Faculty Profiles - Ando Mizuo

Papers - Ando Mizuo

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Clinical Value of the Epstein-Barr Virus and p16 Status in Patients with Nasopharyngeal Carcinoma: A Single-Centre Study in Japan Reviewed

Yuki Saito, Tetsuo Ushiku, Go Omura, Kazuo Yasuhara, Masafumi Yoshida, Wataru Takahashi, Mizuo Ando, Masashi Fukayama, Tatsuya Yamasoba

ORL-JOURNAL FOR OTO-RHINO-LARYNGOLOGY HEAD AND NECK SURGERY 78 ( 6 ) 334 - 343 2016

Language：English Publishing type：Research paper (scientific journal) Publisher：KARGER

Background: The clinical significance of the Epstein-Barr virus (EBV) status and p16 expression was unknown in nasopharyngeal carcinoma (NPC). Methods: We retrospectively studied our pathology database for 13 years to determine the prevalence of EBV and p16 expression and their association with prognosis in cases of NPC. We performed immunohistochemistry for the p16 protein and in situ hybridization (ISH) for EBV-encoded small RNAs and human papillomavirus (HPV) DNA. Results: Of the 43 patients with NPC, 27 (63%), 6 (14%), and 10 (23%) cases were EBV positive, EBV negative with keratinization, and EBV negative without keratinization, respectively. No cases were HPV positive by ISH. Among the 21 EBV-positive tumours that were tested for p16, only 2 tumours were p16 positive. The keratinization-positive group included only males, typically > 60 years of age (5 of 6) and with T4 tumours (3 of 6). In contrast, the EBV-positive cohort tended to be younger (< 60 years, 13 of 27) and have progressive N-stage tumours (N2-3, 14 of 27). The keratinization and EBV-negative cohort included predominantly males (9 of 10) who were likely p16 negative (4 of 10) and smokers (7 of 10). Multivariate analysis confirmed that keratinization was an independent prognostic factor for progression-free survival. Conclusion: In areas, such as Japan, that are nonendemic for both EBV and HPV, the causality of NPC appears to be more heterogeneous. (C) 2017 S. Karger AG, Basel

DOI： 10.1159/000455901

Maxillary carcinosarcoma: Identification of a novel MET mutation in both carcinomatous and sarcomatous components through next generation sequencing Reviewed

Mizuo Ando, Yuki Saito, Teppei Morikawa, Go Omura, Kenya Kobayashi, Ken Akashi, Masafumi Yoshida, Yasuhiro Ebihara, Chisato Fujimoto, Masashi Fukayama, Tatsuya Yamasoba, Takahiro Asakage

HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK 37 ( 12 ) E179 - E185 2015.12

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Background. Carcinosarcoma is a rare tumor with biphasic growth of the carcinomatous and sarcomatous components. Prognosis is generally poor and characterization of the molecular mechanisms may provide information for the development of novel antitumor agents and biomarkers.
Methods and Results. We present the case of 66-year-old man with a complaint of nasal obstruction. He was diagnosed with maxillary carcinosarcoma and coexisting papilloma. He underwent multimodal treatment but died of uncontrolled local disease 10 months after the initial presentation. Genetic testing using next-generation sequencing (NGS) revealed that both the carcinomatous and sarcomatous components carried a somatic mutation in the conserved domain of the mesenchymal-epithelial transition factor (MET) proto-oncogene.
Conclusion. Our observation highlighted the importance of the MET gene in the oncogenesis of maxillary carcinosarcoma and is indicative of the common clonal origin of both malignant components. This suggested a possibility of treating MET mutation-positive carcinosarcomas with c-MET inhibitors. (C) 2015 Wiley Periodicals, Inc.

DOI： 10.1002/hed.24043

Retrospective study of laryngeal preservation treatment for hypopharyngeal carcinoma with transoral resection or induction chemotherapy Reviewed

Takahiro Asakage, Mizuo Ando, Masafumi Yoshida, Yuki Saito, Go Omura, Tatsuya Yamasoba

Journal of Otolaryngology of Japan 118 ( 9 ) 1118 - 1123 2015.9

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Oto-Rhino-Laryngological Society of Japan Inc.

