Annual Report 2017
Department of Clinical Genomics
hikawa, Hiromi Sakamoto, Masahiro Gotoh, Kazuhiko Aoyagi, Takashi Kubo, Misuzu Tsukamoto, Yoko Odaka, Mineko Ushiama, Sachiyo Mitani, Fumito Yamazaki, Masumi Shimizu, Noriko Abe, Sayaka Mito, Erika Arakawa, Tomoko Ikegami, Akiko Sakamoto
Introduction
The aim of the Department of Clinical Genomics is to contribute to realize genome medicine for cancer patients through the development and implementation of next-generation sequencing (NGS)-based genomic tests and the identification of novel biomarkers and therapeutic targets from NGS analyses of cancer tissues. We have been developing two types of NGS-based panel tests: the germline test for hereditary cancer syndromes and the somatic test for a personalized anticancer therapy selection. In addition, we are providing genomic analysis services as a part of core facility functions of the Fundamental Innovative Oncology Core Center (FIOC) of the National Cancer Center Research Institute (NCCRI).
Research activities
1. Development of the germline NGS panel test for hereditary cancer syndromes
We developed the NCC Oncopanel FC (Familial Cancer) test, an NGS panel test which can analyze 147 hereditary cancer syndrome-associated genes. This test shortened turn-around time substantially by simultaneous sequencing of target genes as compared to the previous capillary sequencing tests of each single gene one by one. Germline clinical testing using this system was performed for patients and their relatives visiting the Outpatient Genetic Counseling Clinic in the NCC-Hospital (NCCH) or other collaborating hospitals. Totally 480 patients were analyzed from January 2017 to March 2018. Detected variants were annotated for clinical significance by researchers of our department and physicians of the Department of Genetic Medicine and Services in the NCCH. At present, a number of variants remained as "variants of uncertain significance (VUS)". Data and knowledge accumulation would be crucial for the germline clinical sequencing.
2. Development of the somatic NGS panel test for a therapy selection
We had developed and continuously improved the NCC Oncopanel test, an NGS panel test which can detect mutations and amplifications of ~100 genes and fusions of ~10 genes from FFPE tumor tissue samples. In 2017, we supported the second stage of the TOP-GEAR study, in which the NCC Oncopanel test was used as a clinical test to detect actionable genetic alterations for cancer patients. We also prepared the data to show the clinical validity of this test. The NCC Oncopanel test will be implemented as an advanced medical service in the NCCH from April 2018. In addition, we started the development of a novel NGS panel test for pediatric cancers in collaboration with the Pediatric Cancer Panel Development Working Team, which consists of members recommended by the Japan Children's Cancer Group (JCCG), the Japanese Society of Pediatric Hematology/Oncology (JSPHO), the National Center for Child Health and Development (NCCHD), and the NCC. This panel test aimed molecular diagnosis and risk stratification as well as a therapy selection of pediatric cancers.
3. Identification of novel biomarkers and therapeutic targets
Through the use of NGS technologies, we are searching novel biomarkers and therapeutic targets for sarcoma, gastric cancer, and pediatric cancer. In 2017, we conducted comprehensive genomic profiling of dedifferentiated liposarcoma (DDLPS) in collaboration with the Japan Sarcoma Genome Consortium (JSGC), genomic characterization of adolescent and young adult (AYA) sarcoma, and investigation of predictive biomarker of Pazopanib therapy response in soft tissue sarcoma.
4. Core facility genomic analysis services
We provided NGS and microarray analysis services as a part of 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), targeted sequencing of more than 150 samples, RNA sequencing of more than 50 samples, and SNP array analysis of more than 3,000 samples were performed in 2017.
Education
The Department of Clinical Genomics accepted two undergraduate and one graduate students as trainees.
