Faculty Profiles - HIRASAWA Akira

Two Japanese kindreds occurring endometrial cancer meeting new clinical criteria for hereditary non-polyposis colorectal cancer (HNPCC), Amsterdam Criteria II

K Banno, N Susumu, T Hirao, M Yanokura, A Hirasawa, D Aoki, Y Udagawa, K Sugano, S Nozawa

JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH 30 ( 4 ) 287 - 292 2004.8

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING ASIA

Hereditary non-polyposis colorectal cancer (HNPCC), also called Lynch syndrome, is an autosomal dominantly inherited disorder of cancer susceptibility. Patients with HNPCC exhibit an increased risk for HNPCC-associated extracolonic tumors such as cancer of the endometrium. HNPCC is associated with germline mutations in DNA mismatch repair (MMR) genes: hMLH1, hMSH2 and hMSH6.
Here, we describe two Japanese kindreds (0.5%) who met the new clinical criteria for HNPCC, Amsterdam criteria II, from among 375 endometrial cancer patients treated at Keio University Hospital from 1990 to 2002. From these results, it was found that female HNPCC patients comprised approximately 0.5% of all endometrial cancer patients. Decreased expression of two MMR gene protein products (hMLH1 and hMSH6) was confirmed immunohistochemically in these two endometrial tumors in HNPCC kindreds. This case report provides important information on Japanese HNPCC patients occurring endometrial cancer.

DOI： 10.1111/j.1447-0756.2004.00195.x

Association of HNPCC and endometrial cancers Reviewed

Kouji Banno, Nobuyuld Susumu, Megumi Yanokura, Takeshi Hirao, Takashi Iwata, Akira Hirasawa, Daisuke Aoki, Kokichi Sugano, Shiro Nozawa

International Journal of Clinical Oncology 9 ( 4 ) 262 - 269 2004.8

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

Hereditary nonpolyposis colorectal cancer (HNPCC) is among the representative familial cancers that are autosomally dominant inherited disorders. Because endometrial cancers develop at high rates in women with HNPCC, it is suggested that some endometrial cancers are familial cancers that are induced by mutations of the DNA mismatch repair (MMR) genes, as in HNPCC. To understand the clinical pathology of familial endometrial cancers that are associated with HNPCC, we surveyed the family histories of 385 patients with endometrial cancer and found that 0.5% of endometrial cancers met the new diagnostic criteria of HNPCC. From molecular and biological analyses, we found microsatellite instability in 30.8% of endometrial cancers and germline mutations of MMR genes in 8.3%. These results suggest a close relationship of MMR gene mutations to the development of endometrial cancers. For a better understanding of the clinical pathology of HNPCC-associated familial endometrial cancers, it is critical for gynecologists to perform a large multicenter study, including detailed family histories.

DOI： 10.1007/s10147-004-0402-8

Scopus

Overexpression of PDZK1 within the 1q12-q22 amplicon is likely to be associated with drug-resistance phenotype in multiple myeloma. Reviewed International journal

Jun Inoue, Takemi Otsuki, Akira Hirasawa, Issei Imoto, Yoshinobu Matsuo, Shiroh Shimizu, Masafumi Taniwaki, Johji Inazawa

The American journal of pathology 165 ( 1 ) 71 - 81 2004.7

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC

We investigated DNA copy number aberrations in 37 cell lines derived from multiple myelomas (MMs) using comparative genomic hybridization, and 11 (29.7%) showed high-level gain indicative of gene amplification at 1q12-q22. A corresponding transcriptional mapping using oligonucleotide arrays extracted three up-regulated genes (IRTA2, PDZK1, and S100A6) within the smallest region of overlapping in amplifications. Among them PDZK1 showed amplification and consequent overexpression in the MM cell lines. Amplification of PDZK1 was observed in primary cases of MM as well. MM cell lines with amplification of PDZK1 exhibited the resistance to melphalan-, cis-platin-, and vincristin-induced cell death compared with MM cell lines without its amplifications. Furthermore, down-regulation of PDZK1 with an anti-sense oligonucleotide sensitized a cell line KMS-11 to melphalan, cis-platin, and vincristin. Taken together, our results indicate that PDZK1 is likely to be one of targets for 1q12-q22 amplification in MM and may be associated with the malignant phenotype, including drug resistance, in this type of tumor.

