Papers - NISHIHARA, Hiroshi

Diffuse-Type Tenosynovial Giant Cell Tumor Arising in the Temporomandibular Joint Extending to the External Auditory Canal: A Case Report and Literature Review.

Suzuki S, Tsuda H, Bandoh N, Goto T, Uemura A, Aoyama T, Nishio A, Makino S, Yamaguchi T, Aimono E, Nishihara H, Harabuchi Y

Ear, nose, & throat journal 102 ( 5 ) 291 - 296 2023.05

Accepted,  ISSN  0145-5613

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Clinical predominance of whole‐exome sequencing to evaluate microsatellite instability status

Reika Takamatsu, Kohei Nakamura, Okihide Suzuki, Chihiro Okada, Ryo Mori, Ryutaro Kawano, Hideyuki Hayashi, Marin Ishikawa, Eriko Aimono, Sachio Nohara, Shigeki Tanishima, Arisa Ueki, Hideyuki Ishida, Hiroshi Nishihara

Cancer Science (Wiley)   2023.04

Accepted,  ISSN  1347-9032

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The DNA integrity number and concentration are useful parameters for successful comprehensive genomic profiling test for cancer using formalin-fixed paraffin embedded tissue.

Emmy Yanagita, Hiroshi Yamada, Tetsuro Kobayashi, Eriko Aimono, Kohei Nakamura, Akira Hirasawa, Hiroshi Nishihara

Pathology international 73 ( 5 ) 198 - 206 2023.03

Accepted

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The acquisition of high-quality biospecimens and the appropriate handling of these materials are indispensable for successful clinical sequencing. We developed a cancer clinical sequencing system targeting 160 cancer genes: PleSSision-Rapid. Through the PleSSision-Rapid system, we have analyzed DNA quality evaluated by DIN (DNA integrity number) with 1329 formalin-fixed paraffin embedded (FFPE) samples including 477 prospectively collected tissues for genomic test (P) and 852 archival samples after routine pathological diagnosis (A1/A2). As a result, the samples with more than DIN 2.1 was 92.0% (439/477) in prospectively collected sample (P), while it was 85.6% (332/388) and 76.7% (356/464) in two types of archival samples (A1/A2). We performed the PleSSision-Rapid sequence using the samples with over DIN 2.1 and DNA concentration >10 ng/μL with which we were able to construct a DNA library, and the probability of sequence success was almost equivalent during all types of specimen processing, at 90.7% (398/439) in (P), 92.5% (307/332) in (A1) and 90.2% (321/356) in (A2), respectively. Our result indicated the clinical benefit to prepare the prospective collection of FFPE materials for indisputable clinical sequence, and that DIN ≥ 2.1 would be a solid parameter for sample preparation of comprehensive genomic profiling tests.

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がんゲノムプロファイリング検査データに基づく十二指腸腫瘍のゲノム病理学的特徴

石川 麻倫, 川野 竜太郎, 四十物 絵理子, 中村 康平, 加藤 容崇, 林 秀幸, 谷嶋 成樹, 西原 広史

日本病理学会会誌 ((一社)日本病理学会)  112 ( 1 ) 267 - 267 2023.03

Accepted,  ISSN  0300-9181

分子病理診断として運用する院内がん遺伝子検査Rapid-Neoの有用性

川野 竜太郎, 柳田 絵美衣, 山田 寛, 石川 麻倫, 中村 康平, 林 秀幸, 谷嶋 成樹, 西原 広史

日本病理学会会誌 ((一社)日本病理学会)  112 ( 1 ) 341 - 342 2023.03

Accepted,  ISSN  0300-9181

DOCK2は日本人集団におけるCOVID-19の重症化遺伝子で,宿主免疫応答に重要な役割を担う

南宮 湖, 枝廣 龍哉, 高野 友美, 西原 広史, 熊ノ郷 淳, 小池 竜司, 木村 彰方, 井元 清哉, 宮野 悟, 小川 誠司, 金井 隆典, 岡田 随象, 福永 興壱

日本呼吸器学会誌 ((一社)日本呼吸器学会)  12 ( 増刊 ) 271 - 271 2023.03

Accepted,  ISSN  2186-5876

Japanese nationwide observational multicenter study of tumor BRCA1/2 variant testing in advanced ovarian cancer.