We have performed transoral surgical resection for patients with T1/T2 hypopharyngeal cancer and induction chemotherapy with docetaxel for patients with T2/T3 disease. The patients were analyzed in order to determine the current situation of larynx preservation in patients with hypopharyngeal cancer. The data of a total of 83 patients with hypopharyngeal cancer were analyzed retrospectively. The primary subsites were: pyriform sinus (PS) in 61 patients, posterior wall (PW) in 13 patients, and postcricoid (PC) in 9 patients. The number of patients classified as having T1, T2, T3 and T4 disease were 14, 29, 23 and 17, respectively. The main therapies employed in the patients were as follows: transoral surgical resection plus radiation therapy for Tl disease, radiation therapy, induction chemotherapy, and partial resection for T2 disease, induction chemotherapy, radiation therapy, and pharyngo-laryngoesophagectomy for T3 disease, and pharyngo-laryngoesophagectomy plus induction chemotherapy for T4 disease. The 5-year larynx preservation rates in the patients with T1, T2, T3 and T4 disease were 100%, 73%, 39% and 35%, respectively. Our method was able to improve the larynx preservation rate without having any adverse effect on the survival rate. However, the strength of treatment for T 3 disease needs to be improved, because a large number of recurrences and deaths due to the primary disease were encountered in this patient group.

DOI： 10.3950/jibiinkoka.118.1118

Prognostic value of p16 expression irrespective of human papillomavirus status in patients with oropharyngeal carcinoma Reviewed

Yuki Saito, Masafumi Yoshida, Go Omura, Kenya Kobayashi, Chisato Fujimoto, Mizuo Ando, Takashi Sakamoto, Takahiro Asakage, Tatsuya Yamasoba

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 45 ( 9 ) 828 - 836 2015.9

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

In a previous study, we reported the value of p16 expression and alcohol consumption in oropharyngeal carcinoma in Japan. We now report the clinical significance of human papillomavirus status and p16 expression in oropharyngeal carcinoma in Japan.
Over a 9-year period, a retrospective case comparison study of the pathology database was conducted at the University of Tokyo to identify tumor samples of oropharyngeal carcinoma. We performed immunohistochemistry for the p16 protein, in situ hybridization for human papillomavirus-deoxyribonucleic acid and polymerase chain reaction for the human papillomavirus-deoxyribonucleic acid oncogene E6 in oropharyngeal carcinoma in Japanese patients. We evaluated the human papillomavirus status in patients with oropharyngeal carcinoma to determine its prevalence and association with prognosis. We defined human papillomavirus(+) and human papillomavirus(-) oropharyngeal carcinoma cohorts as those with and without polymerase chain reaction for the human papillomavirus-deoxyribonucleic acid oncogene E6 or in situ hybridization-human papillomavirus.
In oropharyngeal carcinoma, the prevalences of p16(+)human papillomavirus(+), p16(+)human papillomavirus(-), p16(-)human papillomavirus(+) and p16(-)human papillomavirus(-) were 32% (48/150), 7% (10/150), 2% (3/150) and 59% (89/150), respectively. Low tobacco and alcohol consumption, tonsil or base of tongue localization, but not age, were associated with p16(+)human papillomavirus(+). Low alcohol consumption was associated with p16(+)human papillomavirus(-). There was a significant difference in overall survival between p16(+)human papillomavirus(-) and p16(-)human papillomavirus(-) (P = 0.03). In multivariate Cox regression models, p16 was the independent prognostic factor, regardless of human papillomavirus status.
p16 expression was a reliable prognostic biomarker regardless of human papillomavirus status.

