Annual Report 2023

Division of Molecular Oncology

Keisuke Kataoka, Junji Koya, Yasunori Kogure, Sumito Shingaki, Yuki Saito, Fumie Ueki, Yoko Hokama, Yoshiko Ito, Kayo Miura, Koichi Murakami, Mariko Tabata, Kentaro Yamaguchi, Yuta Ito, Mitsuhiro Yuasa, Sara Horie, Tomohiko Tanigawa, Kota Mizuno, Yosuke Mizukami, Takahiro Inoue, Haryoon Kim,  Zen Tamura

Introduction

 The advent of next-generation sequencing (NGS) technologies has enabled us to delineate the genetic landscape of human cancers. We have worked on the integrated genetic analysis of diverse cancer types, especially on hematologic malignancies using cutting-edge genomic techniques.

The Team and What We Do

 By combining genomics (such as whole-genome sequencing and multi-omics single-cell analysis) with molecular and functional approaches (such as CRISPR screening), we aim to:

1. Genetically dissect the molecular pathogenesis of human cancers.

2. Identify novel potential therapeutic targets and/or biomarkers.

3. Establish the clinical relevance of genetic alterations.

Research Activities

 In a study of 261 relapsed/refractory multiple myeloma (RRMM) cases treated with ixazomib, lenalidomide, and dexamethasone, we conducted targeted sequencing on bone marrow plasma cells (BMPCs) and circulating tumor DNA (ctDNA) to explore the impact of driver mutations on prognosis. We identified 24 recurrently mutated genes in BMPCs and 47 in ctDNA, with notable mutations such as TP53 appearing predominantly in ctDNA, indicating subclonal origins. Mutations in genes like KRAS, TP53, DIS3, BRAF, NRAS, and ATM in ctDNA were linked to poorer progression-free survival (PFS). A prognostic index incorporating ctDNA mutation counts, plasma DNA concentration, and clinical factors effectively stratified patients into three risk categories with differing 2-year PFS rates. Notably, TP53 and KRAS mutations often emerged post-therapy, highlighting ctDNA’s superior prognostic value over BMPC mutations. This study underscores ctDNA mutations as key predictive markers for disease progression in RRMM (Kogure Y, Blood, 2024).

 Using 48,627 samples from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT), we presented a pan-cancer landscape of driver alterations and their clinical actionability in Japanese patients. Comparison with White patients in Genomics Evidence Neoplasia Information Exchange (GENIE) demonstrated high TP53 mutation frequencies in Asian patients across multiple cancer types. Integration of C-CAT, GENIE, and The Cancer Genome Atlas data revealed many cooccurring and mutually exclusive relationships between driver mutations. At pathway level, mutations in epigenetic regulators frequently cooccur with PI3K pathway molecules. Furthermore, we found significant cooccurring mutations within the epigenetic pathway. Accumulation of mutations in epigenetic regulators causes increased proliferation-related transcriptomic signatures. Loss-of-function of many epigenetic drivers inhibits cell proliferation in their wild-type cell lines, but this effect is attenuated in those harboring mutations of not only the same but also different epigenetic drivers. Our analyses dissect various genetic properties and provide valuable resources for precision medicine in cancer (Horie S, Cancer Discov, 2024).

Future Prospects

 As shown in the above, we aim to delineate the entire picture of genetic aberrations in human cancers using cutting-edge genomic techniques. Based on the genetic findings, we will identify novel potential drug targets and/or biomarkers and clarify the molecular pathogenesis underlying cancer development and progression of. In addition, we will establish the clinical significance of these alterations, which will help the advancement of cancer precision medicine.