Oda K, Aoki D, Tsuda H, Nishihara H, Aoyama H, Inomata H, Shimada M, Enomoto T

Cancer science 114 ( 1 ) 271 - 280 2023.01

Accepted,  ISSN  1347-9032

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The association between germline BRCA1 and BRCA2 pathogenic variants (mutations: gBRCAm) and ovarian cancer risk is well established. Germline testing alone cannot detect somatic BRCA1/2 pathogenic variants (sBRCAm), which is calculated based on the proportion of tumor BRCAm (tBRCAm) from tumor samples and gBRCAm. Homologous recombination deficiency (HRD) results mainly from genetic/epigenetic alterations in homologous recombination repair-related genes and can be evaluated by genomic instability status. In Japan, the prevalence of tBRCAm, sBRCAm, and HRD remains unclear. This multicenter, cross-sectional, observational study, CHaRacterIzing the croSs-secTional approach to invEstigate the prevaLence of tissue BRCA1/2 mutations in newLy diagnosEd advanced ovarian cancer patients (CHRISTELLE), evaluated the prevalence of tBRCAm, sBRCAm, and HRD in tumor specimens from newly diagnosed patients with ovarian cancer who underwent gBRCA testing. Of the 205 patients analyzed, 26.8% had a tBRCAm, including tBRCA1m (17.6%) and tBRCA2m (9.3%). The overall prevalence of tBRCAm, gBRCAm, sBRCAm, and HRD-positive status was 26.8%, 21.5%, 6.3%, and 60.0%, respectively. The calculated sBRCAm/tBRCAm ratio was 23.6% (13/55), and the prevalence of gBRCA variant of uncertain significance was 3.9%. These results suggest gBRCA testing alone cannot clearly identify the best course of treatment, highlighting the importance of sBRCA testing in Japan. The present results also suggest that testing for tBRCA and HRD should be encouraged in advanced ovarian cancer patients to drive precision medicine.

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Genomic analysis of aggressive ductal adenocarcinoma of the prostate.

Hiroaki Kobayashi, Takeo Kosaka, Kohei Nakamura, Tokuhiro Kimura, Hiroshi Nishihara, Mototsugu Oya

Cancer medicine 12 ( 7 ) 8445 - 8451 2022.12

Accepted

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BACKGROUND: Genomic profile analysis using next-generation sequencing can potentially elucidate the pathogenesis of rare cancers. Ductal adenocarcinoma, a rare subtype of prostate cancer, has an aggressive nature. This is the first study to analyze the genomic profile of ductal adenocarcinoma in an Asian population. METHODS: We identified 12 patients newly diagnosed with ductal adenocarcinoma of the prostate at two hospitals, and nine patients (75.0%) had the pure type. Genomic assessment was performed using either the PleSSision testing platform or FoundationOne CDx. RESULTS: At least one genomic alteration occurred in 11 patients (91.7%), and the most frequently mutated gene was tumor suppressor protein p53 (TP53), which was found in six cases (50.0%). Alterations characteristic of this cohort were found in four cases (33.3%) of retinoblastoma transcriptional corepressor 1 (RB1), which was only observed in the pure type. Compared to previous study results, the frequency of genetic alterations in the phosphoinositide 3-kinase (PI3K) pathway (n = 3; 25.0%) and Wnt-β-catenin pathway (n = 5; 41.7%) was comparable, but no alterations in the DNA damage repair (DDR) pathway were observed. None of the patients presented high tumor mutation burden or microsatellite instability. CONCLUSIONS: We found that the Asian cohort with ductal adenocarcinoma had actionable alterations, and a high frequency of alterations in TP53 and RB1 reflected the aggressive nature of the tumor. Genetic analysis using next-generation sequencing is expected to help elucidate the pathogenesis of ductal adenocarcinoma.

