo Ueda
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Genotype ,Gastroenterology ,ABO Blood-Group System ,Asian People ,Risk Factors ,Internal medicine ,ABO blood group system ,medicine ,Humans ,Genetic Predisposition to Disease ,Risk factor ,Allele ,Alleles ,Aged ,Blood type ,business.industry ,Reverse Transcriptase Polymerase Chain Reaction ,Confounding ,Case-control study ,General Medicine ,Odds ratio ,Middle Aged ,Pancreatic Neoplasms ,Oncology ,Case-Control Studies ,Immunology ,Female ,business - Abstract
Several studies have investigated a possible association between the ABO blood group and the risk of pancreatic cancer (PC), but this association has not been fully evaluated in Asian populations. The present study aimed to assess the impact of genotype-derived ABO blood types, particularly ABO alleles, on the risk of PC in a Japanese population. We conducted a case-control study using 185 PC and 1465 control patients who visited Aichi Cancer Center in Nagoya, Japan. Using rs8176719 as a marker for the O allele, and rs8176746 and rs8176747 for the B allele, all participants' two ABO alleles were inferred. The impact of ABO blood type on PC risk was examined by multivariate analysis, with adjustment for potential confounders to estimate odds ratios (OR) and 95% confidence intervals (CI). An increased risk of PC was observed with the addition of any non-O allele (trend P = 0.012). Compared with subjects with the OO genotype, those with AO and BB genotypes had significantly increased OR of 1.67 (CI, 1.08-2.57) and 3.28 (CI, 1.38-7.80), respectively. Consistent with earlier reports showing a higher risk of PC for individuals with the non-O blood type, the previously reported protective allele (T) for rs505922 was found to be strongly correlated (r(2) = 0.96) with the O allele. In conclusion, this case-control study showed a statistically significant association between ABO blood group and PC risk in a Japanese population. Further studies are necessary to define the mechanisms by which the ABO gene or closely linked genetic variants influence PC risk.
- Published
- 2011
18. Soy consumption reduces the risk of non-small-cell lung cancers with epidermal growth factor receptor mutations among Japanese
- Author
-
Kaoru Hirose, Tetsuya Mitsudomi, Hidemi Ito, Keitaro Matsuo, Kenji Wakai, Yasushi Yatabe, Akio Hiraki, Takeshi Suzuki, Takayuki Kosaka, and Kazuo Tajima
- Subjects
Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Adenocarcinoma ,Logistic regression ,Japan ,Risk Factors ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,Medicine ,Mutational status ,Humans ,Epidermal growth factor receptor ,Aged ,Lung ,biology ,business.industry ,Soy Foods ,General Medicine ,Odds ratio ,Feeding Behavior ,Middle Aged ,Reproductive Factors ,Control subjects ,respiratory tract diseases ,Diet ,ErbB Receptors ,Endocrinology ,medicine.anatomical_structure ,Case-Control Studies ,Mutation ,biology.protein ,Carcinoma, Squamous Cell ,Carcinoma, Large Cell ,Female ,Non small cell ,business - 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.
- Published
- 2008
19. Interleukin-2 potentiation of cetuximab antitumor activity for epidermal growth factor receptor-overexpressing gastric cancer xenografts through antibody-dependent cellular cytotoxicity
- Author
-
Masae Tatematsu, Tadao Manabe, Masayasu Hara, Yasushi Yatabe, Hayao Nakanishi, Makoto Matsui, and Kunio Tsujimura
- Subjects
Interleukin 2 ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Transplantation, Heterologous ,Cetuximab ,Antineoplastic Agents ,Apoptosis ,G(M1) Ganglioside ,Antibodies, Monoclonal, Humanized ,chemistry.chemical_compound ,Mice ,Growth factor receptor ,Stomach Neoplasms ,Internal medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Epidermal growth factor receptor ,Neoplasm Metastasis ,Antibody-dependent cell-mediated cytotoxicity ,biology ,business.industry ,Antibody-Dependent Cell Cytotoxicity ,Cancer ,Antibodies, Monoclonal ,Drug Synergism ,General Medicine ,medicine.disease ,Immunohistochemistry ,digestive system diseases ,ErbB Receptors ,Endocrinology ,Cytokine ,Oncology ,chemistry ,Cancer research ,biology.protein ,Interleukin-2 ,Growth inhibition ,business ,Neoplasm Transplantation ,medicine.drug - Abstract
Cetuximab, a chimeric monoclonal antibody to epidermal growth factor receptor (EGFR), has been proved to have clinically significant antitumor activity against advanced colorectal cancers, but its therapeutic activity for gastric cancers remains unclear. In the present study, we investigated the antitumor effect and action mechanism of cetuximab using EGFR high-expressing (MKN-28) and EGFR low-expressing (GLM-1) gastric cancer cell lines without gene amplification. Cetuximab showed neither significant growth inhibition nor induction of apoptosis in either cell line in vitro, and only slightly inhibited ligand-induced phosphorylation of protein kinase B and extracellular signal-regulated kinase in MKN-28 cells. In contrast, cetuximab significantly inhibited subcutaneous and intraperitoneal tumor growth of MKN-28 cells, but not GLM-1 cells, in nude mice. This antitumor activity was significantly enhanced and diminished in nude mice by treatment with interleukin-2 (IL-2) and antiasialo GM1 antibody, which can expand and deplete natural killer (NK) cells, respectively. Antibody-dependent cellular cytotoxicity (ADCC) of cetuximab, as measured by (51)Cr release assay, was significantly higher in MKN-28 than in GLM-1 cells. This ADCC activity was enhanced by IL-2 and reduced by heat-aggregate of human immunoglobulin G, an inhibitor for FcR-III of NK cells. These results suggest that cetuximab in combination with IL-2 shows significant antitumor activity against EGFR high-expressing gastric cancer mainly through NK cell-mediated ADCC. Combination therapy with cetuximab and IL-2 would thus offer a new potential therapeutic approach for a subset of EGFR-overexpressing gastric cancers.