Overexpression of PDZK1 within the 1q12-q22 amplicon is likely to be associated with drug resistance phenotype in multiple myeloma

J Inoue, T Otsuki, A Hirasawa, Imoto, I, Y Matsuo, S Shimizu, M Taniwaki, J Inazawa

AMERICAN JOURNAL OF PATHOLOGY 165 ( 1 ) 71 - 81 2004.7

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC

子宮体癌に対する新たな治療戦略

平沢晃, 青木大輔, 野澤志朗

産科と婦人科 71 ( 2 ) 201-207 - 207 2004.2

術前細胞診にて癌腫成分のみを示した子宮体部異所性癌肉腫の一例

HIRASAWA AKIRA

日本婦人科腫瘍学会雑誌 22 ( 4 ) 393-398 2004

Outline of treatment for endometrial cancer

Aoki Daisuke, Hirasawa Akira, Susumu Nobuyuki, Nozawa Shiro

Nippon rinsho. Japanese journal of clinical medicine 62 Suppl 10 324 - 328 2004

腹腔内出血を繰り返した卵巣顆粒細胞腫晩期再発の一例.

HIRASAWA AKIRA

日本産科婦人科学会東京地方部会会誌 53 ( 3 ) 362-366 - 366 2004

Unfavorable prognostic factors associated with high frequency of microsatellite instability and comparative genomic hybridization analysis in endometrial cancer. International journal

Akira Hirasawa, Daisuke Aoki, Jun Inoue, Issei Imoto, Nobuyuki Susumu, Kokichi Sugano, Shiro Nozawa, Johji Inazawa

Clinical cancer research : an official journal of the American Association for Cancer Research 9 ( 15 ) 5675 - 82 2003.11

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

PURPOSE: Although many articles have been published regarding chromosomal instability (CI) and microsatellite instability (MI) in endometrial adenocarcinoma, the relationship between prognostic factors and the biological mechanisms accounting for genetic instability in these tumors has not yet been precisely defined. To do that, it will be necessary to clarify the molecular mechanisms involved in endometrial carcinogenesis. EXPERIMENTAL DESIGN: Tissue samples from 43 human primary endometrioid endometrial adenocarcinomas (EACs) were analyzed for CI and MI status using comparative genomic hybridization and 11 microsatellite loci, respectively. Methylation status of the promoter of MLH1 was also determined. We analyzed all three of these parameters in relation to each other and to clinicopathological factors. RESULTS: Sixty-five percent of the EACs we examined had detectable CI. Frequent copy number gains were seen at 1q25-41 (23%), 8q11.1-q21.1 (23%), 8q21.3-qter (21%); 28% of these tumors exhibited high-frequency MI (MSI-H); Methylation of the MLH1 promoter was observed in 92% of EACs with MSI-H. Southern blotting showed amplification of MYCN in one tumor, which has been documented for the first time in a primary human EAC. CONCLUSIONS: MSI-H was correlated with histological grade, International Federation of Gynecologists and Obstetricians (FIGO) stage, myometrial invasion, and lymphonode metastasis. Our comparative genomic hybridization results demonstrated that the number of chromosomes involved in genomic alterations in EACs was distinctively fewer than those in other types of tumor. The carcinogenetic process leading to EAC appears to be highly complex; for example, MI and CI may act synergistically, whereas CI and/or MI are likely to be linked with tumor heterogeneity.

