Annual Report 2021
Department of Clinical Genomics
Hitoshi Ichikawa, Kouya Shiraishi, Masahiro Gotoh, Kazuhiko Aoyagi, Masaru Katoh, Hiromi Sakamoto, Teruhiko Yoshida, Takashi Kubo, Makoto Hirata, Mineko Ushiama, Sachiyo Mitani, Yoko Odaka, Yuka Nishina, Masumi Shimizu, Noriko Abe, Erika Arakawa, Tomoyo Oda, Akiko Sakamoto, Akane Sei
Introduction
The aim of the Department of Clinical Genomics is to contribute to improving genome medicine for cancer patients through the development and implementation of next-generation sequencing (NGS)-based genomic tests and the identification of novel pathogenic variants and biomarkers from NGS analyses of cancer patient genomes. We have been developing two types of NGS-based panel tests: the germline test for hereditary cancer syndromes and the somatic tests for therapy selection, diagnosis, and prognostic prediction. In addition, we are providing genomic analysis services as a part of the core facility functions of the Fundamental Innovative Oncology Core (FIOC) of the National Cancer Center Research Institute (NCCRI).
Research activities
1. Development of the germline NGS test for hereditary cancer syndromes
The development and evaluation of the NCC Oncopanel FC (Familial Cancer) test, an NGS-based multi-gene panel test for hereditary cancer syndromes, has been continued. Germline clinical testing using this system was performed on patients and their relatives visiting the Outpatient Genetic Counseling Clinic in the NCC Hospital (NCCH) or other collaborating hospitals. A total of 298 patients were analyzed in FY2021. Detected variants were deposited in the open-access variant-level database, MGeND (https://mgend.med.kyoto-u.ac.jp/).
2. Development of somatic NGS tests for therapy selection, diagnosis, and prognostic prediction
We have been continuously working on improving the NCC Oncopanel test, an NGS panel test that we developed and obtained PMDA approval for as a clinical test to detect actionable genetic alterations for therapy selection for cancer patients. Moreover, we have worked on developing NGS panel tests for pediatric and adolescent and young adult (AYA) cancer patients. For pediatric and AYA patients, genomic information is important not only for therapy selection but also for molecular diagnosis and risk stratification. However, the currently approved NGS panel tests do not cover genes necessary for molecular diagnosis and risk stratification of those patients, and additional panel tests are desired. Therefore, we are involved in the development of two NGS panel tests. One is the NCC Oncopanel Ped test, which is a modified version of the NCC Oncopanel test to enhance its capacity to detect gene mutations and amplifications for pediatric patients. For this panel test, a clinical study to explore its clinical feasibility and utility was started as a sub-study of the TOP-GEAR study from 2019. The other is the TOP2 (Todai OncoPanel 2) test, which is a relatively large panel test to detect mutations and amplifications of hundreds of genes and also to detect hundreds of fusion genes through the simultaneous use of an RNA panel. For this panel test, an additional sub-study of the TOP-GEAR was started in February 2021. In FY2021, several pediatric and AYA patients were analyzed using the NCC Oncopanel Ped test or the TOP2 test.
3. Core facility genomic analysis services
We have provided NGS and SNP array analysis services as a part of the core facility functions of the FIOC of the NCCRI. Upon requests from researchers not only in the NCCRI but also in the NCCH and the NCC Hospital East (NCCHE), whole exome sequencing of 41 samples, targeted sequencing of 185 samples, and RNA sequencing of 190 samples were performed in FY2021. As part of the research support, we have performed NGS-based sequencing runs using the NextSeq 500 and the Ion Proton on more than 2,000 cases.
Education
The Department of Clinical Genomics has accepted three graduate students as trainees.
Future prospects
As the clinical introduction of cancer genomic medicine progresses, we aim to develop more useful genomic tests. In the next fiscal year, under the leadership of the newly appointed chief, we will focus on dry analysis and the development of human resources to put it into practice.