DOI： 10.1093/jjco/hyv085

Nerve Growth Factor Signals as Possible Pathogenic Biomarkers for Perineural Invasion in Adenoid Cystic Carcinoma Reviewed

Kenya Kobayashi, Mizuo Ando, Yuki Saito, Kenji Kondo, Go Omura, Aya Shinozaki-Ushiku, Masashi Fukayama, Takahiro Asakage, Tatsuya Yamasoba

OTOLARYNGOLOGY-HEAD AND NECK SURGERY 153 ( 2 ) 218 - 224 2015.8

Language：English Publishing type：Research paper (scientific journal) Publisher：SAGE PUBLICATIONS LTD

Objective The molecular mechanisms underlying perineural invasion (PNI)a characteristic pathological feature of adenoid cystic carcinoma (ACC)remain largely unclear. Recently, nerve growth factor (NGF) has been implicated in perineural invasion in certain malignancies. Overexpression of Myb related to the MYB-NFIB fusion gene in ACC has also been correlated with perineural invasion and survival. However, this concept is controversial. The aim of this study was to examine the expression of NGF together with its receptors, tropomyosin receptor kinase A (TrkA) and p75NRT, and Myb in ACC and assess their relationship with perineural invasion and survival.
Study Design Case series with chart review.
Setting The University of Tokyo Hospital.
Subjects and Methods We retrospectively analyzed 37 patients with ACC surgically treated from 1991 to 2011. We examined expression levels of NGF, TrkA, p75NRT, and Myb in the ACC specimens and their correlations with PNI and prognosis.
Results NGF, TrkA, p75NRT, and Myb overexpression rates were 65%, 65%, 30%, and 62%, respectively. Pearson product-moment correlation coefficient revealed a strong correlation between NGF/TrkA immunostaining and PNI (NGF: r = 0.68, P < .0001; TrkA: r = 0.53, P = .0007). Moreover, NGF overexpression was significantly associated with worse 8-year local control rate (27% vs 80%, P = .005). However, p75NRT and Myb expression was related to neither perineural invasion nor survival.
Conclusion Our findings demonstrated that NGF and TrkA overexpression, but not Myb and p75NRT overexpression, may contribute to PNI and thus cause local recurrence in patients with ACC.

DOI： 10.1177/0194599815584762

Disease control and clinicopathological prognostic factors of total pharyngolaryngectomy for hypopharyngeal cancer: a single-center study Reviewed

Go Omura, Mizuo Ando, Yuki Saito, Kenya Kobayashi, Tatsuya Yamasoba, Takahiro Asakage

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 20 ( 2 ) 290 - 297 2015.4

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

Total pharyngolaryngectomy (TPL) is a conventional and standard surgical method for locoregional control of advanced hypopharyngeal cancer (HPC). This study aimed to define the clinicopathological prognostic factors of TPL by evaluating our surgical experience of TPL in the treatment of HPCs.
We retrospectively reviewed the clinical charts of patients with HPC who were treated between 1995 and 2011 at the University of Tokyo Hospital and enrolled 119 patients who underwent TPL as an initial curative treatment.
The mean follow-up period was 46 months (range, 2-164 months). The 5-year overall survival (OS), disease-specific survival (DSS), locoregional control rates, and relapse-free survival for all patients were 44, 53, 76, and 50 %, respectively. In multivariate analysis, the number of a parts per thousand yen4 metastatic lymph nodes (LNs) was a significant poor prognostic factor for both OS and DSS (p = 0.03 and p = 0.01). Patients with moderate to severe comorbidities had poor prognoses for OS (p = 0.002). In addition, patients with the number of a parts per thousand yen4 metastatic LNs had a higher incidence of distant metastases (p < 0.0001).
The locoregional control rate following TPL was acceptable and the number of metastatic LNs was associated with the incidence of distant metastases.

DOI： 10.1007/s10147-014-0709-z

Frequent copy gain of the MET gene in hypopharyngeal and laryngeal cancer in Japanese population. Reviewed

Akashi K, Ebihara Y, Omura G, Saito Y, Yoshida M, Ando M, Asakage T, Yamasoba T, Murakami Y

Journal of Cancer Therapy ( 6 ) 1093 - 1102 2015

Salvage Surgery for Local Residual or Recurrent Pharyngeal Cancer After Radiotherapy or Chemoradiotherapy Reviewed

Go Omura, Yuki Saito, Mizuo Ando, Kenya Kobayashi, Yasuhiro Ebihara, Tatsuya Yamasoba, Takahiro Asakage