Unfavorable prognostic factors associated with high frequency of microsatellite instability and comparative genomic hybridization analysis in endometrial cancer Reviewed

A Hirasawa, D Aoki, J Inoue, Imoto, I, N Susumu, K Sugano, S Nozawa, J Inazawa

CLINICAL CANCER RESEARCH 9 ( 15 ) 5675 - 5682 2003.11

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Although many articles have been published regarding chromosomal instability (CI) and microsatellite instability (MI) in endometrial adenocarcinoma, the relationship between prognostic factors and the biological mechanisms accounting for genetic instability in these tumors has not yet been precisely defined. To do that, it will be necessary to clarify the molecular mechanisms involved in endometrial carcinogenesis.
Experimental Design: Tissue samples from 43 human primary endometrioid endometrial adenocarcinomas (EACs) were analyzed for CI and MI status using comparative genomic hybridization And It microsatellite loci, respectively. Methylation status of the promoter of MLH1 was also determined. We analyzed all three of these parameters in relation to each other and to clinicopathological factors.
Results: Sixty-five percent of the EACs we examined had detectable CI. Frequent copy number gains were seen at 1q25-41 (23%), 8q11.1-q21.1 (23%), 8q21.3-qter (21%); 28% of these tumors exhibited high-frequency MI (MSI-H); Methylation of the MLH1 promoter was observed in 92% of EACs with MSI-H. Southern blotting showed amplification of MYCN in one tumor, which has been documented for the first time in a primary human EAC.
Conclusions: MSI-H was correlated with histological grade, International Federation of Gynecologists and Obstetricians (FIGO) stage, myometrial invasion, and lymphonode metastasis. Our comparative genomic hybridization results demonstrated that the number of chromosomes involved in genomic alterations in EACs was distinctively fewer than those in other types of tumor. The carcinogenetic process leading to EAC appears to be highly complex; for example, MI and CI may act synergistically, whereas CI and/or MI are likely to be linked with tumor heterogeneity.

Unfavorable prognostic factors associated with high frequency of microsatellite instability and comparative genomic hybridization analysis in endometrial cancer

A Hirasawa, D Aoki, J Inoue, Imoto, I, N Susumu, K Sugano, S Nozawa, J Inazawa

CLINICAL CANCER RESEARCH 9 ( 15 ) 5675 - 5682 2003.11

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Identification of germline MSH2 gene mutations in endometrial cancer not fulfilling the new clinical criteria for hereditary nonpolyposis colorectal cancer. Reviewed International journal

Kouji Banno, Nobuyuki Susumu, Takeshi Hirao, Megumi Yanokura, Akira Hirasawa, Daisuke Aoki, Yasuhiro Udagawa, Kokichi Sugano, Shiro Nozawa

Cancer genetics and cytogenetics 146 ( 1 ) 58 - 65 2003.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Endometrial cancer is the second most common malignancy in patients with hereditary nonpolyposis colorectal cancer (HNPCC). This cancer is caused by germline mutations in one of the DNA mismatch repair (MMR) genes. The present study was undertaken to analyze the relation between microsatellite instability (MSI) and germline mutations of MMR genes. We analyzed MSI in 38 cases of endometrial cancer. MSI was present in one or more (out of 5 examined) regions in 11 (29%) cases. Furthermore, alterations in MLH1 and MSH2, two culprit genes representative of HNPCC, were examined in the 11 MSI-positive patients using polymerase chain reaction-single-strand conformation polymorphism and sequencing. Germline mutations, namely, 1) a missense mutation at codon 688 (ATG-->ATA, Met-->Ile) and 2) a missense mutation at codon 390 (CTT-->TTT, Leu-->Phe) of the MSH2 gene, were found in 2 of the 11 patients (18%). Although these two cases do not fulfill the new Amsterdam criteria, they had strong family histories of colorectal and endometrial carcinoma. Our results show that genetic testing is important in cases of endometrial cancer with a history suggestive of HNPCC even if the new Amsterdam criteria are not fulfilled.

DOI： 10.1016/S0165-4608(03)00157-2

Identification of germline MSH2 gene mutations in endometrial cancer not fulfilling the new clinical criteria for hereditary nonpolyposis colorectal cancer

K Banno, N Susumu, T Hirao, M Yanokura, A Hirasawa, D Aoki, Y Udagawa, K Sugano, S Nozawa

CANCER GENETICS AND CYTOGENETICS 146 ( 1 ) 58 - 65 2003.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

