Faculty Profiles - HIRASAWA Akira

Papers - HIRASAWA Akira

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最新産婦人科遺伝診療ABC 10.婦人科腫瘍領域における遺伝診療総論

坂井美佳, 坂井美佳, 竹原和宏, 平沢晃

産科と婦人科 88 ( 1 ) 65 - 72 2021

Authorship：Corresponding author Language：Japanese Publisher：(株)診断と治療社

遺伝性乳がん卵巣がん症候群(HBOC)やLynch症候群を代表とする遺伝性腫瘍は婦人科腫瘍とのかかわりが深い。特にごく最近では2019年のBRCA1/2遺伝学的検査のコンパニオン診断とがんゲノム医療の保険診療化、そして2020年4月のHBOC診療の一部保険診療化に伴い、産婦人科医にとって遺伝性腫瘍の知識は不可欠なものとなっている。個々の遺伝情報を知ることは、がん治療および予防の観点から有用性が高い。(著者抄録)

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00525&link_issn=&doc_id=20201221170010&doc_link_id=%2Fae4sanke%2F2021%2F008801%2F011%2F0065-0072%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fae4sanke%2F2021%2F008801%2F011%2F0065-0072%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Molecular Features and Clinical Management of Hereditary Gynecological Cancers. International journal

Arisa Ueki, Akira Hirasawa

International journal of molecular sciences 21 ( 24 ) 2020.12

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

Hereditary gynecological cancers are caused by several inherited genes. Tumors that arise in the female reproductive system, such as ovaries and the uterus, overlap with hereditary cancers. Several hereditary cancer-related genes are important because they might lead to therapeutic targets. Treatment of hereditary cancers should be updated in line with the advent of various new methods of evaluation. Next-generation sequencing has led to rapid, economical genetic analyses that have prompted a concomitant and significant paradigm shift with respect to hereditary cancers. Molecular tumor profiling is an epochal method for determining therapeutic targets. Clinical treatment strategies are now being designed based on biomarkers based on tumor profiling. Furthermore, the National Comprehensive Cancer Network (NCCN) guidelines significantly changed the genetic testing process in 2020 to initially consider multi-gene panel (MGP) evaluation. Here, we reviewed the molecular features and clinical management of hereditary gynecological malignancies, such as hereditary breast and ovarian cancer (HBOC), and Lynch, Li-Fraumeni, Cowden, and Peutz-Jeghers syndromes. We also reviewed cancer-susceptible genes revealed by MGP tests.

DOI： 10.3390/ijms21249504

Attitudes toward and current status of disclosure of secondary findings from next-generation sequencing: a nation-wide survey of clinical genetics professionals in Japan International journal

Mio Tsuchiya, Takahiro Yamada, Rina Akaishi, Haruka Hamanoue, Akira Hirasawa, Maki Hyodo, Issei Imoto, Tomoki Kosho, Kenji Kurosawa, Hiromi Murakami, Kaname Nakatani, Fumio Nomura, Aiko Sasaki, Kenji Shimizu, Mariko Tamai, Hiroshi Umemura, Atsushi Watanabe, Akiko Yoshida, Hiroshi Yoshihashi, Junko Yotsumoto, Shinji Kosugi

JOURNAL OF HUMAN GENETICS 65 ( 12 ) 1045 - 1053 2020.12

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

The management of secondary findings (SFs), which are beyond the intended purpose of the analysis, from clinical comprehensive genomic analysis using next generation sequencing (NGS) presents challenges. Policy statements regarding their clinical management have been announced in Japan and other countries. In Japan, however, the current status of and attitudes of clinical genetics professionals toward reporting them are unclear. We conducted a questionnaire survey of clinical genetics professionals at two time points (2013 and 2019) to determine the enforcement of the SF management policy in cases of comprehensive genetic analysis of intractable diseases and clinical cancer genome profiling testing. According to the survey findings, 40% and 70% of the respondents stated in the 2013 and 2019 surveys, respectively, that they had an SF policy in the field of intractable diseases, indicating that SF policy awareness in Japan has changed significantly in recent years. Furthermore, a total of 80% of respondents stated that their facility had established a policy for clinical cancer genome profiling testing in the 2019 survey. In both surveys, the policies included the selection criteria for genes to be disclosed and the procedure to return SFs, followed by recommendations and proposals regarding SFs in Japan and other countries. To create a better list of the genes to be disclosed, further examination is needed considering the characteristics of each analysis.