LARYNGOSCOPE 124 ( 9 ) 2075 - 2080 2014.9

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Objectives/Hypothesis: Local residual or recurrent pharyngeal cancer after definitive radiotherapy (RT) or chemoradiotherapy (CRT) is correlated to poor prognosis. We analyzed the efficacy of salvage surgery for patients with local residual or recurrent pharyngeal cancer after RT or CRT.
Study Design: Retrospective clinical study with chart review.
Methods: Between 2001 and 2011, we treated 207 patients with resectable pharyngeal cancer, including 98 patients with oropharyngeal cancer (OPC) and 109 patients with hypopharyngeal cancer (HPC) who received definitive RT or CRT. Local residual or recurrence developed in 59 patients (23 with OPC; 36 with HPC), of whom 42 (18 with OPC; 24 with HPC) underwent salvage surgery. These 42 patients were investigated in this study.
Results: The initial treatments were RT; RT with induction chemotherapy (IC); and concurrent CRT in 12, 9, and 21 patients, respectively. The median radiation dose was 70 Gy. The 3-year disease-specific survival rate after salvage surgery was 40% (median, 26 months). The significant prognostic factors were stage IV prior to initial therapy (P=.049), development of concurrent local and regional relapse (P=.02), and OPC (P=.04).
Conclusions: The efficacy of salvage surgery for local residual or recurrent pharyngeal cancer was limited. Oropharynx origin, stage IV prior to initial therapy, and concurrent regional relapses were significantly poor prognostic factors. Salvage surgery for HPC is worth challenging aggressively. Conversely, the indication of salvage surgery for OPCs should be carefully considered because of its low cure rate.

DOI： 10.1002/lary.24695

Negative Human Papillomavirus Status and Excessive Alcohol Consumption are Significant Risk Factors for Second Primary Malignancies in Japanese Patients with Oropharyngeal Carcinoma Reviewed

Yuki Saito, Yasuhiro Ebihara, Tetsuo Ushiku, Go Omura, Kenya Kobayashi, Mizuo Ando, Takashi Sakamoto, Masashi Fukayama, Tatsuya Yamasoba, Takahiro Asakage

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 44 ( 6 ) 564 - 569 2014.6

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

To determine the clinical significance of human papillomavirus subclinical infection in patients with oropharyngeal squamous cell carcinoma in Japan.
Over a 9-year period, a retrospective case comparison study of the pathology database was conducted at the University of Tokyo to identify samples of oropharyngeal squamous cell carcinoma. We performed in situ hybridization for human papillomavirus-DNA to identify subclinical human papillomavirus infections among patients with oropharyngeal squamous cell carcinoma. Second primary malignancies were classified as synchronous, if identified within 6 months of the diagnosis of the first tumor, or metachronous, if identified after this 6-month period. Univariate and multivariate analyses using logistic stepwise regression models were performed to identify factors associated with synchronous and metachronous second primary malignancy.
Of the 150 patients with oropharyngeal squamous cell carcinoma, 14% (21/150) and 20.7% (31/150) developed synchronous and metachronous second primary malignancies, respectively. Esophageal carcinoma was the most frequent second primary malignancy (10/21 for synchronous and 10/31 for metachronous second primary malignancies). The prevalence of oropharyngeal squamous cell carcinoma positive for human papillomavirus was 31% (47/150). Multivariate analysis identified alcohol consumption as a significant unfavorable risk factor for the occurrence of synchronous second primary malignancy, and either a human papillomavirus-negative status or N0 classification was a significant unfavorable risk factor for the occurrence of metachronous second primary malignancy.
Evaluation of the human papillomavirus status may help identify patients at risk for metachronous second primary malignancy. Upper gastrointestinal endoscopy is very important in the diagnosis of oropharyngeal squamous cell carcinoma among heavy drinkers in Japan.