DOI： 10.1016/S0165-4608(03)00157-2

遺伝性子宮内膜癌とは −特にDNAミスマッチ修復遺伝子について

阪埜浩司, 進伸幸, 矢野倉恵, 平尾健, 岩田卓, 平沢晃, 青木大輔, 野澤志朗

産婦人科の世界 55 ( 8 ) 863-870 - 870 2003.8

Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets

A Hirasawa, F Saito-Ohara, J Inoue, D Aoki, N Susumu, T Yokoyama, S Nozawa, J Inazawa, Imoto, I

CLINICAL CANCER RESEARCH 9 ( 6 ) 1995 - 2004 2003.6

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Although tumor stage is considered a prognostic feature for ovarian clear cell adenocarcinomas (OC- CAs), it is not likely to fully account for the clinical and biological variability characteristic of the disease. The aim of this study was to investigate aberrations of DNA copy number in OCCA tumors and identify genetic markers that would increase our understanding of the pathogenesis of OCCA and assist in more accurately predicting the outcome for an individual patient with this disease.
Experimental Design: We determined copy number aberrations among 20 primary OCCA tumors by means of comparative genomic hybridization and investigated their relationship to clinicopathological data. We also measured expression levels of candidate target genes within critical regions by quantitative real-time reverse transcription-PCRs and compared those data with copy number status and patient outcomes.
Results: We identified several nonrandom chromosomal aberrations among the 20 primary OCCA tumors examined. Among them, gain of DNA at 17q21-q24 showed significantly negative correlation with disease-free and overall survival (P = 0.0012 and 0.0039, respectively, log-rank test). This correlation held even for patients with stage I tumors. Among 15 candidate genes within the 17q21-q24 region, we found significantly elevated expression of PPM1D and APPBP2, and their heightened expression correlated negatively with disease-free survival (P = 0.0090, log-rank test adjusted for multiple comparisons).
Conclusions: Information gained from our relatively large panel of OCCA tumors suggested that 17q21-q24 gain and consequent overexpression of two potential targets, PPM1D and APPBP2, are associated with malignant phenotypes of this tumor and may be useful predictors for prognosis.

Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets Reviewed

A Hirasawa, F Saito-Ohara, J Inoue, D Aoki, N Susumu, T Yokoyama, S Nozawa, J Inazawa, Imoto, I

CLINICAL CANCER RESEARCH 9 ( 6 ) 1995 - 2004 2003.6

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets. International journal

Akira Hirasawa, Fumiko Saito-Ohara, Jun Inoue, Daisuke Aoki, Nobuyuki Susumu, Tetsuji Yokoyama, Shiro Nozawa, Johji Inazawa, Issei Imoto

Clinical cancer research : an official journal of the American Association for Cancer Research 9 ( 6 ) 1995 - 2004 2003.6

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

PURPOSE: Although tumor stage is considered a prognosticfeature for ovarian clear cell adenocarcinomas (OCCAs), it is not likely to fully account for the clinical and biological variability characteristic of the disease. The aim of this study was to investigate aberrations of DNA copy number in OCCA tumors and identify genetic markers that would increase our understanding of the pathogenesis of OCCA and assist in more accurately predicting the outcome for an individual patient with this disease. EXPERIMENTAL DESIGN: We determined copy number aberrations among 20 primary OCCA tumors by means of comparative genomic hybridization and investigated their relationship to clinicopathological data. We also measured expression levels of candidate target genes within critical regions by quantitative real-time reverse transcription-PCRs and compared those data with copy number status and patient outcomes. RESULTS: We identified several nonrandom chromosomal aberrations among the 20 primary OCCA tumors examined. Among them, gain of DNA at 17q21-q24 showed significantly negative correlation with disease-free and overall survival (P = 0.0012 and 0.0039, respectively, log-rank test). This correlation held even for patients with stage I tumors. Among 15 candidate genes within the 17q21-q24 region, we found significantly elevated expression of PPM1D and APPBP2, and their heightened expression correlated negatively with disease-free survival (P = 0.0090, log-rank test adjusted for multiple comparisons). CONCLUSIONS: Information gained from our relatively large panel of OCCA tumors suggested that 17q21-q24 gain and consequent overexpression of two potential targets, PPM1D and APPBP2, are associated with malignant phenotypes of this tumor and may be useful predictors for prognosis.