DOI： 10.1038/s10038-020-0802-2

Retrospective evaluation of risk-reducing salpingo-oophorectomy for BRCA1/2 pathogenic variant carriers among a cohort study in a single institution. International journal

Yusuke Kobayashi, Akira Hirasawa, Tatsuyuki Chiyoda, Arisa Ueki, Kenta Masuda, Kumiko Misu, Miho Kawaida, Shigenori Hayashi, Fumio Kataoka, Kouji Banno, Kenjiro Kosaki, Daisuke Aoki

Japanese journal of clinical oncology 51 ( 2 ) 213 - 217 2020.10

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

BACKGROUND: Risk-reducing salpingo-oophorectomy is performed for the primary prevention of ovarian cancer in patients with hereditary breast-ovarian cancer syndrome. We performed risk-reducing salpingo-oophorectomy for the first time in Japan in 2008, and we experienced 20 cases of risk-reducing salpingo-oophorectomy through 2019. In the past, the use of risk-reducing salpingo-oophorectomy in Japan was restricted because it was not covered by a Japanese National Health Insurance. Since April 2020, risk-reducing salpingo-oophorectomy has been covered by insurance for patients with breast-ovarian cancer syndrome and pre-existing breast cancer, and this surgery is expected to become more widely implemented in Japan. METHODS: To contribute to the widespread use of risk-reducing salpingo-oophorectomy in the future, we retrospectively reviewed 20 cases of risk-reducing salpingo-oophorectomy at our hospital cohort study to clarify the issues in its implementation. RESULTS: The variant genes for which risk-reducing salpingo-oophorectomy was indicated were BRCA1 and BRCA2 in 13 (65%) and 7 patients (35%), respectively. The median age at which risk-reducing salpingo-oophorectomy was performed was 49 years (range, 38-58), 13 patients (65%) had gone through menopause, and 16 patients (80%) had a history of breast cancer. Of the five patients (25%) with vasomotor symptoms, four received Chinese medicine, and only one received hormone replacement therapy. Occult cancer was detected in the removed ovaries in two patients (10%), although no postoperative peritoneal carcinogenesis has been observed to date. CONCLUSIONS: Women who paid for risk-reducing salpingo-oophorectomy out of pocket were older than the recommended age at which the procedure should be performed, and this may explain the higher rate of occult cancers than previously reported. We need to perform risk-reducing salpingo-oophorectomy at the recommended age to ensure that the procedure is effective for primary prevention.

DOI： 10.1093/jjco/hyaa173

Patient-derived ovarian cancer organoids capture the genomic profiles of primary tumours applicable for drug sensitivity and resistance testing. International journal

Yoshiko Nanki, Tatsuyuki Chiyoda, Akira Hirasawa, Aki Ookubo, Manabu Itoh, Masaru Ueno, Tomoko Akahane, Kaori Kameyama, Wataru Yamagami, Fumio Kataoka, Daisuke Aoki

Scientific reports 10 ( 1 ) 12581 - 12581 2020.7

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

The use of primary patient-derived organoids for drug sensitivity and resistance testing could play an important role in precision cancer medicine. We developed expandable ovarian cancer organoids in < 3 weeks; these organoids captured the characteristics of histological cancer subtypes and replicated the mutational landscape of the primary tumours. Seven pairs of organoids (3 high-grade serous, 1 clear cell, 3 endometrioid) and original tumours shared 59.5% (36.1-73.1%) of the variants identified. Copy number variations were also similar among organoids and primary tumours. The organoid that harboured the BRCA1 pathogenic variant (p.L63*) showed a higher sensitivity to PARP inhibitor, olaparib, as well as to platinum drugs compared to the other organoids, whereas an organoid derived from clear cell ovarian cancer was resistant to conventional drugs for ovarian cancer, namely platinum drugs, paclitaxel, and olaparib. The overall success rate of primary organoid culture, including those of various histological subtypes, was 80% (28/35). Our data show that patient-derived organoids are suitable physiological ex vivo cancer models that can be used to screen effective personalised ovarian cancer drugs.