DOI： 10.1093/jjco/hyu042

Leukemic evolution of donor-derived cells harboring IDH2 and DNMT3A mutations after allogeneic stem cell transplantation Reviewed

T. Yasuda, T. Ueno, K. Fukumura, A. Yamato, M. Ando, H. Yamaguchi, M. Soda, M. Kawazu, E. Sai, Y. Yamashita, M. Murata, H. Kiyoi, T. Naoe, H. Mano

LEUKEMIA 28 ( 2 ) 426 - 428 2014.2

Clinical Features of Human Papilloma Virus-Related Head and Neck Squamous Cell Carcinoma of an Unknown Primary Site Reviewed

Kenya Kobayashi, Yuki Saito, Go Omura, Mizuo Ando, Takashi Sakamoto, Tatsuya Yamasoba, Takahiro Asakage

ORL-JOURNAL FOR OTO-RHINO-LARYNGOLOGY HEAD AND NECK SURGERY 76 ( 3 ) 137 - 146 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：KARGER

Purpose: Head and neck squamous cell carcinoma of an unknown primary site (HNSCCUP) is a heterogeneous group of tumors that includes the human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma. To investigate the relationship between HNSCCUP and HPV, we reviewed p16 overexpression and HPV DNA in lymph node metastases and examined their correlation with the primary site and clinical features. Materials and Methods: Thirty-three patients with HNSCCUP were retrospectively studied. Dissected neck metastases were analyzed for p16 overexpression by immunohistochemistry, and the presence of HPV DNA was investigated by in situ hybridization. Results: Of the 33 patients, 8 (24%) exhibited p16 overexpression. p16-positive lymph node metastases contained significantly more HPV DNA and were most frequently associated with occult primary lesions in the oropharynx and a favorable prognosis. Patients with a lower alcohol consumption, only level II/III metastasis, and cystic lymph node metastasis tended to have p16 overexpression. Conclusions: This is the first report on the relationship of HNSCCUP with p16 and HPV DNA status in Asian patients. In total, 24% of the HNSCCUP patients were p16 positive. p16 overexpression in neck metastasis was predictive of both an occult primary lesion in the oropharynx and an association with HPV infection. Alcohol consumption, location, and features of neck metastasis were correlated with p16 expression. (C) 2014 S. Karger AG, Basel

DOI： 10.1159/000363190

High incidence of null-type mutations of the TP53 gene in Japanese patients with head and neck squamous cell carcinoma Reviewed

Ebihara Y, Iwai M, Ito T, Omura G, Saito Y, Yoshida M, Ando M, Asakage T, Yamasoba T, Murakami Y

Journal of Cancer Therapy 5 664 - 671 2014

STK10 missense mutations associated with anti-apoptotic function Reviewed

Kazutaka Fukumura, Yoshihiro Yamashita, Masahito Kawazu, Eirin Sai, Shin-Ichiro Fujiwara, Naoya Nakamura, Kengo Takeuchi, Mizuo Ando, Kohei Miyazono, Toshihide Ueno, Keiya Ozawa, Hiroyuki Mano

Oncology Reports 30 ( 4 ) 1542 - 1548 2013.10

Language：English Publishing type：Research paper (scientific journal) Publisher：4

Peripheral T-cell lymphoma (PTCL) is an aggressive lymphoma with a 5-year overall survival rate of &lt
30%. To identify carcinogenesis-related genes in PTCL, we conducted high-throughput resequencing of target-captured cDNA in a PTCL specimen, revealing a total of 19 missense mutations among 18 independent genes. One of such substitutions, c.2201G&gt
A in STK10 cDNA, replaces an arginine residue to a histidine (R634H) in the encoded protein. Of note, while wild-type STK10 suppresses NF-κ
B activity and potentiates dexamethasone-induced apoptosis, the R634H change significantly decreases such pro-apoptotic activity. This c.2201G&gt
A change of STK10 was also identified in another PTCL specimen, but now registered as a single nucleotide polymorphism in the latest dbSNP database. Furthermore, other somatic mutations of STK10 have been reported, and we now reveal that some of them (L85P and K277E) have more profound anti-apoptotic effects compared to R634H. These results suggest that STK10 functions as a tumor suppressor gene, and that dysfunction of STK10 activity either through polymorphism or somatic mutations may confer anti-apoptotic effects contributing to carcinogenesis.

