Annual Report 2022

Division of Molecular Oncology

Keisuke Kataoka, Junji Koya, Yasunori Kogure, Sumito Shingaki, Yuki Saito, Mariko Tabata, Fumie Ueki, Yoko Hokama, Yoshiko Ito, Yuta Ito, Mitsuhiro Yuasa, Kentaro Yamaguchi, Sara Horie, Kota Mizuno, Tomohiko Tanigawa, Yosuke Mizukami, Zen Tamura, Koichi Murakami, Yusuke Kubota, Masatoshi Sakurai

Introduction

 The advent of next-generation sequencing (NGS) technologies has empowered 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

 We devised an integrated DNA/RNA profiling assay for detecting various types of somatic alterations and germline variants at once. Particularly, our assay can successfully identify copy number alterations and structural variations. Using this assay, we conducted a prospective study to investigate the feasibility and clinical usefulness of comprehensive genomic profiling for 452 recurrently altered genes in hematological malignancies. We analyzed a total of 176 patients and detected at least one alteration in 171 (97%) patients, with a median number of 7 alterations (0-55). Among them, 145 (82%), 86 (49%), and 102 (58%) patients harbored at least one clinically relevant alteration for diagnosis, treatment, and prognosis, respectively. These results suggest the clinical utility of NGS-based genomic profiling, particularly for diagnosis and prognostic prediction, thereby highlighting the promise of precision medicine for hematological malignancies (S Fukuhara, Can Sci. 2022).

 In addition, we performed multi-omics single-cell analysis to elucidate the effect of Pd-l2 expression on cellular and molecular architecture of tumor microenvironment in B-cell lymphoma. We also conducted integrated epigenetic analysis and CRISPR tiling screening in human B cells to reveal the mechanisms regulating Pd-l2 expression. Our findings provide insights into the regulation of PD-L2 expression and its mediated immune evasion (S Shingaki, Leukemia. 2023).

 Furthermore, we constructed PRSs from 14 genome-wide association studies (median n = 64,905) across 12 cancer types by multiple methods and calibrated them using the UK Biobank resources (n = 335,048). Meta-analyses across different cancer types within The Cancer Genome Atlas (n = 7,965) revealed that higher PRS values were associated with earlier cancer onset and lower burden of somatic alterations, including total mutations, chromosome/arm somatic copy-number alterations (SCNA), and focal SCNAs. Our results suggest that common germline cancer risk variants allow early tumor development before the accumulation of many somatic alterations characteristic of later stages of carcinogenesis (S Namba and Y Saito, Can Res. 2023).

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. 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 2022

Journal

1. Sakata R, Chu PS, Kawaida M, Emoto K, Sakurai M, Nishida R, Asakura K, Morikawa R, Taniki N, Kataoka K, Kanai T, Nakamoto N. Concurrent de novo Thymoma-associated Paraneoplastic Type 1 Autoimmune Hepatitis and Pure Red Cell Aplasia after Thymectomy: A Case Report and Literature Review. Internal medicine (Tokyo, Japan), 62:243-249, 2023

2. Oyama T, Matsuda K, Honda A, Maki H, Masamoto Y, Murakami D, Toya T, Sakurai M, Kataoka K, Doki N, Kurokawa M. Clinical characteristics of steroid-responsive but dependent chronic graft-versus-host disease: a multicenter retrospective analysis. International journal of hematology, 117:260-268, 2023

3. Namba S, Saito Y, Kogure Y, Masuda T, Bondy ML, Gharahkhani P, Gockel I, Heider D, Hillmer A, Jankowski J, MacGregor S, Maj C, Melin B, Ostrom QT, Palles C, Schumacher J, Tomlinson I, Whiteman DC, Okada Y, Kataoka K. Common Germline Risk Variants Impact Somatic Alterations and Clinical Features across Cancers. Cancer research, 83:20-27, 2023

4. Shingaki S, Koya J, Yuasa M, Saito Y, Tabata M, McClure MB, Ogawa S, Katayama K, Togashi Y, Imoto S, Kogure Y, Kataoka K. Tumor-promoting function and regulatory landscape of PD-L2 in B-cell lymphoma. Leukemia, 37:492-496, 2023

5. Sakurai M, Ishitsuka K, Ito R, Wilkinson AC, Kimura T, Mizutani E, Nishikii H, Sudo K, Becker HJ, Takemoto H, Sano T, Kataoka K, Takahashi S, Nakamura Y, Kent DG, Iwama A, Chiba S, Okamoto S, Nakauchi H, Yamazaki S. Chemically defined cytokine-free expansion of human haematopoietic stem cells. Nature, 615:127-133, 2023

6. McClure MB, Kogure Y, Ansari-Pour N, Saito Y, Chao HH, Shepherd J, Tabata M, Olopade OI, Wedge DC, Hoadley KA, Perou CM, Kataoka K. Landscape of Genetic Alterations Underlying Hallmark Signature Changes in Cancer Reveals TP53 Aneuploidy-driven Metabolic Reprogramming. Cancer research communications, 3:281-296, 2023