DOI： 10.1038/s41598-020-69488-9

Japan society of clinical oncology/Japanese society of medical oncology-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors, cooperated by the Japanese society of pediatric hematology/oncology.

Yoichi Naito, Saori Mishima, Kiwamu Akagi, Ataru Igarashi, Masafumi Ikeda, Susumu Okano, Shunsuke Kato, Tadao Takano, Katsuya Tsuchihara, Keita Terashima, Hiroshi Nishihara, Hiroyki Nishiyama, Eiso Hiyama, Akira Hirasawa, Hajime Hosoi, Osamu Maeda, Yasushi Yatabe, Wataru Okamoto, Shigeru Ono, Hiroaki Kajiyama, Fumio Nagashima, Yutaka Hatanaka, Mitsuru Miyachi, Yasuhiro Kodera, Takayuki Yoshino, Hiroya Taniguchi

International journal of clinical oncology 25 ( 3 ) 403 - 417 2020.3

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

BACKGROUND: The development of novel antitumor agents and accompanying biomarkers has improved survival across several tumor types. Previously, we published provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors. Recently, efficacy of tropomyosin receptor kinase inhibitors against neurotrophic receptor tyrosine kinase (NTRK) fusion gene-positive advanced solid tumors have been established as the second tumor-agnostic treatment, making it necessary to develop the guideline prioritized for these patients. METHODS: Clinical questions regarding medical care were formulated for patients with NTRK-positive advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO) and Japanese Society of Medical Oncology (JSMO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and Japanese Society of Pediatric Hematology/Oncology, and the public comments among all Societies' members was done. RESULTS: The current guideline describes 3 clinical questions and 15 recommendations for whom, when, and how NTRK fusion should be tested, and what is recommended for patients with NTRK fusion-positive advanced solid tumors. CONCLUSION: In the NTRK guideline, the committee proposed 15 recommendations for performing NTRK testing properly to select patients who are likely to benefit from tropomyosin receptor kinase inhibitors.

DOI： 10.1007/s10147-019-01610-y

Japan Society of Clinical Oncology provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors, cooperated by Japanese Society of Medical Oncology, First Edition. Reviewed

Saori Mishima, Hiroya Taniguchi, Kiwamu Akagi, Eishi Baba, Yutaka Fujiwara, Akira Hirasawa, Masafumi Ikeda, Osamu Maeda, Kei Muro, Hiroshi Nishihara, Hiroyki Nishiyama, Tadao Takano, Katsuya Tsuchihara, Yasushi Yatabe, Yasuhiro Kodera, Takayuki Yoshino

International journal of clinical oncology 25 ( 2 ) 217 - 239 2020.2

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

BACKGROUND: Novel therapeutic agents have improved survival outcomes in patients with advanced solid tumors. In parallel, the development of predictive biomarkers to identify patients who are likely to benefit from a certain treatment has also contributed to the improvement of survival. Recently, clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. In Japan, a PD-1 inhibitor for dMMR advanced solid tumors, regardless of the primary tumor site, has been approved. However, there are some issues related to administering immune checkpoint inhibitors in the clinical practice setting, making it necessary to develop the guidelines. METHODS: Clinical questions (CQs) regarding medical care were formulated for patients with dMMR advanced solid tumors, and evidence to the CQs was collected by manual search to prepare recommendations. Then, the committee members voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other factors. RESULTS: The current guideline, which we consider a provisional clinical opinion at this point, describes the 11 requirements to be considered in terms of patients for whom dMMR testing is recommended, the timing and methods of dMMR testing, and clinical care systems required to perform dMMR testing properly and to administer immune checkpoint inhibitors safely. CONCLUSION: This provisional clinical opinion proposes the requirements for performing dMMR testing properly to select patients who are likely to benefit from immune checkpoint inhibitors and administering them safely.