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Derivative Chromosome 3 Loss from t(3;6)(q12;q14) Followed by Differential VHL Mutations Underlie Multifocal ccRCC.

Mizutani K, Yokoi S, Sawada S, Sakamoto I, Kameyama K, Kamei S, Hirade K, Sugiyama S, Matsunaga K, Yamada T, Kato Y, Nishihara H, Ishihara S, Deguchi T

Cancer genomics & proteomics 19 ( 6 ) 740 - 746 2022.11

Accepted,  ISSN  1109-6535

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Background/Aim: The Von Hippel-Lindau (VHL) gene encodes a protein (pVHL) that plays an important role in proteasome degradation of hypoxia inducible factor α (HIFα) through E3 activation. Accumulation of HIFα by loss of functional pVHL promotes tumorigenesis, thus, VHL has tumor suppressor gene capability in clear cell renal cell carcinoma (ccRCC). VHL is the most frequently mutated gene in ccRCC. The complete loss of VHL is mainly achieved by loss of chromosome 3p, which has a VHL coding region in combination with mutation or hypermethylation of the remaining copy of VHL. Given the risk of constitutional chromosome 3 translocation for RCC, it is important to detect the translocation and understand the mechanism underlying the development of multifocal ccRCC. Case Report: A 67- year-old female patient diagnosed with multifocal RCC underwent robot-assisted partial nephrectomy (RAPN) for three kidney tumors. A cancer gene panel test using next generation sequencing (NGS) detected differential VHL mutations (c.533T>G; p.L178R, c.465_466insTA; p.T157Ifs*3, c.343C>A; p.H115N), while VHL mutation was not detected in peripheral blood DNA. A tendency toward copy number loss of genes on der(3) was also detected in all tumors, but not in the germline one. A karyotype analysis revealed a germline translocation between 3 and 6, t(3;6)(q12;q14). Conclusion: Chromosome 3 translocation and loss of derivative chromosome containing 3p and subsequent somatic differential VHL mutations in this case strongly support the previously proposed three-step model to explain the development of familial conventional ccRCC.

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Characterizing cyclin-dependent kinase 12(CDK12)-altered aggressive prostate cancer: a twelve-case series

Tomohiro Iwasawa, Takeo Kosaka, Yota Yasumizu, Hiroshi Hongo, Yoshinori Yanai, Yuto Baba, Kazuhiro Matsumoto, Kohei Nakamura, Hiroshi Nishihara, Mototsugu Oya

International Journal of Clinical Oncology (Springer Science and Business Media LLC)  27 ( 12 ) 1867 - 1873 2022.10

Accepted,  ISSN  1341-9625

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Abstract

Background

Prostate cancer harboring cyclin-dependent kinase 12 (CDK12) abnormalities is a hot topic due to its distinctive clinical features, such as sensitivity to immune checkpoint inhibitors. In the last few years, precision medicine using comprehensive genome sequencing has become familiar, and the era of precision oncology has arrived in the field of prostate cancer. This study aimed to present the demographic characteristics of patients with CDK12 alterations.

Methods

In 12 patients with detected CDK12 alterations in our hospital between 2015 and 2021, we evaluated their genomic features and clinical course. CDK12 allelic status was classified into three groups: monoallelic loss, potentially biallelic loss, and biallelic loss based on the genome analyses.

Results

Seven patients already had metastatic cancer at the time of diagnosis, and all 12 patients had Gleason grade  ≥ 4. Most cases of biallelic loss or potentially biallelic loss were metastatic cancers at the initial staging, and all these cases were categorized into Gleason grade 5. Two of the 12 patients had BRCA2/RB1 co-loss, and the other two had whole genome duplication. Five patients had a long-term survival of  > 6 years, but two patients died within 4 years of diagnosis.

Conclusion

This is the first Japanese prostate cancer case series with CDK12 alterations. CDK12-altered prostate cancer is a heterogeneous disease, and accumulating cases with detailed information leads to precision oncology.

