Annual Report 2019

Department of Clinical Genomics

Hitoshi Ichikawa, Masahiro Gotoh, Kazuhiko Aoyagi, Hiromi Sakamoto, Teruhiko Yoshida, Takashi Kubo, Yoko Odaka, Mineko Ushiama, Sachiyo Mitani, Masumi Shimizu, Noriko Abe, Erika Arakawa, Akiko Sakamoto, Yuka Nishina, Tomoyo Oda

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 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 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 times 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. A total of 336 patients were analyzed from April 2019 to March 2020. Detected variants from 107 patients and their relatives were annotated for clinical significance at the Expert Panel for Familial Cancers, which is composed of the researchers of our department and physicians and genetic counselors of the Department of Genetic Medicine and Services in the NCCH. At present, a number of variants remain 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 tests for therapy selection, diagnosis, and prognostic prediction

 We developed the NCC Oncopanel test, an NGS panel test which can detect mutations and amplifications of 114 genes and fusions of 12 genes from FFPE tumor tissue samples. Since June 2019, this test has been reimbursed under the Nation’s insurance system as a clinical test to detect actionable genetic alterations for therapy selection of cancer patients. In addition, we also developed a novel NGS panel test for pediatric cancers, NCC Oncopanel Ped. This test aims for molecular diagnosis and risk stratification in addition to therapy selection of pediatric cancers, and can detect mutations and amplifications of 211 genes and fusions of nine genes. We started a clinical study to examine its clinical feasibility and utility as a sub-study of the TOP-GEAR study from October 2019.

3. Identification of novel biomarkers and therapeutic targets

 Through the NGS analysis of cancer genomes, we are searching novel biomarkers and therapeutic targets for sarcoma and pediatric cancer. As one of such projects, we conducted comprehensive genomic profiling of dedifferentiated liposarcoma (DDLPS) in collaboration with the Japan Sarcoma Genome Consortium (JSGC). DDLPS is a major subtype among the various subtypes of sarcoma, and is defined as a high-grade non-lipogenic sarcoma with a juxtaposed, well-differentiated lipogenic area. Whole-exome and RNA sequencing data from 115 DDLPS tumors including 37 NCCH cases were analyzed. Several somatic copy-number alterations, including the gain of 12q15, were identified as frequent genomic alterations. CTDSP1/2-DNM3OS fusion genes were also identified in a subset of DDLPS tumors. The comparative analysis between well-differentiated and dedifferentiated components in eight cases identified two categories of genomic alterations: shared alterations, associated with tumorigenesis, and dedifferentiated-specific alterations, associated with malignant transformation. These analyses revealed the mechanisms underlying the development and progression of DDLPS.

4. Core facility genomic analysis services

 We provided NGS and SNP array 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), whole-exome sequencing of 231 samples, targeted sequencing of 350 samples, RNA sequencing of 53 samples, and SNP array analysis of 302 samples were performed from April 2019 to March 2020.

Education

 The Department of Clinical Genomics accepted an undergraduate student as a trainee.