DOI： 10.1007/s10147-019-01498-8

多発小腸GISTに対し手術を施行した神経線維腫症1型の1例 Reviewed

母里淑子, 重安邦俊, 吉岡貴裕, 永坂岳司, 原賀順子, 香川俊輔, 寺石文則, 豊岡伸一, 平沢晃, 藤原俊義

家族性腫瘍 19 ( 2 ) 77 - 82 2020.2

Identification of a novel uterine leiomyoma GWAS locus in a Japanese population. International journal

Kensuke Sakai, Chizu Tanikawa, Akira Hirasawa, Tatsuyuki Chiyoda, Wataru Yamagami, Fumio Kataoka, Nobuyuki Susumu, Chikashi Terao, Yoichiro Kamatani, Atsushi Takahashi, Yukihide Momozawa, Makoto Hirata, Michiaki Kubo, Nobuo Fuse, Takako Takai-Igarashi, Atsushi Shimizu, Akimune Fukushima, Aya Kadota, Kokichi Arisawa, Hiroaki Ikezaki, Kenji Wakai, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Shoichiro Tsugane, Daisuke Aoki, Koichi Matsuda

Scientific reports 10 ( 1 ) 1197 - 1197 2020.1

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

Uterine leiomyoma is one of the most common gynaecologic benign tumours, but its genetic basis remains largely unknown. Six previous GWAS identified 33 genetic factors in total. Here, we performed a two-staged GWAS using 13,746 cases and 70,316 controls from the Japanese population, followed by a replication analysis using 3,483 cases and 4,795 controls. The analysis identified 9 significant loci, including a novel locus on 12q23.2 (rs17033114, P = 6.12 × 10-25 with an OR of 1.177 (1.141-1.213), LINC00485). Subgroup analysis indicated that 5 loci (3q26.2, 5p15.33, 10q24.33, 11p15.5, 13q14.11) exhibited a statistically significant effect among multiple leiomyomas, and 2 loci (3q26.2, 10q24.33) exhibited a significant effect among submucous leiomyomas. Pleiotropic analysis indicated that all 9 loci were associated with at least one proliferative disease, suggesting the role of these loci in the common neoplastic pathway. Furthermore, the risk T allele of rs2251795 (3q26.2) was associated with longer telomere length in both normal and tumour tissues. Our findings elucidated the significance of genetic factors in the pathogenesis of leiomyoma.

DOI： 10.1038/s41598-020-58066-8

Establishment and characterization of a new malignant peritoneal mesothelioma cell line, KOG-1, from the ascitic fluid of a patient with pemetrexed chemotherapy resistance.

Tomoko Akahane, Akira Hirasawa, Issei Imoto, Aki Okubo, Manabu Itoh, Yoshiko Nanki, Tomoko Yoshihama, Eichiro Tominaga, Daisuke Aoki

Human cell 33 ( 1 ) 272 - 282 2020.1

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

Malignant peritoneal mesothelioma (MPeM) is a rare and aggressive form of malignant mesothelioma. Sufficient biological tools for studying the functional characteristics of this cancer have not been developed. Therefore, in this study, a novel human cancer cell line, KOG-1, was established from ascites fluids isolated from a 39-year-old Japanese woman with pemetrexed-resistant MPeM. Cells were dendritic or linear immediately after thawing, showed a jigsaw puzzle-like and spindle arrangement during growth, and formed monolayers without contact inhibition in two-dimensional (2D) culture. The population doubling time was 13.7 h. Karyotypic and molecular genetic analyses showed that chromosome numbers ranged from 62 to 142, with a peak of 73 with complicated copy number alterations. No germline BAP1 pathogenic variant was detected. Cells expressed various tumor markers of mesothelioma, such as calretinin, podoplanin, and Wilms tumor 1 (WT-1). Drug sensitivity and resistance testing with a set of 36 drugs using 2D and three-dimensional (3D) culture models demonstrated that KOG-1 cells showed high and low sensitivity to pemetrexed under 2D and 3D culture conditions, respectively, whereas control ovarian cancer cell lines showed low sensitivity to pemetrexed under both culture conditions. This newly established cell line will be a valuable biological resource to expand the feasibility of functional studies as well as drug testing for potential therapeutic purposes in MPeM.