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ASO Author Reflections: Does Elevation of the Prognostic Factor Plasma Fibrinogen Level Reflect the Tumor Microenvironment at the Primary Site?

Hoshino S, Matsuda S, Kawakubo H, Yamaguchi S, Nakamura K, Aimono E, Matsui K, Irino T, Fukuda K, Nakamura R, Okita H, Nishihara H, Takeuchi H, Kitagawa Y

Annals of surgical oncology 29 ( 11 ) 6905 - 6906 2022.10

Accepted,  ISSN  1068-9265

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Elevation of the Prognostic Factor Plasma Fibrinogen Reflects the Immunosuppressive Tumor Microenvironment in Esophageal Squamous Cell Carcinoma.

Shota Hoshino, Satoru Matsuda, Hirofumi Kawakubo, Shigeo Yamaguchi, Kohei Nakamura, Eriko Aimono, Kazuaki Matsui, Tomoyuki Irino, Kazumasa Fukuda, Rieko Nakamura, Hajime Okita, Hiroshi Nishihara, Hiroya Takeuchi, Yuko Kitagawa

Annals of surgical oncology 29 ( 11 ) 6894 - 6904 2022.10

Accepted,  ISSN  1068-9265

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INTRODUCTION: Despite previous reports on the clinical significance of plasma fibrinogen (FNG) levels as a prognostic indicator of ESCC, its underlying mechanism remains unclear. This study aimed to validate the prognostic impact of plasma FNG levels and clarify its relationship with primary tumors in patients with esophageal squamous cell carcinoma (ESCC). METHODS: The prognostic impact of FNG was evaluated in patients with ESCC who underwent esophagectomy between 2000 and 2019. The RNA sequencing of the primary ESCC site, which was from pre-operative biopsy, was performed, followed by immune profile characterization using an immunogram. Those profiles were assessed via the immunohistochemical staining of tumor-associated macrophages (TAMs) and clinical response to nivolumab. RESULTS: Multivariate analysis identified FNG as a significant prognostic factor in ESCC. The immunogram suggested an immunosuppressive tumor environment in the high-FNG group. Immunostaining with the TAM markers CD163 and CD204, revealed that the high-FNG group had significantly higher number of TAMs compared with the low-FNG group. The immunosuppressive characteristics were clinically validated in patients with metastatic ESCC; those who had elevated FNG levels showed poor response to nivolumab. CONCLUSION: This study successfully validated the prognostic impact of plasma FNG levels in an expanded cohort with ESCC. Accordingly, our findings showed that increased plasma FNG reflects an immunosuppressive tumor microenvironment that facilitates tumor progression and poor responses to nivolumab.

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The first Japanese case of intraductal cancer of the prostate with checkpoint kinase 2 mutation

Hiroshi Hongo, Takeo Kosaka, Kohei Nakamura, Shuji Mikami, Hiroshi Nishihara, Mototsugu Oya

Asian Journal of Urology (Elsevier BV)  9 ( 4 ) 480 - 482 2022.10

Accepted,  ISSN  2214-3882

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食道癌におけるクラスタリングを用いた炎症凝固サブタイプの提唱とMolecular profiling

松田 諭, 川久保 博文, 星野 尚大, 後藤 匡啓, 小林 亮太, 福田 和正, 中村 理恵子, 中村 康平, 西原 広史, 北川 雄光

日本胸部外科学会定期学術集会 ((一社)日本胸部外科学会)  75回   JP2 - 5 2022.10

Accepted

[Panel Discussion - Problems in the Cancer Genomic Medicine].