- Published
- 2008
20. Epidermal growth factor receptor mutation, but not sex and smoking, is independently associated with favorable prognosis of gefitinib-treated patients with lung adenocarcinoma
- Author
-
Hiroki Otani, Tetsuya Mitsudomi, Katsuyuki Kiura, Takayuki Kosaka, Yuichiro Ohe, Keitaro Matsuo, Shuji Ichihara, Yasushi Yatabe, Keisuke Aoe, Yoshiro Fujiwara, Hiroshi Date, Shinichi Toyooka, Toshimi Takano, Junichi Soh, and Katsuyuki Hotta
- Subjects
Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.drug_class ,Antineoplastic Agents ,Adenocarcinoma ,medicine.disease_cause ,Tyrosine-kinase inhibitor ,Gefitinib ,Sex Factors ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Carcinoma ,Humans ,Epidermal growth factor receptor ,Lung cancer ,Mutation ,biology ,business.industry ,Smoking ,Cancer ,General Medicine ,medicine.disease ,Prognosis ,ErbB Receptors ,Treatment Outcome ,Immunology ,biology.protein ,Quinazolines ,Female ,business ,medicine.drug - 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.
- Published
- 2008
21. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer
- Author
-
Tetsuya Mitsudomi and Yasushi Yatabe
- Subjects
Cancer Research ,Lung Neoplasms ,Antineoplastic Agents ,Treatment of lung cancer ,Biology ,medicine.disease_cause ,Gefitinib ,medicine ,Humans ,Epidermal growth factor receptor ,Enzyme Inhibitors ,Lung cancer ,General Medicine ,Protein-Tyrosine Kinases ,medicine.disease ,respiratory tract diseases ,ErbB Receptors ,Oncology ,Mutation ,Cancer research ,biology.protein ,Biomarker (medicine) ,Erlotinib ,KRAS ,Tyrosine kinase ,medicine.drug - Abstract
Recent discovery of mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene in lung adenocarcinoma greatly stimulated biomarker research on predictive factors for EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib. Although patients with activating mutations of the EGFR generally respond to EGFR TKIs very well, it is natural to assume that there is no sole determinant, considering great complexity and redundancy of the EGFR pathway. Subsequently, roles of different types of EGFR mutations or mutations of genes that are members of the EGFR pathway such as KRAS and HER2 have been evaluated. In this review, we summarize the recent findings about how mutations of the EGFR and related genes affect sensitivity to EFGR-TKIs. We also discuss molecular mechanisms of acquired resistance to EGFR-TKIs that is almost inevitable in EGFR-TKI therapy. The door for genotype-based treatment of lung cancer is beginning to open, and through these efforts, it will be possible to slow the progression of lung cancer and eventually, to decrease mortality from lung cancer.
- Published
- 2007
22. LKB1 gene mutations in Japanese lung cancer patients
- Author
-
Takashi Takahashi, Tetsuya Mitsudomi, Hiroyuki Achiwa, Ryoichi Onozato, Takayuki Kosaka, Yasushi Yatabe, and Hiroyuki Kuwano
- Subjects
Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,Lung Neoplasms ,STK11 ,Gene mutation ,Adenocarcinoma ,Protein Serine-Threonine Kinases ,medicine.disease_cause ,AMP-Activated Protein Kinase Kinases ,Japan ,Cell Line, Tumor ,Carcinoma ,Medicine ,Humans ,RNA, Neoplasm ,Mutation frequency ,skin and connective tissue diseases ,Lung cancer ,Mutation ,Sex Characteristics ,business.industry ,Reverse Transcriptase Polymerase Chain Reaction ,Respiratory disease ,General Medicine ,DNA, Neoplasm ,Exons ,medicine.disease ,Oncology ,Cancer research ,Carcinoma, Squamous Cell ,Female ,business - 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.