DOI： 10.1007/s13577-019-00286-w

Familial Pancreatic Cancer with PALB2 and NBN Pathogenic Variant: A Case Report Reviewed International journal

阿部紘大, 植木有紗, 浦川優作, 北郷実, 吉浜智子, 南木佳子, 北川雄光, 青木大輔, 小崎健次郎, 平沢晃

日本癌学会学術総会抄録集(Web) 79th ( 1 ) 5 - 5 2020

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

<title>Abstract</title><sec>
<title>Background</title>
Family history is one of the risk factors for pancreatic cancer. It is suggested that patients with pancreatic cancer who have a familial history harbor germline pathogenic variants of <italic>BRCA1</italic> and/or <italic>BRCA2</italic> (<italic>BRCA1/2</italic>), <italic>PALB2</italic>, or <italic>ATM</italic>. Recently, some germline variants of familial pancreatic cancers (FPCs), including <italic>PALB2,</italic> have been detected. Several countries, including Japan, perform screening workups and genetic analysis for pancreatic cancers. We have been carrying out active surveillance for FPC through epidemiological surveys, imaging analyses, and genetic analysis.

</sec><sec>
<title>Case presentation</title>
Here, we present the case of a female patient harboring pathogenic variants of <italic>PALB2</italic> and <italic>NBN</italic>, with a family history of multiple pancreatic cancer in her younger brother, her aunt, and her father. Moreover, her father harbored a <italic>PALB2</italic> pathogenic variant and her daughter harbored the same <italic>NBN</italic> pathogenic variant. Given the <italic>PALB2</italic> and <italic>NBN</italic> variants, we designed surveillance strategies for the pancreas, breast, and ovary.

</sec><sec>
<title>Conclusions</title>
Further studies are required to develop strategies for managing FPCs to facilitate prompt diagnosis before their progression.

</sec>

DOI： 10.1186/s13053-020-00160-z

Other Link： http://link.springer.com/article/10.1186/s13053-020-00160-z/fulltext.html

Prevalence of disease-causing genes in Japanese patients with BRCA1/2-wildtype hereditary breast and ovarian cancer syndrome. International journal

Tomoko Kaneyasu, Seiichi Mori, Hideko Yamauchi, Shozo Ohsumi, Shinji Ohno, Daisuke Aoki, Shinichi Baba, Junko Kawano, Yoshio Miki, Naomichi Matsumoto, Masao Nagasaki, Reiko Yoshida, Sadako Akashi-Tanaka, Takuji Iwase, Dai Kitagawa, Kenta Masuda, Akira Hirasawa, Masami Arai, Junko Takei, Yoshimi Ide, Osamu Gotoh, Noriko Yaguchi, Mitsuyo Nishi, Keika Kaneko, Yumi Matsuyama, Megumi Okawa, Misato Suzuki, Aya Nezu, Shiro Yokoyama, Sayuri Amino, Mayuko Inuzuka, Tetsuo Noda, Seigo Nakamura

NPJ breast cancer 6 25 - 25 2020

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

Panel sequencing of susceptibility genes for hereditary breast and ovarian cancer (HBOC) syndrome has uncovered numerous germline variants; however, their pathogenic relevance and ethnic diversity remain unclear. Here, we examined the prevalence of germline variants among 568 Japanese patients with BRCA1/2-wildtype HBOC syndrome and a strong family history. Pathogenic or likely pathogenic variants were identified on 12 causal genes for 37 cases (6.5%), with recurrence for 4 SNVs/indels and 1 CNV. Comparisons with non-cancer east-Asian populations and European familial breast cancer cohorts revealed significant enrichment of PALB2, BARD1, and BLM mutations. Younger onset was associated with but not predictive of these mutations. Significant somatic loss-of-function alterations were confirmed on the wildtype alleles of genes with germline mutations, including PALB2 additional somatic truncations. This study highlights Japanese-associated germline mutations among patients with BRCA1/2 wildtype HBOC syndrome and a strong family history, and provides evidence for the medical care of this high-risk population.