List of papers published in 2023

Journal

1. Sugiyama M, Arakawa A, Kogure Y, Shirakawa N, Watanabe M, Ito Y, Tanimura K, Tao K, Nakajima M, Watanabe Y, Miyagi-Maeshima A, Fukuhara S, Kataoka K, Izutsu K, Fukuda T, Ogawa C. Different phenotype relapse of myeloid/lymphoid neoplasms with FGFR1 rearrangement with long remission. Pediatric blood & cancer, 71:e30721, 2024

2. Koresawa-Shimizu R, Suzuki R, Uehara Y, Hiramoto N, Sawa M, Fukuda T, Kataoka K, Kanda Y, Oyake T, Kubota Y, Uchida N, Yano S, Kobayashi H, Tanaka J, Atsuta Y, Kondo E. Comparison of MEAM, MCEC and LEED high-dose chemotherapy followed by autologous stem cell transplantation in relapsed/refractory diffuse large B-cell lymphoma: data from the Japan Society for Hematopoietic and Cellular Therapy Registry. Bone marrow transplantation, 59:125-127, 2024

3. Shimomura Y, Komukai S, Kitamura T, Tachibana T, Kurosawa S, Itonaga H, Tsukamoto S, Doki N, Katayama Y, Ito A, Sawa M, Ueda Y, Nakamae H, Nawa Y, Tanaka M, Arai Y, Ota S, Kataoka K, Nishida T, Kanda J, Fukuda T, Atsuta Y, Ishiyama K. The prognosis and risk factors for patients with complex karyotype myelodysplastic syndrome undergoing allogeneic haematopoietic stem cell transplantation. British journal of haematology, 204:612-622, 2024

4. Yamada A, Yasunaga JI, Liang L, Zhang W, Sunagawa J, Nakaoka S, Iwami S, Kogure Y, Ito Y, Kataoka K, Nakagawa M, Iwanaga M, Utsunomiya A, Koh KR, Watanabe T, Nosaka K, Matsuoka M. Anti-HTLV-1 immunity combined with proviral load as predictive biomarkers for adult T-cell leukemia-lymphoma. Cancer science, 115:310-320, 2024

5. Kim H, Mizuno K, Masuda K, Sakurai M, Ara T, Naito K, Uehara Y, Yamamoto G, Osada M, Machida S, Horio T, Fukushima K, Mori Y, Ichinohe T, Fukuda T, Atsuta Y, Kataoka K. A Nationwide Retrospective Analysis of Allogeneic Hematopoietic Stem Cell Transplantation for Adult Hemophagocytic Lymphohistiocytosis. Transplantation and cellular therapy, 30:419.e1-419.e12, 2024

6. Horie S, Saito Y, Kogure Y, Mizuno K, Ito Y, Tabata M, Kanai T, Murakami K, Koya J, Kataoka K. Pan-Cancer Comparative and Integrative Analyses of Driver Alterations Using Japanese and International Genomic Databases. Cancer discovery, 14:786-803, 2024

7. Toya T, Mizuno K, Sakurai M, Kato J, Mori T, Doki N, Masuda S, Aotsuka N, Tsukamoto S, Sakaida E, Nakajima Y, Fujisawa S, Machida S, Aoyama Y, Yokoyama H, Shono K, Hatta Y, Usuki K, Kataoka K, Kanda Y. Differential clinical impact of letermovir prophylaxis according to graft sources: a KSGCT multicenter retrospective analysis. Blood advances, 8:1084-1093, 2024

8. Kogure Y, Handa H, Ito Y, Ri M, Horigome Y, Iino M, Harazaki Y, Kobayashi T, Abe M, Ishida T, Ito S, Iwasaki H, Kuroda J, Shibayama H, Sunami K, Takamatsu H, Tamura H, Hayashi T, Akagi K, Shinozaki T, Yoshida T, Mori I, Iida S, Maeda T, Kataoka K. ctDNA improves prognostic prediction in relapsed/refractory MM receiving ixazomib, lenalidomide, and dexamethasone. Blood, 143:2401-2413, 2024

9. Tao K, Inamoto Y, Furukawa H, Hosoba R, Takeda W, Maeshima A, Aoki J, Ito A, Tanaka T, Kim SW, Makita S, Fukuhara S, Kogure Y, Kataoka K, Izutsu K, Fukuda T. Romidepsin-induced durable remission for relapsed nodal peripheral T-cell lymphoma with T follicular helper phenotype after allogeneic hematopoietic cell transplantation. International journal of hematology, 118:292-298, 2023

