Annual Report 2023

Department of Genetic Medicine and Services

Makoto Hirata, Teruhiko Yoshida, Hourin Cho, Kokichi Sugano, Shigenobu Suzuki, Mitsuya Ishikawa, Nobuyoshi Hiraoka, Shigeki Sekine, Taisuke Mori, Kuniko Sunami, Noboru Yamamoto, Takahisa Matsuda, Hiromi Sakamoto, Mineko Ushiama, Takashi Kohno, Mamoru Kato, Hitoshi Ichikawa, Satoyo Oda, Noriko Tanabe, Tomoko Watanabe, Manami Matsukawa

Introduction

 It has been estimated that roughly 5% of all cancer cases are caused by a highly penetrant monogenic mutation. The major causative genes for most hereditary cancer syndromes were identified in the 1990s. Since then, genetic diagnosis has been considered as a part of standard medical care in oncology clinics. The National Cancer Center Hospital (NCCH) launched the Outpatient Genetic Counseling Clinic in 1998 as part of a collaboration with the NCC Research Institute, specifically the Fundamental Innovative Oncology Core (FIOC). However, several issues remain to be addressed in cancer medical genetics, as shown in Figure 1.

The Team and What We Do

 The Department of Genetic Medicine and Services (GeMS) comprises 12 doctors, five researchers, and three genetic counselors. Most of these staff hold a concurrent post of another department and research division, except the genetic counselors.

 As shown on the NCCH website, the aim and mission of the clinical service of the Outpatient Genetic Counseling Clinic, which are the major routine clinical activities of our department, are:

1) To provide consultation and appropriate medical and genetic information (that is, genetic counseling) to anyone who has a concern related to heredity cancer.

2) To provide genetic testing when appropriate.

3) To support early diagnosis and treatment based on family history and/or genetic test results.

4) To discuss the clinical sequencing results of patients by participating in the Expert panel.

 For the period of April 2023 to March 2024, 446 clients and their relatives visited the clinic. Of these, 204 families and 259 clients newly visited this period. In total, 2,305 families have visited the clinic since its inception in 1998. Details are shown in Table 1.

Research Activities

 Although at least one causative gene has been identified for each of the major hereditary cancer syndromes, overall sensitivity of the current genetic tests is far from 100% and may be around 70-80%, even for the cases that meet clinical and/or screening criteria for hereditary cancer syndromes. The false negative cases may include both inadequate technical sensitivity of the current genetic test methods on the established causative genes (allelic heterogeneity) and also yet-to-be-identified genes representing locus heterogeneity. There has been great expectation that the introduction of next generation sequencers (NGS) would change the situation. The staff of the Department of GeMS have established a new Common Protocol to perform NGS-based germline clinical sequencing for patients with negative test results by conventional genetic tests, who would represent a part of the Undiagnosed Disease Patients in the oncology field. The Common Protocol has been adopted by other hospitals and institutions in a long-standing multi-institute collaborative research group based on the National Cancer Center Research and Development Fund and its predecessor. In addition to whole exome/genome sequencing (WES/WGS), a multi-gene panel has been developed based on Agilent SureSelect technology.

Clinical Trials

 We have participated in an expert panel of clinical sequencing conducted by health insurance systems since May 29, 2019. In addition, we have participated in the TOP2 panel of the Japanese Children's Cancer Study Group (JCCG), which have been conducted as research this year, following on from last year.

Education

 The Department has accepted attendees for outpatient genetic counseling so that they could be eligible to take the examination for clinical geneticists and certified genetic counselors acknowledged by the Japanese Society of Human Genetics and the Japanese Society of Genetic Counseling and/or Hereditary Cancer Specialists acknowledged by the Japanese Society for Hereditary Tumors. In FY2023, four doctors registered as trainees for clinical geneticists and one doctor passed the exam. As for Hereditary Cancer Specialists, five doctors registered as trainees, and three passed the exam. We accepted two residents in FY2023. Furthermore, from this year, we accepted five visitors: an oncologist from Kyoto University Hospital, a breast surgeon from the University of Tokyo Hospital, a pediatrician from Osaka City General Hospital, a certified genetic counselor from National Cancer Center Hospital East, and a medical student from Jichi Medical University.

Future Prospects

 The Department of GeMS was launched in November 2015. Although this section reports on the routine clinical activity of the Department and clinical research associated directly with the Outpatient Genetic Counseling Clinic, the scope and mission of the Department extend beyond hereditary cancer syndromes and include support of the genomic biomarker-driven personalized cancer treatments offered by other clinical departments (Figure. 2). The core technology of the new discipline, also known as a precision medicine, is next-generation sequencers, which would bring massive amounts of genomic data to cancer diagnosis, treatment and prevention. The crux of this emerging opportunity is how to convert the sequence data to clinically valid and useful knowledge, which could include incidental or secondary findings. The Department of GeMS is expected to support other departments in the era of genomic medicine.