DOI： 10.1038/s41523-020-0163-1

Training Medical Staff with Basic Skills for Data Science in Genomic Medicine

冨田秀太, 森田瑞樹, 山下範之, 平沢晃, 豊岡伸一

薬学雑誌(Web) 140 ( 5 ) 657 - 661 2020

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

The development of specialized training programs for medical personnel, particularly nurses, clinical laboratory technicians, and pharmacists, is considered critical for the promotion of genomic medicine throughout Japan. Specifically, medical personnel skilled at analyzing and understanding high-throughput genomic data are in high demand. In this symposium, we will introduce the basic knowledge and skills necessary for processing genomic data.

DOI： 10.1248/yakushi.19-00217-2

DV200 Index for Assessing RNA Integrity in Next-Generation Sequencing. International journal

Takehiro Matsubara, Junichi Soh, Mizuki Morita, Takahiro Uwabo, Shuta Tomida, Toshiyoshi Fujiwara, Susumu Kanazawa, Shinichi Toyooka, Akira Hirasawa

BioMed research international 2020 9349132 - 9349132 2020

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

Poor quality of biological samples will result in an inaccurate analysis of next-generation sequencing (NGS). Therefore, methods to accurately evaluate sample integrity are needed. Among methods for evaluating RNA quality, the RNA integrity number equivalent (RINe) is widely used, whereas the DV200, which evaluates the percentage of fragments of >200 nucleotides, is also used as a quality assessment standard. In this study, we compared the RINe and DV200 RNA quality indexes to determine the most suitable RNA index for the NGS analysis. Seventy-one RNA samples were extracted from formalin-fixed paraffin-embedded tissue samples (n = 30), fresh-frozen samples (n = 25), or cell lines (n = 16). After assessing RNA quality using the RINe and DV200, we prepared two kinds of stranded mRNA sequencing libraries. Finally, we calculated the correlation between each RNA quality index and the amount of library product (1st PCR product per input RNA). The DV200 measure showed stronger correlation with the amount of library product than the RINe (R2 = 0.8208 for the DV200 versus 0.6927 for the RINe). Receiver operating characteristic curve analyses revealed that the DV200 was the better marker for predicting efficient library production than the RINe using a threshold of >10 ng/ng for the amount of the 1st PCR product per input RNA (cutoff value for the RINe and DV200, 2.3 and 66.1%; area under the curve, 0.99 and 0.91; sensitivity, 82% and 92%; and specificity, 93% and 100%, respectively). Our results indicate that NGS libraries prepared using RNA samples with the DV200 value > 66.1% exhibit greater sensitivity and specificity than those prepared with the RINe values > 2.3. These findings suggest that the DV200 is superior to the RINe, especially for low-quality RNA, because it is a more consistent assessment of the amount of the 1st NGS library product per input.

DOI： 10.1155/2020/9349132

がんゲノム医療と実地臨床での課題

HIRASAWA AKIRA

日本婦人科腫瘍学会雑誌 37 ( 4 ) 666 - 667 2019.10

BRCA1/2遺伝子バリアントとがん発症・臨床病理学的特徴および発症リスク因子を明らかにするための卵巣がん未発症を対象としたバイオバンク・コホート研究（JGOG3024)

HIRASAWA AKIRA

BRCA1/2遺伝子バリアントとがん発症・臨床病理学的特徴および発症リスク因子を明らかにするための卵巣がん未発症を対象としたバイオバンク・コホート研究（JGOG3024) 18th 67 - 69 2019.8

Genome-wide DNA methylation profile of early-onset endometrial cancer: its correlation with genetic aberrations and comparison with late-onset endometrial cancer. International journal