- Published
- 2007
23. Genomic profiling of malignant pleural mesothelioma with array-based comparative genomic hybridization shows frequent non-random chromosomal alteration regions including JUN amplification on 1p32
- Author
-
Sivasundaram Karnan, Yasushi Yatabe, Masao Seto, Toyoaki Hida, Tetsuo Taniguchi, Hiroyuki Tagawa, Takayuki Fukui, Yoshitsugu Horio, Tetsuya Mitsudomi, Kohei Yokoi, Yoshitaka Sekido, Yuichi Ueda, and Toshihiko Yokoyama
- Subjects
Genetic Markers ,Male ,Mesothelioma ,Cancer Research ,Pleural Neoplasms ,Gene Dosage ,Locus (genetics) ,Biology ,Genome ,Polymerase Chain Reaction ,chemistry.chemical_compound ,p14arf ,Genes, jun ,Cell Line, Tumor ,Gene duplication ,Gene expression ,medicine ,Humans ,Oligonucleotide Array Sequence Analysis ,Genetics ,Chromosome Aberrations ,Gene Expression Profiling ,Cancer ,Chromosome Mapping ,Nucleic Acid Hybridization ,General Medicine ,medicine.disease ,Molecular biology ,Oncology ,chemistry ,Chromosomes, Human, Pair 1 ,Female ,Nucleic Acid Amplification Techniques ,DNA ,Comparative genomic hybridization ,Microsatellite Repeats - Abstract
Genome-wide array-based comparative genomic hybridization analysis of malignant pleural mesotheliomas (MPM) was carried out to identify regions that display DNA copy number alterations. Seventeen primary tumors and nine cell lines derived from 22 individuals were studied, some of them originating from the same patients. Regions of genomic aberrations observed in >20% of individuals were 1q, 5p, 7p, 8q24 and 20p with gains, and 1p36.33, 1p36.1, 1p21.3, 3p21.3, 4q22, 4q34-qter, 6q25, 9p21.3, 10p, 13q33.2, 14q32.13, 18q and 22q with losses. Two regions at 1p32.1 and 11q22 showed a high copy gain. The 1p32.1 region contained a protooncogene, JUN, and we further demonstrated overexpression of JUN with real-time polymerase chain reaction analysis. As MPM cell lines did not overexpress JUN, our findings suggested that induction of JUN expression was involved in the development of MPM cells in vivo, which also might result in gene amplification in a subset of MPM. Meanwhile, the most frequent alteration was the 9p21.3 deletion, which includes the p16INK4a/p14ARF locus. With polymerase chain reaction analysis, we determined the extent of the homozygous deletion regions of the p16INK4a/p14ARF locus in MPM cell lines, which indicated that the deletion regions varied among cell lines. Our results with array comparative genomic hybridization analysis provide new insights into the genetic background of MPM, and also give some clues to develop a new molecular target therapy for MPM. (Cancer Sci 2007; 98: 438–446)
- Published
- 2007
24. Prognostic models in patients with non-small-cell lung cancer using artificial neural networks in comparison with logistic regression
- Author
-
Yasushi Yatabe, Takeshi Kobayashi, Takashi Takahashi, Hiroyuki Honda, Taizo Hanai, Yusuke Nakayama, and Tetsuya Mitsudomi
- Subjects
Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Adenocarcinoma ,Logistic regression ,Predictive Value of Tests ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Biomarkers, Tumor ,Humans ,Stage (cooking) ,Lung cancer ,Survival rate ,Survival analysis ,Aged ,Neoplasm Staging ,Aged, 80 and over ,business.industry ,Large cell ,Statistical model ,General Medicine ,Middle Aged ,medicine.disease ,Prognosis ,Surgery ,Survival Rate ,Logistic Models ,Predictive value of tests ,Carcinoma, Squamous Cell ,Carcinoma, Large Cell ,Female ,Neural Networks, Computer ,business - Abstract
It is difficult to precisely predict the outcome of each individual patient with non-small-cell lung cancer (NSCLC) by using conventional statistical methods and ordinary clinico-pathological variables. We applied artificial neural networks (ANN) for this purpose. We constructed a prognostic model for 125 NSCLC patients with 17 potential input variables, including 12 clinico-pathological variables (age, sex, smoking index, tumor size, p factor, pT, pN, stage, histology) and 5 immunohistochemical variables (p27 percentage, p27 intensity, p53, cyclin D1, retinoblastoma (RB)), by using the parameter-increasing method (PIM). Using the resultant ANN model, prediction was possible in 104 of 125 patients (83%, judgment ratio (JR)) and accuracy for prediction of survival at 5 years was 87%. On the other hand, JR and survival prediction accuracy in the logistic regression (LR) model were 37% and 78%, respectively. In addition, ANN outperformed LR for prediction of survival at 1 or 3 years. In these cases, PIM selected p27 intensity and cyclin D1 for the 3-year survival model and p53 for the 1-year survival model in addition to clinico-pathological variables. Finally, even in an independent validation data set of 48 patients, who underwent surgery 10 years later, the present ANN model could predict outcome of patients at 5 years with the JR and accuracy of 81% and 77%, respectively. This study demonstrates that ANN is a potentially more useful tool than conventional statistical methods for predicting survival of patients with NSCLC and that inclusion of relevant molecular markers as input variables enhances its predictive ability.
- Published
- 2003
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.