DOI： 10.3892/or.2013.2605

Cancer-associated missense mutations of caspase-8 activate nuclear factor-kappa B signaling Reviewed

Mizuo Ando, Masahito Kawazu, Toshihide Ueno, Kazutaka Fukumura, Azusa Yamato, Manabu Soda, Yoshihiro Yamashita, Young L. Choi, Tatsuya Yamasoba, Hiroyuki Mano

CANCER SCIENCE 104 ( 8 ) 1002 - 1008 2013.8

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with a 5-year survival rate of similar to 50%. With the use of a custom cDNA-capture system coupled with massively parallel sequencing, we have now investigated transforming mechanisms for this malignancy. The cDNAs of cancer-related genes (n = 906) were purified from a human HNSCC cell line (T3M-1 Cl-10) and subjected to high-throughput resequencing, and the clinical relevance of non-synonymous mutations thus identified was evaluated with luciferase-based reporter assays. A CASP8 (procaspase-8) cDNA with a novel G-to-C point mutation that results in the substitution of alanine for glycine at codon 325 was identified, and the mutant protein, CASP8 (G325A), was found to activate nuclear factor-kappa B (NF-kappa B) signaling to an extent far greater than that achieved with the wild-type protein. Moreover, forced expression of wild-type CASP8 suppressed the growth of T3M-1 Cl-10 cells without notable effects on apoptosis. We further found that most CASP8 mutations previously detected in various epithelial tumors also increase the ability of the protein to activate NF-kappa B signaling. Such NF-kappa B activation was shown to be mediated through the COOH-terminal region of the second death effector domain of CASP8. Although CASP8 mutations associated with cancer have been thought to promote tumorigenesis as a result of attenuation of the proapoptotic function of the protein, our results now show that most such mutations, including the novel G325A identified here, separately confer a gain of function with regard to activation of NF-kappa B signaling, indicating another role of CASP8 in the transformation of human malignancies including HNSCC.

DOI： 10.1111/cas.12191

Cancer-associated missense mutations of caspase-8 activate nuclear factor-κB signaling Reviewed

Mizuo Ando, Masahito Kawazu, Toshihide Ueno, Kazutaka Fukumura, Azusa Yamato, Manabu Soda, Yoshihiro Yamashita, Young L. Choi, Tatsuya Yamasoba, Hiroyuki Mano

Cancer Science 104 ( 8 ) 1002 - 1008 2013.8

Language：English Publishing type：Research paper (scientific journal) Publisher：8

Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with a 5-year survival rate of ~50%. With the use of a custom cDNA-capture system coupled with massively parallel sequencing, we have now investigated transforming mechanisms for this malignancy. The cDNAs of cancer-related genes (n = 906) were purified from a human HNSCC cell line (T3M-1 Cl-10) and subjected to high-throughput resequencing, and the clinical relevance of non-synonymous mutations thus identified was evaluated with luciferase-based reporter assays. A CASP8 (procaspase-8) cDNA with a novel G-to-C point mutation that results in the substitution of alanine for glycine at codon 325 was identified, and the mutant protein, CASP8 (G325A), was found to activate nuclear factor-κB (NF-κB) signaling to an extent far greater than that achieved with the wild-type protein. Moreover, forced expression of wild-type CASP8 suppressed the growth of T3M-1 Cl-10 cells without notable effects on apoptosis. We further found that most CASP8 mutations previously detected in various epithelial tumors also increase the ability of the protein to activate NF-κB signaling. Such NF-κB activation was shown to be mediated through the COOH-terminal region of the second death effector domain of CASP8. Although CASP8 mutations associated with cancer have been thought to promote tumorigenesis as a result of attenuation of the proapoptotic function of the protein, our results now show that most such mutations, including the novel G325A identified here, separately confer a gain of function with regard to activation of NF-κB signaling, indicating another role of CASP8 in the transformation of human malignancies including HNSCC. © 2013 Japanese Cancer Association.