10. Shiraishi Y, Koya J, Chiba K, Okada A, Arai Y, Saito Y, Shibata T, Kataoka K. Precise characterization of somatic complex structural variations from tumor/control paired long-read sequencing data with nanomonsv. Nucleic acids research, 51:e74, 2023

11. Kameda T, Kataoka K, Kamiunten A, Hidaka M, Miyoshi H, Nakano N, Nosaka K, Yoshimitsu M, Yasunaga JI, Kogure Y, Shide K, Miyahara M, Sakamoto T, Akizuki K, Hidaka T, Kubuki Y, Koya J, Kawano N, Yamashita K, Kawano H, Toyama T, Maeda K, Marutsuka K, Imaizumi Y, Kato K, Sugio T, Tokunaga M, Tashiro Y, Takaori-Kondo A, Miyazaki Y, Akashi K, Ishitsuka K, Matsuoka M, Ohshima K, Watanabe T, Kitanaka A, Utsunomiya A, Ogawa S, Shimoda K. Integrated genetic and clinical prognostic factors for aggressive adult T-cell leukemia/lymphoma. Haematologica, 108:2178-2191, 2023

12. Sakurai M, Kogure Y, Mizuno K, Matsuki E, Kataoka K. Long-term reduction in the incidence of aplastic anemia and immune thrombocytopenia during the COVID-19 pandemic. Haematologica, 108:2546-2550, 2023

13. Itonaga H, Miyazaki Y, Aoki K, Shingai N, Ozawa Y, Fukuda T, Kataoka K, Kawakita T, Ueda Y, Ara T, Tanaka M, Katayama Y, Sawa M, Eto T, Kanda J, Atsuta Y, Ishiyama K. Allogeneic transplantation of bone marrow versus peripheral blood stem cells from HLA-identical relatives in patients with myelodysplastic syndromes and oligoblastic acute myeloid leukemia: a propensity score analysis of a nationwide database. Annals of hematology, 102:1215-1227, 2023

14. Kataoka K, Saito Y. Multiple Mutations within Individual Oncogenes: Examples and Clinical Implications. The Keio journal of medicine, 72:88-92, 2023

15. Takahashi E, Imai H, Tsuyuki Y, Taniguchi N, Kogure Y, Kataoka K, Tsuchida T, Baba S, Tsuzuki T, Shimauchi T, Nakamura S. Enhanced PD-L1 expression on tumor cells in primary CD30-positive cutaneous large T-cell lymphoma: a report of lymph node lesions of four cases. Journal of clinical and experimental hematopathology, 63:49-57, 2023

16. Fujii N, Onizuka M, Fukuda T, Ikegame K, Kawakita T, Nakamae H, Kobayashi T, Kataoka K, Tanaka M, Kondo T, Kato K, Sato A, Ichinohe T, Atsuta Y, Ogata M, Suzuki R, Nakasone H. Clinical characteristics of late-onset interstitial pneumonia after allogeneic hematopoietic stem cell transplantation. International journal of hematology, 118:242-251, 2023

17. Shiroshita K, Kobayashi H, Watanuki S, Karigane D, Sorimachi Y, Tamaki S, Haraguchi M, Yamamoto M, Nakamura-Ishizu A, Okamoto S, Kataoka K, Takubo K. Distinct roles of the preparatory and payoff phases of glycolysis in hematopoietic stem cells. Experimental hematology, 124:56-67, 2023

18. Okada Y, Kimura F, Kurita N, Takahashi H, Shimazu Y, Mizuno S, Uchida N, Kataoka K, Hiramoto N, Ota S, Kako S, Tsukada N, Kanda Y, Kurahashi S, Doki N, Nishikawa A, Kim SW, Hangaishi A, Kanda J, Fukuda T, Atsuta Y, Kondo E, Kawamura K, Nakasone H. Adverse impact of delay of platelet recovery after autologous hematopoietic cell transplantation for aggressive non-Hodgkin lymphoma and multiple myeloma. Cytotherapy, 25:1212-1219, 2023