List of papers published in January 2017 - March 2018
Journal
1. Yoshida A, Kobayashi E, Kubo T, Kodaira M, Motoi T, Motoi N, Yonemori K, Ohe Y, Watanabe SI, Kawai A, Kohno T, Kishimoto H, Ichikawa H, Hiraoka N. Clinicopathological and molecular characterization of SMARCA4-deficient thoracic sarcomas with comparison to potentially related entities. Mod Pathol, 30:797-809, 2017
2. Asano N, Yoshida A, Ichikawa H, Mori T, Nakamura M, Kawai A, Hiraoka N. Immunohistochemistry for trimethylated H3K27 in the diagnosis of malignant peripheral nerve sheath tumours. Histopathology, 70:385-393, 2017
3. Hirabayashi S, Ohki K, Nakabayashi K, Ichikawa H, Momozawa Y, Okamura K, Yaguchi A, Terada K, Saito Y, Yoshimi A, Ogata-Kawata H, Sakamoto H, Kato M, Fujimura J, Hino M, Kinoshita A, Kakuda H, Kurosawa H, Kato K, Kajiwara R, Moriwaki K, Morimoto T, Nakamura K, Noguchi Y, Osumi T, Sakashita K, Takita J, Yuza Y, Matsuda K, Yoshida T, Matsumoto K, Hata K, Kubo M, Matsubara Y, Fukushima T, Koh K, Manabe A, Ohara A, Kiyokawa N. ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype. Haematologica, 102:118-129, 2017
4. Nagasawa T, Azuma M, Aki M, Yamada M, Ushiama M, Tanabe N, Nakajima T, Sugano K, Sakamoto H, Yoshida T. System Development Aiming Efficient Recording of Pedigree Information and Database Construction for Genetic Counseling Clinic. Studies in health technology and informatics, 245:1278, 2017
5. Hayashi H, Kohno T, Ueno H, Hiraoka N, Kondo S, Saito M, Shimada Y, Ichikawa H, Kato M, Shibata T, Morizane C, Sakamoto Y, Shimada K, Komatsu Y, Sakamoto N, Okusaka T. Utility of Assessing the Number of Mutated KRAS, CDKN2A, TP53, and SMAD4 Genes Using a Targeted Deep Sequencing Assay as a Prognostic Biomarker for Pancreatic Cancer. Pancreas, 46:335-340, 2017
6. Nishimura T, Tamaoki M, Komatsuzaki R, Oue N, Taniguchi H, Komatsu M, Aoyagi K, Minashi K, Chiwaki F, Shinohara H, Tachimori Y, Yasui W, Muto M, Yoshida T, Sakai Y, Sasaki H. SIX1 maintains tumor basal cells via transforming growth factor-beta pathway and associates with poor prognosis in esophageal cancer. Cancer Sci, 108:216-225, 2017
7. Tamai M, Furuichi Y, Kasai S, Ando N, Harama D, Goi K, Inukai T, Kagami K, Abe M, Ichikawa H, Sugita K. TGFbeta1 synergizes with FLT3 ligand to induce chemoresistant quiescence in acute lymphoblastic leukemia with MLL gene rearrangements. Leuk Res, 61:68-76, 2017
8. Asano N, Yoshida A, Mitani S, Kobayashi E, Shiotani B, Komiyama M, Fujimoto H, Chuman H, Morioka H, Matsumoto M, Nakamura M, Kubo T, Kato M, Kohno T, Kawai A, Kondo T, Ichikawa H. Frequent amplification of receptor tyrosine kinase genes in well-differentiated/dedifferentiated liposarcoma. Oncotarget, 8:12941-12952, 2017
9. Nakaoku T, Kohno T, Araki M, Niho S, Chauhan R, Knowles PP, Tsuchihara K, Matsumoto S, Shimada Y, Mimaki S, Ishii G, Ichikawa H, Nagatoishi S, Tsumoto K, Okuno Y, Yoh K, McDonald NQ, Goto K. A secondary RET mutation in the activation loop conferring resistance to vandetanib. Nat Commun, 9:625, 2018
10. Ono H, Sakamoto H, Yoshida T, Saeki N. Prostate stem cell antigen is expressed in normal and malignant human brain tissues. Oncol Lett, 15:3081-3084, 2018