List of papers published in 2019

Journal

1. Wong JYY, Zhang H, Hsiung CA, Shiraishi K, Yu K, Matsuo K, Wong MP, Hong YC, Wang J, Seow WJ, Wang Z, Song M, Kim HN, Chang IS, Chatterjee N, Hu W, Wu C, Mitsudomi T, Zheng W, Kim JH, Seow A, Caporaso NE, Shin MH, Chung LP, An SJ, Wang P, Yang Y, Zheng H, Yatabe Y, Zhang XC, Kim YT, Cai Q, Yin Z, Kim YC, Bassig BA, Chang J, Ho JCM, Ji BT, Daigo Y, Ito H, Momozawa Y, Ashikawa K, Kamatani Y, Honda T, Hosgood HD, Sakamoto H, Kunitoh H, Tsuta K, Watanabe SI, Kubo M, Miyagi Y, Nakayama H, Matsumoto S, Tsuboi M, Goto K, Shi J, Song L, Hua X, Takahashi A, Goto A, Minamiya Y, Shimizu K, Tanaka K, Wei F, Matsuda F, Su J, Kim YH, Oh IJ, Song F, Su WC, Chen YM, Chang GC, Chen KY, Huang MS, Chien LH, Xiang YB, Park JY, Kweon SS, Chen CJ, Lee KM, Blechter B, Li H, Gao YT, Qian B, Lu D, Liu J, Jeon HS, Hsiao CF, Sung JS, Tsai YH, Jung YJ, Guo H, Hu Z, Wang WC, Chung CC, Burdett L, Yeager M, Hutchinson A, Berndt SI, Wu W, Pang H, Li Y, Choi JE, Park KH, Sung SW, Liu L, Kang CH, Zhu M, Chen CH, Yang TY, Xu J, Guan P, Tan W, Wang CL, Hsin M, Sit KY, Ho J, Chen Y, Choi YY, Hung JY, Kim JS, Yoon HI, Lin CC, Park IK, Xu P, Wang Y, He Q, Perng RP, Chen CY, Vermeulen R, Wu J, Lim WY, Chen KC, Li YJ, Li J, Chen H, Yu CJ, Jin L, Chen TY, Jiang SS, Liu J, Yamaji T, Hicks B, Wyatt K, Li SA, Dai J, Ma H, Jin G, Song B, Wang Z, Cheng S, Li X, Ren Y, Cui P, Iwasaki M, Shimazu T, Tsugane S, Zhu J, Chen Y, Yang K, Jiang G, Fei K, Wu G, Lin HC, Chen HL, Fang YH, Tsai FY, Hsieh WS, Yu J, Stevens VL, Laird-Offringa IA, Marconett CN, Rieswijk L, Chao A, Yang PC, Shu XO, Wu T, Wu YL, Lin D, Chen K, Zhou B, Huang YC, Kohno T, Shen H, Chanock SJ, Rothman N, Lan Q. Tuberculosis infection and lung adenocarcinoma: Mendelian randomization and pathway analysis of genome-wide association study data from never-smoking Asian women. Genomics, 112:1223-1232, 2020

2. Yamamoto Y, Kondo S, Matsuzaki J, Esaki M, Okusaka T, Shimada K, Murakami Y, Enomoto M, Tamori A, Kato K, Aoki Y, Takizawa S, Sakamoto H, Niida S, Takeshita F, Ochiya T. Highly Sensitive Circulating MicroRNA Panel for Accurate Detection of Hepatocellular Carcinoma in Patients With Liver Disease. Hepatol Commun, 4:284-297, 2020

3. Ito M, Fujiwara Y, Kubo T, Matsushita H, Kumamoto T, Suzuki T, Sunami K, Yamamoto N, Kohno T. Clonal Hematopoiesis From Next Generation Sequencing of Plasma From a Patient With Lung Adenocarcinoma: A Case Report. Front Oncol, 10:113, 2020

4. Ohno M, Matsuzaki J, Kawauchi J, Aoki Y, Miura J, Takizawa S, Kato K, Sakamoto H, Matsushita Y, Takahashi M, Miyakita Y, Ichimura K, Narita Y, Ochiya T. Assessment of the Diagnostic Utility of Serum MicroRNA Classification in Patients With Diffuse Glioma. JAMA Netw Open, 2:e1916953, 2019

5. Sunami K, Ichikawa H, Kubo T, Kato M, Fujiwara Y, Shimomura A, Koyama T, Kakishima H, Kitami M, Matsushita H, Furukawa E, Narushima D, Nagai M, Taniguchi H, Motoi N, Sekine S, Maeshima A, Mori T, Watanabe R, Yoshida M, Yoshida A, Yoshida H, Satomi K, Sukeda A, Hashimoto T, Shimizu T, Iwasa S, Yonemori K, Kato K, Morizane C, Ogawa C, Tanabe N, Sugano K, Hiraoka N, Tamura K, Yoshida T, Fujiwara Y, Ochiai A, Yamamoto N, Kohno T. Feasibility and utility of a panel testing for 114 cancer-associated genes in a clinical setting: A hospital-based study. Cancer Sci, 110:1480-1490, 2019

6. Sekine S, Kiyono T, Ryo E, Ogawa R, Wakai S, Ichikawa H, Suzuki K, Arai S, Tsuta K, Ishida M, Sasajima Y, Goshima N, Yamazaki N, Mori T. Recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poroma and porocarcinoma. J Clin Invest, 129:3827-3832, 2019