19. Tabata M, Sato Y, Kogure Y, McClure MB, Oshikawa-Kumade Y, Saito Y, Shingaki S, Ito Y, Yuasa M, Koya J, Yoshida K, Kohno T, Miyama Y, Morikawa T, Chiba K, Okada A, Ogawa S, Ushiku T, Shiraishi Y, Kume H, Kataoka K. Inter- and intra-tumor heterogeneity of genetic and immune profiles in inherited renal cell carcinoma. Cell reports, 42:112736, 2023

20. Hashimoto K, Kobayashi K, Nakamura Y, Yukino Y, Tsuji G, Kim H, Kataoka K, Amagai M. Prolonged mucosal topical application of cyclosporin A for severe stomatitis of paraneoplastic pemphigus. The Australasian journal of dermatology, 64:439-441, 2023

21. Takamatsu H, Matsuda T, Mizuno S, Takahashi T, Fuchida SI, Hanamura I, Kataoka K, Tsukada N, Matsumoto M, Hangaishi A, Doki N, Uchida N, Sawa M, Maruyama Y, Kurahashi S, Nagafuji K, Harazaki Y, Kako S, Iida S, Ichinohe T, Kanda Y, Atsuta Y, Sunami K. Changing trends in the risk factors for second primary malignancies after autologous stem cell transplantation for multiple myeloma before and after the introduction of proteasome inhibitors and immunomodulatory drugs. Haematologica, 108:3399-3408, 2023

22. Fuji S, Hakoda A, Kanda J, Fukuda T, Doki N, Katayama Y, Uchida N, Ozawa Y, Kanda Y, Tanaka M, Kataoka K, Ara T, Sawa M, Onizuka M, Onishi Y, Kimura T, Ichinohe T, Atsuta Y, Shintani A, Morishima S. Impact of HLA disparity on overall mortality risk in patients with extensive chronic GVHD: The HLA Working Group of Japanese Society for Transplantation and Cellular Therapy. Bone marrow transplantation, 58:1257-1259, 2023

23. Suzuki K, Shimazu Y, Minakata D, Ikeda T, Takahashi H, Tsukada N, Kanda Y, Doki N, Nishiwaki K, Miwa A, Sawa M, Kataoka K, Hiramoto N, Ota S, Itagaki M, Ichinohe T, Atsuta Y, Yano S, Kawamura K. Efficacy of Autologous Stem Cell Transplantation for Myeloma Patients with Suboptimal Response: A Multicenter Retrospective Analysis. Transplantation and cellular therapy, 29:688.e1-688.e13, 2023

24. Watanabe M, Kanda J, Fukuda T, Uchida N, Ikegame K, Kataoka K, Kobayashi H, Ara T, Ishikawa J, Matsuoka KI, Sugio Y, Nakazawa H, Ikeda T, Atsuta Y, Kondo E, Suzuki R. Impact of GVHD on lymphoma progression: Nationwide study from Japanese Society for Transplantation and Cellular Therapy. British journal of haematology, 203:446-459, 2023

25. Fujita S, Kasahara H, Kato J, Koda Y, Shiroshita K, Yamaguchi K, Okayama M, Abe R, Kikuchi T, Shimizu T, Mori T, Kataoka K, Okamoto S. The Impact of Pretransplant Use of Tyrosine Kinase Inhibitors on Allogeneic Stem Cell Transplantation in Patients with Chronic Myeloid Leukemia-A Single-institution Retrospective Study. Internal medicine (Tokyo, Japan), 63:1549-1562, 2023

26. Suzuki T, Terada M, Machida R, Kataoka T, Ito Y, Kataoka K, Maruyama D, Nagai H, Lymphoma Study Group of the Japan Clinical Oncology Group. Randomized phase III study of daratumumab versus bortezomib plus daratumumab as maintenance therapy after D-MPB for transplant-ineligible patients with untreated multiple myeloma (JCOG1911, B-DASH study). Japanese Journal of Clinical Oncology, 53:349–354, 2023