List of papers published in 2021
Journal
1. Yoshida A, Arai Y, Satomi K, Kubo T, Ryo E, Matsushita Y, Hama N, Sudo K, Komiyama M, Yatabe Y, Shibata T, Ichikawa H, Ichimura K, Kawai A, Mori T. Identification of novel SSX1 fusions in synovial sarcoma. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc, 35:228-239, 2022
2. Murakami N, Kuno I, Yoshida H, Shiraishi K, Kato T, Igaki H. How should we appropriately classify low-risk uterine cervical cancer patients suitable for de-intensified treatment? Journal of radiation research, 63:312-313, 2022
3. Yagi Y, Abeto N, Shiraishi J, Miyata C, Inoue S, Murakami H, Nakashima M, Sugano K, Ushiama M, Yoshida T, Yamazawa K. A novel pathogenic variant of the FH gene in a family with hereditary leiomyomatosis and renal cell carcinoma. Human genome variation, 9:3, 2022
4. Miyazaki T, Chung S, Sakai H, Ohata H, Obata Y, Shiokawa D, Mizoguchi Y, Kubo T, Ichikawa H, Taniguchi H, Aoki K, Soga T, Nakagama H, Okamoto K. Stemness and immune evasion conferred by the TDO2-AHR pathway are associated with liver metastasis of colon cancer. Cancer science, 113:170-181, 2022
5. Zhang M, Kiyono T, Aoki K, Goshima N, Kobayashi S, Hiranuma K, Shiraishi K, Saya H, Nakahara T. Development of an in vitro carcinogenesis model of human papillomavirus-induced cervical adenocarcinoma. Cancer science, 113:904-915, 2022
6. Takayanagi D, Cho H, Machida E, Kawamura A, Takashima A, Wada S, Tsunoda T, Kohno T, Shiraishi K. Update on Epidemiology, Diagnosis, and Biomarkers in Gastroenteropancreatic Neuroendocrine Neoplasms. Cancers, 14:2022
7. Schmid S, Jiang M, Brown MC, Fares A, Garcia M, Soriano J, Dong M, Thomas S, Kohno T, Leal LF, Diao N, Xie J, Wang Z, Zaridze D, Holcatova I, Lissowska J, świątkowska B, Mates D, Savic M, Wenzlaff AS, Harris CC, Caporaso NE, Ma H, Fernandez-Tardon G, Barnett MJ, Goodman G, Davies MPA, Pérez-Ríos M, Taylor F, Duell EJ, Schoettker B, Brenner H, Andrew A, Cox A, Ruano-Ravina A, Field JK, Marchand LL, Wang Y, Chen C, Tardon A, Shete S, Schabath MB, Shen H, Landi MT, Ryan BM, Schwartz AG, Qi L, Sakoda LC, Brennan P, Yang P, Zhang J, Christiani DC, Reis RM, Shiraishi K, Hung RJ, Xu W, Liu G . Accounting for EGFR Mutations in Epidemiologic Analyses of Non-Small Cell Lung Cancers: Examples Based on the International Lung Cancer Consortium Data. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 31:679-687, 2022
8. Shirasawa M, Yoshida T, Shimoda Y, Takayanagi D, Shiraishi K, Kubo T, Mitani S, Matsumoto Y, Masuda K, Shinno Y, Okuma Y, Goto Y, Horinouchi H, Ichikawa H, Kohno T, Yamamoto N, Matsumoto S, Goto K, Watanabe SI, Ohe Y, Motoi N. Differential Immune-Related Microenvironment Determines Programmed Cell Death Protein-1/Programmed Death-Ligand 1 Blockade Efficacy in Patients With Advanced NSCLC. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer, 16:2078-2090, 2021
9. Yotsukura M, Asamura H, Motoi N, Kashima J, Yoshida Y, Nakagawa K, Shiraishi K, Kohno T, Yatabe Y, Watanabe SI. Long-Term Prognosis of Patients With Resected Adenocarcinoma In Situ and Minimally Invasive Adenocarcinoma of the Lung. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer, 16:1312-1320, 2021
10. Teishikata T, Shiraishi K, Shinno Y, Kobayashi Y, Kashima J, Ishiyama T, Yoshida T, Mori T, Yatabe Y. An Alert to Possible False Positives With a Commercial Assay for MET Exon 14 Skipping. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer, 16:2133-2138, 2021
11. Ishizu K, Hashimoto T, Naka T, Yatabe Y, Kojima M, Kuwata T, Nonaka S, Oda I, Esaki M, Kudo M, Gotohda N, Yoshida T, Yoshikawa T, Sekine S. APC mutations are common in adenomas but infrequent in adenocarcinomas of the non-ampullary duodenum. Journal of gastroenterology, 56:988-998, 2021
12. Okuma HS, Yonemori K, Kojima Y, Tanioka M, Sudo K, Noguchi E, Hijioka S, Wakakuwa K, Kato K, Hirakawa A, Kuchiba A, Kubo T, Ichikawa H, Yoshida A, Yatabe Y, Nakamura K, Mano H, Yamamoto N, Fujiwara Y. Clinical Utility of Circulating Tumor DNA in Advanced Rare Cancers. Frontiers in oncology, 11:732525, 2021
13. Yoshida H, Shiraishi K, Kato T. Molecular Pathology of Human Papilloma Virus-Negative Cervical Cancers. Cancers, 13:2021