7. Hirata M, Asano N, Katayama K, Yoshida A, Tsuda Y, Sekimizu M, Mitani S, Kobayashi E, Komiyama M, Fujimoto H, Goto T, Iwamoto Y, Naka N, Iwata S, Nishida Y, Hiruma T, Hiraga H, Kawano H, Motoi T, Oda Y, Matsubara D, Fujita M, Shibata T, Nakagawa H, Nakayama R, Kondo T, Imoto S, Miyano S, Kawai A, Yamaguchi R, Ichikawa H, Matsuda K. Integrated exome and RNA sequencing of dedifferentiated liposarcoma. Nat Commun, 10:5683, 2019

8. Asano N, Takeshima H, Yamashita S, Takamatsu H, Hattori N, Kubo T, Yoshida A, Kobayashi E, Nakayama R, Matsumoto M, Nakamura M, Ichikawa H, Kawai A, Kondo T, Ushijima T. Epigenetic reprogramming underlies efficacy of DNA demethylation therapy in osteosarcomas. Sci Rep, 9:20360, 2019

9. Satomi-Tsushita N, Shimomura A, Matsuzaki J, Yamamoto Y, Kawauchi J, Takizawa S, Aoki Y, Sakamoto H, Kato K, Shimizu C, Ochiya T, Tamura K. Serum microRNA-based prediction of responsiveness to eribulin in metastatic breast cancer. PLoS One, 14:e0222024, 2019

10. Sato J, Shimomura A, Kawauchi J, Matsuzaki J, Yamamoto Y, Takizawa S, Sakamoto H, Ohno M, Narita Y, Ochiya T, Tamura K. Brain metastasis-related microRNAs in patients with advanced breast cancer. PLoS One, 14:e0221538, 2019

11. Sudo K, Kato K, Matsuzaki J, Boku N, Abe S, Saito Y, Daiko H, Takizawa S, Aoki Y, Sakamoto H, Niida S, Takeshita F, Fukuda T, Ochiya T. Development and Validation of an Esophageal Squamous Cell Carcinoma Detection Model by Large-Scale MicroRNA Profiling. JAMA Netw Open, 2:e194573, 2019

12. Yamazaki F, Nakatani F, Asano N, Wakai S, Sekimizu M, Mitani S, Kubo T, Kawai A, Ichikawa H, Yoshida A. Novel NTRK3 Fusions in Fibrosarcomas of Adults. Am J Surg Pathol, 43:523-530, 2019

13. Sone M, Arai Y, Sugawara S, Kubo T, Itou C, Hasegawa T, Umakoshi N, Yamamoto N, Sunami K, Hiraoka N, Kubo T. Feasibility of genomic profiling with next-generation sequencing using specimens obtained by image-guided percutaneous needle biopsy. Ups J Med Sci, 124:119-124, 2019

14. Sekimizu M, Yoshida A, Mitani S, Asano N, Hirata M, Kubo T, Yamazaki F, Sakamoto H, Kato M, Makise N, Mori T, Yamazaki N, Sekine S, Oda I, Watanabe SI, Hiraga H, Yonemoto T, Kawamoto T, Naka N, Funauchi Y, Nishida Y, Honoki K, Kawano H, Tsuchiya H, Kunisada T, Matsuda K, Inagaki K, Kawai A, Ichikawa H. Frequent mutations of genes encoding vacuolar H+ -ATPase components in granular cell tumors. Genes Chromosomes Cancer, 58:373-380, 2019

15. Makise N, Sekimizu M, Kobayashi E, Yoshida H, Fukayama M, Kato T, Kawai A, Ichikawa H, Yoshida A. Low-grade endometrial stromal sarcoma with a novel MEAF6-SUZ12 fusion. Virchows Arch, 475:527-531, 2019

16. Nakano MH, Udagawa C, Shimo A, Kojima Y, Yoshie R, Zaha H, Abe N, Motonari T, Unesoko M, Tamura K, Shimoi T, Yoshida M, Yoshida T, Sakamoto H, Kato K, Mushiroda T, Tsugawa K, Zembutsu H. A Genome-Wide Association Study Identifies Five Novel Genetic Markers for Trastuzumab-Induced Cardiotoxicity in Japanese Population. Biol Pharm Bull, 42:2045-2053, 2019