List of papers published in 2023

Journal

1. Shiraishi K, Takahashi A, Momozawa Y, Daigo Y, Kaneko S, Kawaguchi T, Kunitoh H, Matsumoto S, Horinouchi H, Goto A, Honda T, Shimizu K, Torasawa M, Takayanagi D, Saito M, Saito A, Ohe Y, Watanabe SI, Goto K, Tsuboi M, Tsuchihara K, Takata S, Aoi T, Takano A, Kobayashi M, Miyagi Y, Tanaka K, Suzuki H, Maeda D, Yamaura T, Matsuda M, Shimada Y, Mizuno T, Sakamoto H, Yoshida T, Goto Y, Yoshida T, Yamaji T, Sonobe M, Toyooka S, Yoneda K, Masago K, Tanaka F, Hara M, Fuse N, Nishizuka SS, Motoi N, Sawada N, Nishida Y, Kumada K, Takeuchi K, Tanno K, Yatabe Y, Sunami K, Hishida T, Miyazaki Y, Ito H, Amemiya M, Totsuka H, Nakayama H, Yokose T, Ishigaki K, Nagashima T, Ohtaki Y, Imai K, Takasawa K, Minamiya Y, Kobayashi K, Okubo K, Wakai K, Shimizu A, Yamamoto M, Iwasaki M, Matsuda K, Inazawa J, Shiraishi Y, Nishikawa H, Murakami Y, Kubo M, Matsuda F, Kamatani Y, Hamamoto R, Matsuo K, Kohno T. Identification of telomere maintenance gene variations related to lung adenocarcinoma risk by genome-wide association and whole genome sequencing analyses. Cancer communications (London, England), 44:287-293, 2024

2. Sunami K, Naito Y, Saigusa Y, Amano T, Ennishi D, Imai M, Kage H, Kanai M, Kenmotsu H, Komine K, Koyama T, Maeda T, Morita S, Sakai D, Hirata M, Ito M, Kozuki T, Sakashita H, Horinouchi H, Okuma Y, Takashima A, Kubo T, Hironaka S, Segawa Y, Yakushijin Y, Bando H, Makiyama A, Suzuki T, Kinoshita I, Kohsaka S, Ohe Y, Ishioka C, Yamamoto K, Tsuchihara K, Yoshino T. A Learning Program for Treatment Recommendations by Molecular Tumor Boards and Artificial Intelligence. JAMA oncology, 10:95-102, 2024

3. Takamizawa S, Koyama T, Sunami K, Sudo K, Hirata M, Kubo T, Tao K, Cho H, Narita Y, Kato K, Yamazaki N, Ohe Y, Okusaka T, Matsui Y, Ogawa C, Yonemori K, Yamamoto N. Identification of barriers to implementation of precision oncology in patients with rare cancers. Cancer science, 115:2023-2035, 2024

4. Komeda Y, Ishikawa H, Yoshida T, Ushiama M, Yoshida S, Nomura K, Kono M, Omoto S, Takenaka M, Hagiwara S, Kashida H, Kudo M. Familial Adenomatous Polyposis with Atypical Clinical Morphology and Genetic Variants. Internal medicine (Tokyo, Japan), 63:1075-1079, 2024

5. Makiuchi S, Tian Y, Fujimoto M, Kuramoto J, Tsuda N, Ojima H, Gotoh M, Hiraoka N, Yoshida T, Kanai Y, Arai E. DNA methylation alterations of ADCY5, MICAL2, and PLEKHG2 during the developmental stage of cryptogenic hepatocellular carcinoma. Hepatology research, 54:284-299, 2024

6. Nakamura W, Hirata M, Oda S, Chiba K, Okada A, Mateos RN, Sugawa M, Iida N, Ushiama M, Tanabe N, Sakamoto H, Sekine S, Hirasawa A, Kawai Y, Tokunaga K, Tsujimoto SI, Shiba N, Ito S, Yoshida T, Shiraishi Y. Assessing the efficacy of target adaptive sampling long-read sequencing through hereditary cancer patient genomes. NPJ genomic medicine, 9:11, 2024

7. Matsui H, Hirata M. Evaluation of the pathogenic potential of germline DDX41 variants in hematopoietic neoplasms using the ACMG/AMP guidelines. International journal of hematology, 119:552-563, 2024

8. Satake T, Kondo S, Tanabe N, Mizuno T, Katsuya Y, Sato J, Koyama T, Yoshida T, Hirata M, Yamamoto N. Pathogenic Germline Variants in BRCA1/2 and p53 Identified by Real-world Comprehensive Cancer Genome Profiling Tests in Asian Patients. Cancer research communications, 3:2302-2311, 2023