DOI： 10.1111/cas.12191

Transforming mutations of RAC guanosine triphosphatases in human cancers Reviewed

Masahito Kawazu, Toshihide Ueno, Kenji Kontani, Yoshitaka Ogita, Mizuo Ando, Kazutaka Fukumura, Azusa Yamato, Manabu Soda, Kengo Takeuchi, Yoshio Miki, Hiroyuki Yamaguchi, Takahiko Yasuda, Tomoki Naoe, Yoshihiro Yamashita, Toshiaki Katada, Young Lim Choi, Hiroyuki Mano

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 110 ( 8 ) 3029 - 3034 2013.2

Language：English Publishing type：Research paper (scientific journal) Publisher：NATL ACAD SCIENCES

Members of the RAS superfamily of small guanosine triphosphatases (GTPases) transition between GDP-bound, inactive and GTP-bound, active states and thereby function as binary switches in the regulation of various cellular activities. Whereas HRAS, NRAS, and KRAS frequently acquire transforming missense mutations in human cancer, little is known of the oncogenic roles of other small GTPases, including Ras-related C3 botulinum toxin substrate (RAC) proteins. We show that the human sarcoma cell line HT1080 harbors both NRAS(Q61K) and RAC1(N92I) mutant proteins. Whereas both of these mutants were able to transform fibroblasts, knockdown experiments indicated that RAC1(N92I) may be the essential growth driver for this cell line. Screening for RAC1, RAC2, or RAC3 mutations in cell lines and public databases identified several missense mutations for RAC1 and RAC2, with some of the mutant proteins, including RAC1(P29S), RAC1(C157Y), RAC2(P29L), and RAC2(P29Q), being found to be activated and transforming. P29S, N92I, and C157Y mutants of RAC1 were shown to exist preferentially in the GTP-bound state as a result of a rapid transition from the GDP-bound state, rather than as a result of a reduced intrinsic GTPase activity. Activating mutations of RAC GTPases were thus found in a wide variety of human cancers at a low frequency; however, given their marked transforming ability, the mutant proteins are potential targets for the development of new therapeutic agents.

DOI： 10.1073/pnas.1216141110

喉頭癌に対する予防的頸部郭清術の検討 Reviewed

齊藤祐毅, 小村豪, 吉田昌史, 安藤瑞生, 蝦原康宏, 朝蔭孝宏, 山岨達也

頭頸部外科 22 ( 3 ) 323 - 326 2013.2

Language：Japanese Publisher：(NPO)日本頭頸部外科学会

2005年1月から2011年12月までの7年間に喉頭癌に対し一次治療として根治手術を行った53症例を検討対象とした。男性44例、女性9例、年齢は46歳～87歳(中央値70歳)、観察期間は4～80ヵ月(中央値24ヵ月)、声門上癌36例、声門癌15例、声門下癌2例であった。潜在リンパ節転移率は声門癌N0で6.7%、声門上癌N0で30%、声門上癌N1、N2bの対側頸部で20%であった。予防的頸部廓清術は声門癌N0には不要で声門上癌N0には適応があると考えられた。N1、N2bの対側頸部の頸部郭清術の適応は今後の検討課題と考えられた。郭清範囲は患側のLevel II～IIIで充分な可能性が示唆された。(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2013&ichushi_jid=J04210&link_issn=&doc_id=20130311410013&doc_link_id=10.5106%2Fjjshns.22.323&url=https%3A%2F%2Fdoi.org%2F10.5106%2Fjjshns.22.323&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Salvage surgery for recurrence of hypopharyngeal carcinoma after definitive radiotherapy or chemoradio-therapy Reviewed

Go Omura, Yuki Saito, Masahumi Yoshida, Mizuo Ando, Yasuhiro Ebihara, Takahiro Asakage

Japanese Journal of Head and Neck Cancer 39 ( 1 ) 55 - 59 2013

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japan Society for Head and Neck Cancer

The aim of this study was to analyze the efficacy of salvage surgery for patients with recurrent hypopharyngeal carcinoma after definitive radiotherapy (RT) or chemoradiotherapy (CRT). From April 2001 to August 2010, 101 patients with hypopharyngeal carcinoma underwent definitive RT or CRT at the University of Tokyo Hospital. Local recurrence developed in 35 patients (35%), of whom 24 patients underwent salvage surgery. The types of surgical procedures were as follows: total pharyngolaryngectomy: 20, partial pharyngectomy: 3, and endoscopic pharyngo-laryngo surgery (ELPS): 1. Three-year overall survival after salvage surgery was 60%. The median survival period was 38 months. Among these patients, postoperative complications occurred in 11 patients (46%). Salvage surgery for recurrent hypopharyngeal carcinoma after definitive RT or CRT is effective for not only for the patients' quality of life, but also for the improvement of prognosis.

