Annual Report 2020

Department of Clinical Genomics

Hitoshi Ichikawa, Kouya Shiraishi, Masahiro Gotoh, Kazuhiko Aoyagi, Yoshinori Ikarashi, 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

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 312 patients were analyzed in FY2020. Detected variants from 110 patients and relatives were annotated for clinical significance at the Expert Panel for Familial Cancers, which is composed of researchers of our department, physicians and genetic counselors of the Department of Genetic Medicine and Services in the NCCH, and 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 by the simultaneous use of an RNA panel. For this panel test, an additional sub-study of the TOP-GEAR was started from February 2021. In FY2020, 23 pediatric patients were analyzed using the NCC Oncopanel Ped test, and 18 pediatric and AYA patients were analyzed using the TOP2 test.

3.  Identification of novel pathogenic variants and biomarkers

 Through the NGS analysis of cancer patient genomes, we are exploring novel pathogenic variants and biomarkers for hereditary cancer syndromes and sarcomas. In FY2020, germline whole-genome sequencing was conducted on approximately 3,000 individuals with hereditary cancer syndromes or cancers at the AYA generation as a multi-institutional collaborative research project. The department played critical roles in sample preparation, data analyses, and annotation and curation of the detected variants. Furthermore, we have continued the genome analysis of many types of sarcomas. In FY2020, the clonal evolution of dedifferentiated liposarcoma (DDLPS) was analyzed by genome and transcriptome analyses of samples obtained from multi-positions of three DDLPS tumor tissues.

4.  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 131 samples, targeted sequencing of 611 samples, RNA sequencing of 46 samples, and SNP array analysis of 330 samples were performed in FY2020.

Education

 The Department of Clinical Genomics has accepted three graduate students as trainees.

List of papers published in 2020

Journal

1. Kohsaka S, Hirata M, Ikegami M, Ueno T, Kojima S, Sakai T, Ito K, Naka N, Ogura K, Kawai A, Iwata S, Okuma T, Yonemoto T, Kobayashi H, Suehara Y, Hiraga H, Kawamoto T, Motoi T, Oda Y, Matsubara D, Matsuda K, Nishida Y, Mano H. Comprehensive molecular and clinicopathological profiling of desmoid tumours. Eur J Cancer, 145:109-120, 2021

2. Arakawa A, Ichikawa H, Kubo T, Motoi N, Kumamoto T, Nakajima M, Yonemori K, Noguchi E, Sunami K, Shiraishi K, Kakishima H, Yoshida H, Hishiki T, Kawakubo N, Kuroda T, Kiyokawa T, Yamada K, Yanaihara N, Takahashi K, Okamoto A, Hirabayashi S, Hasegawa D, Manabe A, Ono K, Matsuoka M, Arai Y, Togashi Y, Shibata T, Nishikawa H, Aoki K, Yamamoto N, Kohno T, Ogawa C. Vaginal Transmission of Cancer from Mothers with Cervical Cancer to Infants. N Engl J Med, 384:42-50, 2021

3. Kase K, Saito M, Nakajima S, Takayanagi D, Saito K, Yamada L, Ashizawa M, Nakano H, Hanayama H, Onozawa H, Okayama H, Endo H, Fujita S, Sakamoto W, Saze Z, Momma T, Mimura K, Ohki S, Shiraishi K, Kohno T, Kono K. ARID1A deficiency in EBV-positive gastric cancer is partially regulated by EBV-encoded miRNAs, but not by DNA promotor hypermethylation. Carcinogenesis, 42:21-30, 2021