Takeshi Makabe, Eri Arai, Takuro Hirano, Nanako Ito, Yukihiro Fukamachi, Yoriko Takahashi, Akira Hirasawa, Wataru Yamagami, Nobuyuki Susumu, Daisuke Aoki, Yae Kanai

Carcinogenesis 40 ( 5 ) 611 - 623 2019.7

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

The present study was performed to clarify the significance of DNA methylation alterations during endometrial carcinogenesis. Genome-wide DNA methylation analysis and targeted sequencing of tumor-related genes were performed using the Infinium MethylationEPIC BeadChip and the Ion AmpliSeq Cancer Hotspot Panel v2, respectively, for 31 samples of normal control endometrial tissue from patients without endometrial cancer and 81 samples of endometrial cancer tissue. Principal component analysis revealed that tumor samples had a DNA methylation profile distinct from that of control samples. Gene Ontology enrichment analysis revealed significant differences of DNA methylation at 1034 CpG sites between early-onset endometrioid endometrial cancer (EE) tissue (patients aged ≤40 years) and late-onset endometrioid endometrial cancer (LE) tissue, which were accumulated among 'transcriptional factors'. Mutations of the CTNNB1 gene or DNA methylation alterations of genes participating in Wnt signaling were frequent in EEs, whereas genetic and epigenetic alterations of fibroblast growth factor signaling genes were observed in LEs. Unsupervised hierarchical clustering grouped EE samples in Cluster EA (n = 22) and samples in Cluster EB (n = 12). Clinicopathologically less aggressive tumors tended to be accumulated in Cluster EB, and DNA methylation levels of 18 genes including HOXA9, HOXD10 and SOX11 were associated with differences in such aggressiveness between the two clusters. We identified 11 marker CpG sites that discriminated EB samples from EA samples with 100% sensitivity and specificity. These data indicate that genetically and epigenetically different pathways may participate in the development of EEs and LEs, and that DNA methylation profiling may help predict tumors that are less aggressive and amenable to fertility preservation treatment.

DOI： 10.1093/carcin/bgz046

遺伝子情報を用いた遺伝性乳癌卵巣癌の予防と治療 Reviewed

HIRASAWA AKIRA

病理と臨床 37 ( 6 ) 522 - 527 2019.6

女性がんの化学予防 Reviewed

HIRASAWA AKIRA

産科と婦人科増刊号 86 ( Suppl. ) 350 - 353 2019.4

Guidelines for office gynecology in Japan: Japan Society of Obstetrics and Gynecology (JSOG) and Japan Association of Obstetricians and Gynecologists (JAOG) 2017 edition. International journal

Ryuji Kawaguchi, Koji Matsumoto, Shigeo Akira, Ken Ishitani, Kazuhiro Iwasaku, Yutaka Ueda, Ryugo Okagaki, Hiroya Okano, Toshimichi Oki, Kaori Koga, Michiko Kido, Takumi Kurabayashi, Yasushi Kuribayashi, Yuichi Sato, Kaori Shiina, Yasushi Takai, Satoshi Tanimura, Osamu Chaki, Masakazu Terauchi, Yukiharu Todo, Yasuyuki Noguchi, Sayaka Nose-Ogura, Tsukasa Baba, Akira Hirasawa, Takuma Fujii, Tsuneo Fujii, Tetsuo Maruyama, Etsuko Miyagi, Kaoru Yanagida, Osamu Yoshino, Mitsutoshi Iwashita, Tsugio Maeda, Takashi Minegishi, Hiroshi Kobayashi

The journal of obstetrics and gynaecology research 45 ( 4 ) 766 - 786 2019.4

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

Six years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the third revised edition was published in 2017. The 2017 Guidelines includes 10 additional clinical questions (CQ), which brings the total to 95 CQ (12 on infectious disease, 28 on oncology and benign tumors, 27 on endocrinology and infertility and 28 on healthcare for women). Currently a consensus has been reached on the Guidelines and therefore the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding recommendation level (A, B, C) is indicated.

DOI： 10.1111/jog.13831

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