DOI： 10.5981/jjhnc.39.55

Other Link： https://search.jamas.or.jp/default/link?pub_year=2013&ichushi_jid=J04195&link_issn=&doc_id=20130507330010&doc_link_id=10.5981%2Fjjhnc.39.55&url=https%3A%2F%2Fdoi.org%2F10.5981%2Fjjhnc.39.55&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Oncogenic MAP2K1 mutations in human epithelial tumors Reviewed

Young Lim Choi, Manabu Soda, Toshihide Ueno, Toru Hamada, Hidenori Haruta, Azusa Yamato, Kazutaka Fukumura, Mizuo Ando, Masahito Kawazu, Yoshihiro Yamashita, Hiroyuki Mano

CARCINOGENESIS 33 ( 5 ) 956 - 961 2012.5

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

The scirrhous subtype of gastric cancer is a highly infiltrative tumor with a poor outcome. To identify a transforming gene in this intractable disorder, we constructed a retroviral complementary DNA (cDNA) expression library from a cell line (OCUM-1) of scirrhous gastric cancer. A focus formation assay with the library and mouse 3T3 fibroblasts led to the discovery of a transforming cDNA, encoding for MAP2K1 with a glutamine-to-proline substitution at amino acid position 56. Interestingly, treatment with a MAP2K1-specific inhibitor clearly induced cell death of OCUM-1 but not of other two cells lines of scirrhous gastric cancer that do not carry MAP2K1 mutations, revealing the essential role of MAP2K1(Q56P) in the transformation mechanism of OCUM-1 cells. By using a next-generation sequencer, we further conducted deep sequencing of the MAP2K1 cDNA among 171 human cancer specimens or cell lines, resulting in the identification of one known (D67N) and four novel (R47Q, R49L, I204T and P306H) mutations within MAP2K1. The latter four changes were further shown to confer transforming potential to MAP2K1. In our experiments, a total of six (3.5%) activating mutations in MAP2K1 were thus identified among 172 of specimens or cell lines for human epithelial tumors. Given the addiction of cancer cells to the elevated MAP2K1 activity for proliferation, human cancers with such MAP2K1 mutations are suitable targets for the treatment with MAP2K1 inhibitors.

DOI： 10.1093/carcin/bgs099

High-throughput resequencing of target-captured cDNA in cancer cells Reviewed

Toshihide Ueno, Yoshihiro Yamashita, Manabu Soda, Kazutaka Fukumura, Mizuo Ando, Azusa Yamato, Masahito Kawazu, Young Lim Choi, Hiroyuki Mano

CANCER SCIENCE 103 ( 1 ) 131 - 135 2012.1

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

The recent advent of whole exon (exome)-capture technology, coupled with second-generation sequencers, has made it possible to readily detect genomic alterations that affect encoded proteins in cancer cells. Such target resequencing of the cancer genome, however, fails to detect most clinically-relevant gene fusions, given that such oncogenic fusion genes are often generated through intron-to-intron ligation. To develop a resequencing platform that simultaneously captures point mutations, insertions-deletions (indels), and gene fusions in the cancer genome, we chose cDNA as the input for target capture and extensive resequencing, and we describe the versatility of such a cDNA-capture system. As a test case, we constructed a custom target-capture system for 913 cancer-related genes, and we purified cDNA fragments for the target gene set from five cell lines of CML. Our target gene set included Abelson murine leukemia viral oncogene homolog 1 (ABL1), but it did not include breakpoint cluster region (BCR); however, the sequence output faithfully detected reads spanning the fusion points of these two genes in all cell lines, confirming the ability of cDNA capture to detect gene fusions. Furthermore, computational analysis of the sequence dataset successfully identified non-synonymous mutations and indels, including those of tumor protein p53 (TP53). Our data might thus support the feasibility of a cDNA-capture system coupled with massively parallel sequencing as a simple platform for the detection of a variety of anomalies in protein-coding genes among hundreds of cancer specimens. (Cancer Sci 2012; 103: 131-135)

DOI： 10.1111/j.1349-7006.2011.02105.x

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