14. Murakami N, Asami Y, Yoshida H, Takayanagi D, Hirose S, Kuno I, Takahashi K, Matsuda M, Shimada Y, Yamano S, Sunami K, Honda T, Nakahara T, Watanabe T, Okuma K, Kuroda T, Kohno T, Kato T, Shiraishi K, Itami J. Distribution of genetic alterations in high-risk early-stage cervical cancer patients treated with postoperative radiation therapy. Scientific reports, 11:10567, 2021
15. Kaneko S, Mitsuyama T, Shiraishi K, Ikawa N, Shozu K, Dozen A, Machino H, Asada K, Komatsu M, Kukita A, Sone K, Yoshida H, Motoi N, Hayami S, Yoneoka Y, Kato T, Kohno T, Natsume T, Keudell GV, Saloura V, Yamaue H, Hamamoto R. Genome-Wide Chromatin Analysis of FFPE Tissues Using a Dual-Arm Robot with Clinical Potential. Cancers, 13:2021
16. Nakagawa M, Kobayashi E, Yamada M, Watanabe T, Hirata M, Tanabe N, Ushiama M, Sakamoto H, Sato C, Mori T, Yoshida A, Yoshida T, Sugano K, Kawai A. Myxofibrosarcoma harboring an MLH1 pathogenic germline variant associated with Muir-Torre syndrome: a case report. Hereditary cancer in clinical practice, 19:34, 2021
17. Kohama I, Asano N, Matsuzaki J, Yamamoto Y, Yamamoto T, Takahashi RU, Kobayashi E, Takizawa S, Sakamoto H, Kato K, Fujimoto H, Chikuda H, Kawai A, Ochiya T. Comprehensive serum and tissue microRNA profiling in dedifferentiated liposarcoma. Oncology letters, 22:623, 2021
18. Kuno I, Takayanagi D, Asami Y, Murakami N, Matsuda M, Shimada Y, Hirose S, Kato MK, Komatsu M, Hamamoto R, Okuma K, Kohno T, Itami J, Yoshida H, Shiraishi K, Kato T. TP53 mutants and non-HPV16/18 genotypes are poor prognostic factors for concurrent chemoradiotherapy in locally advanced cervical cancer. Scientific reports, 11:19261, 2021
19. Yamaguchi K, Kasajima R, Takane K, Hatakeyama S, Shimizu E, Yamaguchi R, Katayama K, Arai M, Ishioka C, Iwama T, Kaneko S, Matsubara N, Moriya Y, Nomizu T, Sugano K, Tamura K, Tomita N, Yoshida T, Sugihara K, Nakamura Y, Miyano S, Imoto S, Furukawa Y, Ikenoue T. Application of targeted nanopore sequencing for the screening and determination of structural variants in patients with Lynch syndrome. Journal of human genetics, 66:1053-1060, 2021
20. Shimamoto Y, Ishiguro S, Takeuchi Y, Nakatsuka SI, Yunokizaki H, Ezoe Y, Nakajima T, Matsuno K, Nakahira H, Tanaka K, Ishihara R, Takayama T, Yoshida T, Ishikawa H. Gastric neoplasms in patients with familial adenomatous polyposis: endoscopic and clinicopathologic features. Gastrointestinal endoscopy, 94:1030-1042.e2, 2021
21. Nakano Y, Satomi K, Okada K, Gotoh M, Ushiama M, Sakamoto H, Yoshida T, Kunihiro N, Hira K, Fukushima H, Inoue T, Hirato J, Ichimura K, Hara J. Malignant brain tumor in an infant showing histopathological features of yolk sac tumor but genetic and epigenetic features of AT/RT. Pediatric blood & cancer, 68:e29192, 2021
22. Ueki A, Sugano K, Misu K, Aimono E, Nakamura K, Tanishima S, Tanaka N, Mikami S, Hirasawa A, Ando M, Yoshida T, Oya M, Nishihara H, Kosaki K. Germline Whole-Gene Deletion of FH Diagnosed from Tumor Profiling. International journal of molecular sciences, 22:2021
23. Hatanaka Y, Kuwata T, Morii E, Kanai Y, Ichikawa H, Kubo T, Hatanaka KC, Sakai K, Nishio K, Fujii S, Okamoto W, Yoshino T, Ochiai A, Oda Y. The Japanese Society of Pathology Practical Guidelines on the handling of pathological tissue samples for cancer genomic medicine. Pathology international, 71:725-740, 2021
24. Liu G, Brenner H, Chen C, Christiani D, Field JK, Hung R, Jie Z, Le Marchand L, Ryan B, Schabath MB, Schwartz AG, Shete S, Shiraishi K, Tardon A, Teare MD, Yang P, Zhang ZF, Xu W. A reply to “Lung cancer outcomes: Are BMI and race clinically relevant?”. Lung cancer (Amsterdam, Netherlands), 154:225-226, 2021
25. Shirasawa M, Yoshida T, Takayanagi D, Shiraishi K, Yagishita S, Sekine K, Kanda S, Matsumoto Y, Masuda K, Shinno Y, Okuma Y, Goto Y, Horinouchi H, Hamada A, Kohno T, Yamamoto N, Watanabe SI, Ohe Y, Motoi N. Activity and Immune Correlates of Programmed Death-1 Blockade Therapy in Patients With Advanced Large Cell Neuroendocrine Carcinoma. Clinical lung cancer, 22:282-291.e6, 2021
26. Yonemaru J, Hashimoto T, Takayanagi D, Naka T, Yatabe Y, Kanemitsu Y, Shiraishi K, Sekine S. NTRK fusion-positive colorectal cancer in Japanese population. Pathology international, 71:355-359, 2021
27. Abe S, Matsuzaki J, Sudo K, Oda I, Katai H, Kato K, Takizawa S, Sakamoto H, Takeshita F, Niida S, Saito Y, Ochiya T. A novel combination of serum microRNAs for the detection of early gastric cancer. Gastric cancer: official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 24:835-843, 2021