Chikashi Ishioka, Manabu Muto, Shinichi Yachida, Hidekazu Shirota, Akira Hirasawa, Kiyoshi Miyagawa, Kazuto Ashizawa, Ichiro Kinoshita, Hiroshi Nishihara, Nariaki Matsuura, Akihiro Sakurai

Gan to kagaku ryoho. Cancer & chemotherapy 49 ( 9 ) 1014 - 1017 2022.09

Accepted,  ISSN  0385-0684

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About 4 and a half years have passed since"Cancer Genome Medicine"was first mentioned in the Third Phase of the Basic Plan to Promote Cancer Control Programs that started in October 2017. Currently, cancer genomic medicine is being carried out by the cancer gene panel test, which is covered by public insurance, mainly at the 12 Cancer Genome Medicine Core Center Hospital designated nationwide by the Ministry of Health, Labor, and Welfare in Japan. Cancer genomic medicine has come to be positioned as a standard medical treatment. However, there are various challenges in operating an expert panel that professionally examines the results of the gene panel tests and reports treatment recommendations and secondary findings that suggest hereditary tumors. In addition, there is an urgent need to disseminate and educate healthcare professionals and patients about cancer genomic medicine. In this panel discussion on January 14, 2022, 10 panelists discussed how to solve these issues and the prospects for the future.

[Additional Remarks on the Issue of Cancer Genomic Medicine-Focusing on Medical Insurance Issues].

Nishihara H

Gan to kagaku ryoho. Cancer & chemotherapy 49 ( 9 ) 1011 - 1013 2022.09

Accepted,  ISSN  0385-0684

Squamous cell carcinoma of the prostate with <scp> <i>SMARCA4</i> </scp> alteration in a Japanese patient

Yuta Kaneko, Takeo Kosaka, Kohei Nakamura, Shuji Mikami, Hiroshi Nishihara, Mototsugu Oya

IJU Case Reports (Wiley)  5 ( 5 ) 323 - 326 2022.09

Accepted,  ISSN  2577-171X

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Cancer genomic medicine in Japan and the roles of pharmacists.

Aomori T, Sakurai H, Nishihara H

Pharmacogenetics and genomics 32 ( 6 ) 242 - 245 2022.08

Accepted,  ISSN  1744-6872

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Genomic landscape of treatment-naïve urological cancers using next-generation sequencing-based panel test in the Japanese population.

Mizutani K, Hirade K, Sugiyama S, Kato Y, Nishihara H, Ishihara S

International journal of urology : official journal of the Japanese Urological Association (WILEY)  29 ( 8 ) 909 - 911 2022.08

Accepted,  ISSN  0919-8172

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Recommendations related to the analytical equivalence assessment of gene panel testing.

Sumimasa Nagai, Hiroshi Nishihara, Takayoshi Suzuki, Kazuto Nishio, Hiroya Taniguchi, Katsuya Tsuchihara, Kohei Nakamura, Reika Takamatsu, Toshihide Ueno, Hiroyuki Aburatani, Takashi Kohno, Shinji Kohsaka

Cancer science 113 ( 10 ) 3282 - 3290 2022.07

Accepted,  ISSN  1347-9032

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Advances in cancer genome care over the past few years have included the development of gene panel testing for various biomarkers. This article summarizes issues and provides recommendations related to analytical performance evaluations for new oncology gene panels. The scope of these recommendations includes comprehensive genomic profiling assays related to gene panel testing that uses histological or serum specimens to detect gene mutations. As a research project of the Japan Agency for Medical Research and Development Research on Regulatory Science of Pharmaceuticals and Medical Devices, we convened the working group committee that consisted of more than 30 experts from academia, industry, and government. We have discussed the points that should be considered to allow maximal simplification of assessments using clinical specimens in evaluating accuracy and limit of detection in equivalence and analytical performance for three years. We provide recommendations specific to each type of gene mutation as well as to reference standards or specimens used for evaluations. In addition, in order to facilitate the discussion on the analytical performance of gene panel tests by multidisciplinary tumor boards of hospitals, the present recommendations also describe the items that companies are expected to provide information on in their packaging inserts and reports, and the items that are expected to be discussed by multidisciplinary tumor boards. Our working group document will be important for participants in multidisciplinary tumor boards including medical oncologists and genome scientists, and developers of gene panels not only in Japan but also in other countries.

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