9. Yamamoto H, Sakamoto H, Kumagai H, Abe T, Ishiguro S, Uchida K, Kawasaki Y, Saida Y, Sano Y, Takeuchi Y, Tajika M, Nakajima T, Banno K, Funasaka Y, Hori S, Yamaguchi T, Yoshida T, Ishikawa H, Iwama T, Okazaki Y, Saito Y, Matsuura N, Mutoh M, Tomita N, Akiyama T, Yamamoto T, Ishida H, Nakayama Y. Clinical Guidelines for Diagnosis and Management of Peutz-Jeghers Syndrome in Children and Adults. Digestion, 104:335-347, 2023

10. Kitamura H, Morizane C, Tanabe N, Go I, Maruki Y, Ohba A, Nagashio Y, Kondo S, Hijioka S, Ueno H, Yoshida T, Okusaka T. Clinical features of germline BRCA1/2 or ATM pathogenic variant positive pancreatic cancer in Japan. Pancreatology, 23:964-969, 2023

11. Tao K, Yamazaki F, Kubo T, Sunami K, Kumamoto T, Arakawa A, Sugiyama M, Watanabe Y, Nakajima M, Shirakawa N, Tanimura K, Koyama T, Hirata M, Sudo K, Tanabe N, Watanabe T, Yoshida T, Kitami M, Yoshida A, Yatabe Y, Nakano Y, Ohira M, Kamijo T, Nakazawa A, Kato M, Ichimura K, Kohno T, Yamamoto N, Hishiki T, Ichikawa H, Ogawa C. Pediatric Precision Medicine at the National Cancer Center Japan: Prospective Genomic Study of Pediatric Patients with Cancer as Part of the TOP-GEAR Project. JCO precision oncology, 7:e2200266, 2023

12. Motoi T, Hirata M, Kukita Y, Satomi K, Tamura H, Adachi S, Matsushita Y, Horiguchi SI, Hishima T, Ikegami M, Okuma T, Tao K, Arakawa A, Ogawa C, Matsuda K, Ichimura K, Nakamura H, Mori T, Yoshida A. KDM2B-Rearranged Soft Tissue Sarcomas Expand the Concept of BCOR-Associated Sarcoma. Modern pathology, 36:100317, 2023

13. Sri-Iesaranusorn P, Sadahiro R, Murakami S, Wada S, Shimizu K, Yoshida T, Aoki K, Uezono Y, Matsuoka H, Ikeda K, Yoshimoto J. Data-driven categorization of postoperative delirium symptoms using unsupervised machine learning. Frontiers in psychiatry, 14:1205605, 2023

14. Nishino M, Fujimori M, Koyama T, Hirata M, Tanabe N, Shimizu T, Yamamoto N, Uchitomi Y. Prevalence of psychological distress, quality of life, and satisfaction among patients and family members following comprehensive genomic profiling testing: Protocol of the Quality of life for Cancer genomics and Advanced Therapeutics (Q-CAT) study. PloS one, 18:e0283968, 2023

15. Naka T, Hashimoto T, Yoshida T, Yatabe Y, Sekine S. KLF4 c.A1322C Mutation Is a Consistent and Specific Genetic Feature of Raspberry-like Foveolar-type Adenoma of the Stomach. The American journal of surgical pathology, 47:521-523, 2023

16. Oda S, Ushiama M, Nakamura W, Gotoh M, Tanabe N, Watanabe T, Odaka Y, Aoyagi K, Sakamoto H, Nakajima T, Sugano K, Yoshida T, Shiraishi Y, Hirata M. A complex rearrangement between APC and TP63 associated with familial adenomatous polyposis identified by multimodal genomic analysis: a case report. Frontiers in oncology, 13:1205847, 2023

17. Shimamoto Y, Takeuchi Y, Ishiguro S, Nakatsuka SI, Yunokizaki H, Ezoe Y, Nakajima T, Tanaka K, Ishihara R, Takayama T, Yoshida T, Sugano K, Mutoh M, Ishikawa H. Genotype-phenotype correlation for extracolonic aggressive phenotypes in patients with familial adenomatous polyposis. Cancer science, 114:4596-4606, 2023

18. Tanabe K, Nakanishi Y, Okubo N, Matsumoto S, Umino Y, Kataoka M, Yajima S, Yoshida T, Miyazaki S, Kuwata T, Ishii G, Watanabe R, Masuda H. Prevalence and characteristics of patients with upper urinary tract urothelial carcinoma having potential Lynch syndrome identified by immunohistochemical universal screening and Amsterdam criteria II. BMC cancer, 23:940, 2023

19. Matsuoka A, Fujimori M, Koyama T, Sato A, Mori K, Hirata M, Tanabe N, Nakachi K, Kato S, Okamoto H, Ogawa K, Komatsu H, Iwasaku M, Miyaji T, Uchitomi Y. Prevalence of psychological distress and associated factors among patients undergoing comprehensive genomic profiling testing: protocol for a multicentre, prospective, observational study. BMJ open, 13:e072472, 2023