4. Jiang M, Fares AF, Shepshelovich D, Yang P, Christiani D, Zhang J, Shiraishi K, Ryan BM, Chen C, Schwartz AG, Tardon A, Shete S, Schabath MB, Teare MD, Le Marchand L, Zhang ZF, Field JK, Brenner H, Diao N, Xie J, Kohno T, Harris CC, Wenzlaff AS, Fernandez-Tardon G, Ye Y, Taylor F, Wilkens LR, Davies M, Liu Y, Barnett MJ, Goodman GE, Morgenstern H, Holleczek B, Thomas S, Brown MC, Hung RJ, Xu W, Liu G. The relationship between body-mass index and overall survival in non-small cell lung cancer by sex, smoking status, and race: A pooled analysis of 20,937 International lung Cancer consortium (ILCCO) patients. Lung Cancer, 152:58-65, 2021

5. Takayanagi D, Hirose S, Kuno I, Asami Y, Murakami N, Matsuda M, Shimada Y, Sunami K, Komatsu M, Hamamoto R, Kato MK, Matsumoto K, Kohno T, Kato T, Shiraishi K, Yoshida H. Comparative Analysis of Genetic Alterations, HPV-Status, and PD-L1 Expression in Neuroendocrine Carcinomas of the Cervix. Cancers (Basel), 13:2021

6. 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. Clin Lung Cancer, 2021

7. Naruse M, Ochiai M, Sekine S, Taniguchi H, Yoshida T, Ichikawa H, Sakamoto H, Kubo T, Matsumoto K, Ochiai A, Imai T. Re-expression of REG family and DUOXs genes in CRC organoids by co-culturing with CAFs. Sci Rep, 11:2077, 2021

8. 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, 24:835-843, 2021

9. Cho H, Yamada M, Sekine S, Tanabe N, Ushiama M, Hirata M, Ogawa G, Gotoh M, Yoshida T, Yoshikawa T, Saito Y, Kuchiba A, Oda I, Sugano K. Gastric cancer is highly prevalent in Lynch syndrome patients with atrophic gastritis. Gastric Cancer, 24:283-291, 2021

10. Endo Y, Fujimoto M, Ito N, Takahashi Y, Kitago M, Gotoh M, Hiraoka N, Yoshida T, Kitagawa Y, Kanai Y, Arai E. Clinicopathological impacts of DNA methylation alterations on pancreatic ductal adenocarcinoma: prediction of early recurrence based on genome-wide DNA methylation profiling. J Cancer Res Clin Oncol, 147:1341-1354, 2021

11. 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, 154:225-226, 2021

12. Ohmomo H, Komaki S, Ono K, Sutoh Y, Hachiya T, Arai E, Fujimoto H, Yoshida T, Kanai Y, Sasaki M, Shimizu A. Evaluation of clinical formalin-fixed paraffin-embedded tissue quality for targeted-bisulfite sequencing. Pathol Int, 71:135-140, 2021

13. Yonemaru J, Hashimoto T, Takayanagi D, Naka T, Yatabe Y, Kanemitsu Y, Shiraishi K, Sekine S. NTRK fusion-positive colorectal cancer in Japanese population. Pathol Int, 71:355-359, 2021

14. Yokomichi H, Nagai A, Hirata M, Mochizuki M, Kojima R, Yamagata Z. Cause-specific mortality rates in patients with diabetes according to comorbid macro- and microvascular complications: BioBank Japan Cohort. Endocrinol Diabetes Metab, 4:e00181, 2021

15. Yoshihama T, Hirasawa A, Sugano K, Yoshida T, Ushiama M, Ueki A, Akahane T, Nanki Y, Sakai K, Makabe T, Yamagami W, Susumu N, Kameyama K, Kosaki K, Aoki D. Germline multigene panel testing revealed a BRCA2 pathogenic variant in a patient with suspected Lynch syndrome. Int Cancer Conf J, 10:6-10, 2021

16. Watanabe T, Honda T, Totsuka H, Yoshida M, Tanioka M, Shiraishi K, Shimada Y, Arai E, Ushiama M, Tamura K, Yoshida T, Kanai Y, Kohno T. Simple prediction model for homologous recombination deficiency in breast cancers in adolescents and young adults. Breast Cancer Res Treat, 182:491-502, 2020

