Annual Report 2022
Department of Clinical Genomics
Kouya Shiraishi, Masahiro Gotoh, Kazuhiko Aoyagi, Hitoshi Ichikawa, Masaru Katoh, Kayoko Tao, Hiromi Sakamoto, Teruhiko Yoshida, Takashi Kubo, Mineko Ushiama, Sachiyo Mitani, Masumi Shimizu, Erika Arakawa
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).
The Team and What We Do
The purpose of the team is to provide genomic analysis support at the request of clinicians and researchers.
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 160 patients were analyzed in FY2022. 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 as a clinical test to detect actionable genetic alterations for therapy selection of cancer patients. Moreover, we have made efforts to develop 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 FY2022, 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/genome sequencing of 1,589 samples, RNA sequencing of 1,960 samples were performed in FY2022. As part of the research support, we have performed NGS-based sequencing runs using the NextSeq 500 and the Ion Proton on more than 1,000 cases.
Education
The Department of Clinical Genomics has accepted two graduate students as trainees.
Future Prospects
As the clinical introduction of cancer genomic medicine progresses, we aim to develop more useful genomic tests. We will provide support for genome analysis in response to requests from both clinicians and researchers. Furthermore, we will focus on dry analysis and the development of human resources to implement it.
List of papers published in 2022
Journal
1. Fukushi G, Yamada M, Kakugawa Y, Gotoh M, Tanabe N, Ushiama M, Watanabe T, Yamazaki T, Matsumoto M, Hirata M, Nakajima T, Sugano K, Yoshida T, Matsuda T, Igarashi Y, Saito Y. Genotype-phenotype correlation of small-intestinal polyps on small-bowel capsule endoscopy in familial adenomatous polyposis. Gastrointestinal endoscopy, 97:59-68.e7, 2023
2. Kao YC, Yoshida A, Hsieh TH, Nord KH, Saba KH, Ichikawa H, Tsai JW, Huang HY, Chih-Hsueh Chen P, Fletcher CDM, Lee JC. Identification of COL1A1/2 Mutations and Fusions With Noncoding RNA Genes in Bizarre Parosteal Osteochondromatous Proliferation (Nora Lesion). Modern pathology, 36:100011, 2023
3. Shimomura A, Yoshida M, Kubo T, Yamashita S, Noguchi E, Nagayama A, Hanamura T, Okazaki M, Mukohara T, Tsuruga A, Tanaka K, Kawamura Y, Higuchi T, Takahashi Y, Kurozumi S, Hayashida T, Ichikawa H, Ushijima T, Suto A. Clinicopathological features, genetic alterations, and BRCA1 promoter methylation in Japanese male patients with breast cancer. Breast cancer research and treatment, 197:593-602, 2023
4. Satomi K, Ohno M, Kubo T, Honda-Kitahara M, Matsushita Y, Ichimura K, Narita Y, Ichikawa H, Yoshida A. Central nervous system sarcoma with ATXN1::DUX4 fusion expands the concept of CIC-rearranged sarcoma. Genes, chromosomes & cancer, 61:683-688, 2022
5. Takemura C, Kashima J, Hashimoto T, Ichikawa H, Honma Y, Goto Y, Watanabe SI, Yatabe Y. A mimic of lung adenocarcinoma: a case report of histological conversion of metastatic thyroid papillary carcinoma. Histopathology, 80:1004-1007, 2022
6. Kojima N, Arai Y, Satomi K, Kubo T, Matsushita Y, Mori T, Matsushita H, Ushijima T, Yatabe Y, Shibata T, Yonemori K, Ichimura K, Ichikawa H, Kawai A, Yoshida A. Co-expression of ERG and CD31 in a subset of CIC-rearranged sarcoma: a potential diagnostic pitfall. Modern pathology, 35:1439-1448, 2022
7. Komatsu M, Ichikawa H, Chiwaki F, Sakamoto H, Komatsuzaki R, Asaumi M, Tsunoyama K, Fukagawa T, Matsushita H, Boku N, Matsusaki K, Takeshita F, Yoshida T, Sasaki H. ARHGAP-RhoA signaling provokes homotypic adhesion-triggered cell death of metastasized diffuse-type gastric cancer. Oncogene, 41:4779-4794, 2022
8. Tsuda N, Tian Y, Fujimoto M, Kuramoto J, Makiuchi S, Ojima H, Gotoh M, Hiraoka N, Yoshida T, Kanai Y, Arai E. DNA methylation status of the SPHK1 and LTB genes underlies the clinicopathological diversity of non-alcoholic steatohepatitis-related hepatocellular carcinomas. Journal of cancer research and clinical oncology, 149:5109-5125, 2023
9. Nakagawa M, Sekimizu M, Endo M, Kobayashi E, Iwata S, Fukushima S, Yoshida A, Kitabayashi I, Ichikawa H, Kawai A, Nakatani F. Prognostic impact of IDH mutations in chondrosarcoma. Journal of orthopaedic science, 27:1315-1322, 2022
10. Yanagihara K, Iino Y, Yokozaki H, Kubo T, Oda T, Kubo T, Komatsu M, Sasaki H, Ichikawa H, Kuwata T, Seyama T, Ochiai A. A Comparative Study of Patient-Derived Tumor Models of Pancreatic Ductal Adenocarcinoma Involving Orthotopic Implantation. Pathobiology, 89:222-232, 2022
11. Katoh M, Katoh M. WNT signaling and cancer stemness. Essays in biochemistry, 66:319-331, 2022