17. Ishigaki K, Akiyama M, Kanai M, Takahashi A, Kawakami E, Sugishita H, Sakaue S, Matoba N, Low SK, Okada Y, Terao C, Amariuta T, Gazal S, Kochi Y, Horikoshi M, Suzuki K, Ito K, Koyama S, Ozaki K, Niida S, Sakata Y, Sakata Y, Kohno T, Shiraishi K, Momozawa Y, Hirata M, Matsuda K, Ikeda M, Iwata N, Ikegawa S, Kou I, Tanaka T, Nakagawa H, Suzuki A, Hirota T, Tamari M, Chayama K, Miki D, Mori M, Nagayama S, Daigo Y, Miki Y, Katagiri T, Ogawa O, Obara W, Ito H, Yoshida T, Imoto I, Takahashi T, Tanikawa C, Suzuki T, Sinozaki N, Minami S, Yamaguchi H, Asai S, Takahashi Y, Yamaji K, Takahashi K, Fujioka T, Takata R, Yanai H, Masumoto A, Koretsune Y, Kutsumi H, Higashiyama M, Murayama S, Minegishi N, Suzuki K, Tanno K, Shimizu A, Yamaji T, Iwasaki M, Sawada N, Uemura H, Tanaka K, Naito M, Sasaki M, Wakai K, Tsugane S, Yamamoto M, Yamamoto K, Murakami Y, Nakamura Y, Raychaudhuri S, Inazawa J, Yamauchi T, Kadowaki T, Kubo M, Kamatani Y. Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases. Nat Genet, 52:669-679, 2020

18. Brhane Y, Yang P, Christiani DC, Liu G, McLaughlin JR, Brennan P, Shete S, Field JK, Tardón A, Kohno T, Shiraishi K, Matsuo K, Bossé Y, Amos CI, Hung RJ. Genetic Determinants of Lung Cancer Prognosis in Never Smokers: A Pooled Analysis in the International Lung Cancer Consortium. Cancer Epidemiol Biomarkers Prev, 29:1983-1992, 2020

19. Tsumura R, Koga Y, Hamada A, Kuwata T, Sasaki H, Doi T, Aikawa K, Ohashi A, Katano I, Ikarashi Y, Ito M, Ochiai A. Report of the use of patient-derived xenograft models in the development of anticancer drugs in Japan. Cancer Sci, 111:3386-3394, 2020

20. Fujita M, Liu X, Iwasaki Y, Terao C, Mizukami K, Kawakami E, Takata S, Inai C, Aoi T, Mizukoshi M, Maejima K, Hirata M, Murakami Y, Kamatani Y, Kubo M, Akagi K, Matsuda K, Nakagawa H, Momozawa Y. Population-based Screening for Hereditary Colorectal Cancer Variants in Japan. Clin Gastroenterol Hepatol, 2020

21. Hirose S, Murakami N, Takahashi K, Kuno I, Takayanagi D, Asami Y, Matsuda M, Shimada Y, Yamano S, Sunami K, Yoshida K, Honda T, Nakahara T, Watanabe T, Komatsu M, Hamamoto R, Kato MK, Matsumoto K, Okuma K, Kuroda T, Okamoto A, Itami J, Kohno T, Kato T, Shiraishi K, Yoshida H. Genomic alterations in STK11 can predict clinical outcomes in cervical cancer patients. Gynecol Oncol, 156:203-210, 2020

22. Lin Y, Nakatochi M, Hosono Y, Ito H, Kamatani Y, Inoko A, Sakamoto H, Kinoshita F, Kobayashi Y, Ishii H, Ozaka M, Sasaki T, Matsuyama M, Sasahira N, Morimoto M, Kobayashi S, Fukushima T, Ueno M, Ohkawa S, Egawa N, Kuruma S, Mori M, Nakao H, Adachi Y, Okuda M, Osaki T, Kamiya S, Wang C, Hara K, Shimizu Y, Miyamoto T, Hayashi Y, Ebi H, Kohmoto T, Imoto I, Kasugai Y, Murakami Y, Akiyama M, Ishigaki K, Matsuda K, Hirata M, Shimada K, Okusaka T, Kawaguchi T, Takahashi M, Watanabe Y, Kuriki K, Kadota A, Okada R, Mikami H, Takezaki T, Suzuki S, Yamaji T, Iwasaki M, Sawada N, Goto A, Kinoshita K, Fuse N, Katsuoka F, Shimizu A, Nishizuka SS, Tanno K, Suzuki K, Okada Y, Horikoshi M, Yamauchi T, Kadowaki T, Yu H, Zhong J, Amundadottir LT, Doki Y, Ishii H, Eguchi H, Bogumil D, Haiman CA, Le Marchand L, Mori M, Risch H, Setiawan VW, Tsugane S, Wakai K, Yoshida T, Matsuda F, Kubo M, Kikuchi S, Matsuo K. Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer. Nat Commun, 11:3175, 2020

23. Mizukami K, Iwasaki Y, Kawakami E, Hirata M, Kamatani Y, Matsuda K, Endo M, Sugano K, Yoshida T, Murakami Y, Nakagawa H, Spurdle AB, Momozawa Y. Genetic characterization of pancreatic cancer patients and prediction of carrier status of germline pathogenic variants in cancer-predisposing genes. EBioMedicine, 60:103033, 2020

24. Onozawa H, Saito H, Sunami K, Kubo T, Yamamoto N, Kasajima R, Ohtsu T, Hiroshima Y, Kanamori H, Yokose T, Miyagi Y. Lung adenocarcinoma in a patient with a cis EGFR L858R-K860I doublet mutation identified using NGS-based profiling test: Negative diagnosis on initial companion test and successful treatment with osimertinib. Thorac Cancer, 11:3599-3604, 2020

25. Sakaue S, Kanai M, Karjalainen J, Akiyama M, Kurki M, Matoba N, Takahashi A, Hirata M, Kubo M, Matsuda K, Murakami Y, Daly MJ, Kamatani Y, Okada Y. Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan. Nat Med, 26:542-548, 2020

26. Tian Y, Arai E, Makiuchi S, Tsuda N, Kuramoto J, Ohara K, Takahashi Y, Ito N, Ojima H, Hiraoka N, Gotoh M, Yoshida T, Kanai Y. Aberrant DNA methylation results in altered gene expression in non-alcoholic steatohepatitis-related hepatocellular carcinomas. J Cancer Res Clin Oncol, 146:2461-2477, 2020

27. Watanabe S, Shimomura A, Kubo T, Sekimizu M, Seo T, Watanabe SI, Kawai A, Yamamoto N, Tamura K, Kohno T, Ichikawa H, Yoshida A. BRAF V600E mutation is a potential therapeutic target for a small subset of synovial sarcoma. Mod Pathol, 33:1660-1668, 2020

28. 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

29. Yokomichi H, Mochizuki M, Hirata M, Nagai A, Kojima R, Horiuchi S, Ooka T, Akiyama Y, Shinohara R, Miyake K, Yamagata Z. All-cause and cardiovascular disease mortality in underweight patients with diabetic nephropathy: BioBank Japan cohort. J Diabetes Investig, 2020

30. Yonemaru J, Takahashi M, Nara S, Ichikawa H, Ishigamori R, Imai T, Hiraoka N. A yolk sac tumor of the pancreas and derived xenograft model effectively responded to VIP chemotherapy. Pancreatology, 20:551-557, 2020

31. Yoshida KI, Machado I, Motoi T, Parafioriti A, Lacambra M, Ichikawa H, Kawai A, Antonescu CR, Yoshida A. NKX3-1 Is a Useful Immunohistochemical Marker of EWSR1-NFATC2 Sarcoma and Mesenchymal Chondrosarcoma. Am J Surg Pathol, 44:719-728, 2020