7. Fukuhara S, Oshikawa-Kumade Y, Kogure Y, Shingaki S, Kariyazono H, Kikukawa Y, Koya J, Saito Y, Tabata M, Yoshifuji K, Mizuno K, Miyagi-Maeshima A, Matsushita H, Sugiyama M, Ogawa C, Inamoto Y, Fukuda T, Sugano M, Yamauchi N, Minami Y, Hirata M, Yoshida T, Kohno T, Kohsaka S, Mano H, Shiraishi Y, Ogawa S, Izutsu K, Kataoka K. Feasibility and clinical utility of comprehensive genomic profiling of hematological malignancies. Cancer science, 113:2763-2777, 2022

8. Yaguchi T, Kimura S, Sekiguchi M, Kubota Y, Seki M, Yoshida K, Shiraishi Y, Kataoka K, Fujii Y, Watanabe K, Hiwatari M, Miyano S, Ogawa S, Takita J. Description of longitudinal tumor evolution in a case of multiply relapsed clear cell sarcoma of the kidney. Cancer reports (Hoboken, N.J.), 5:e1458, 2022

9. Higo T, Suzuki Y, Sato M, Koya J, Mizuno H, Miyauchi M, Masamoto Y, Kataoka K, Sumitomo Y, Tsuruta-Kishino T, Sato T, Kurokawa M. Heterozygous Dnmt3a R878C induces expansion of quiescent hematopoietic stem cell pool. Experimental hematology, 109:45-54, 2022

10. Itonaga H, Kida M, Hamamura A, Uchida N, Ozawa Y, Fukuda T, Ueda Y, Kataoka K, Katayama Y, Ota S, Matsuoka KI, Kondo T, Eto T, Kanda J, Ichinohe T, Atsuta Y, Miyazaki Y, Ishiyama K. Outcome of therapy-related myelodysplastic syndrome and oligoblastic acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation: A propensity score matched analysis. Hematological oncology, 40:752-762, 2022

11. Iwasaki M, Kanda J, Tanaka H, Shindo T, Sato T, Doki N, Fukuda T, Ozawa Y, Eto T, Uchida N, Katayama Y, Kataoka K, Ara T, Ota S, Onizuka M, Kanda Y, Ichinohe T, Atsuta Y, Morishima S. Impact of HLA Epitope Matching on Outcomes After Unrelated Bone Marrow Transplantation. Frontiers in immunology, 13:811733, 2022

12. Takahara T, Ishikawa E, Suzuki Y, Kogure Y, Sato A, Kataoka K, Nakamura S. PD-L1-expressing extranodal diffuse large B-cell lymphoma, NOS with and without PD-L1 3’-UTR structural variations. Journal of clinical and experimental hematopathology, 62:106-113, 2022

13. Yokoyama Y, Nozawa E, Morita M, Ishikawa E, Mori T, Sakurai M, Kikuchi T, Matsuki E, Yamazaki R, Kataoka K, Jibiki A, Kawazoe H, Suzuki S, Nakamura T. Simultaneous quantification of dasatinib, nilotinib, bosutinib, and ponatinib using high-performance liquid chromatography-Photodiode array detection. Journal of clinical laboratory analysis, 36:e24598, 2022

14. Mizuno K, Sakurai M, Kato J, Yamaguchi K, Abe R, Koda Y, Kataoka K, Mori T. Risk factor analysis for cytomegalovirus reactivation under prophylaxis with letermovir after allogeneic hematopoietic stem cell transplantation. Transplant infectious disease, 24:e13904, 2022

15. Fujita S, Morikawa T, Tamaki S, Sezaki M, Takizawa H, Okamoto S, Kataoka K, Takubo K. Quantitative Analysis of Sympathetic and Nociceptive Innervation Across Bone Marrow Regions in Mice. Experimental hematology, 112-113:44-59.e6, 2022

16. Vanden Bempt M, Debackere K, Demeyer S, Van Thillo Q, Meeuws N, Prieto C, Provost S, Mentens N, Jacobs K, Gielen O, Nittner D, Ogawa S, Kataoka K, Graux C, Tousseyn T, Cools J, Dierickx D. Aberrant MYCN expression drives oncogenic hijacking of EZH2 as a transcriptional activator in peripheral T-cell lymphoma. Blood, 140:2463-2476, 2022

17. de Leval L, Alizadeh AA, Bergsagel PL, Campo E, Davies A, Dogan A, Fitzgibbon J, Horwitz SM, Melnick AM, Morice WG, Morin RD, Nadel B, Pileri SA, Rosenquist R, Rossi D, Salaverria I, Steidl C, Treon SP, Zelenetz AD, Advani RH, Allen CE, Ansell SM, Chan WC, Cook JR, Cook LB, d’Amore F, Dirnhofer S, Dreyling M, Dunleavy K, Feldman AL, Fend F, Gaulard P, Ghia P, Gribben JG, Hermine O, Hodson DJ, Hsi ED, Inghirami G, Jaffe ES, Karube K, Kataoka K, Klapper W, Kim WS, King RL, Ko YH, LaCasce AS, Lenz G, Martin-Subero JI, Piris MA, Pittaluga S, Pasqualucci L, Quintanilla-Martinez L, Rodig SJ, Rosenwald A, Salles GA, San-Miguel J, Savage KJ, Sehn LH, Semenzato G, Staudt LM, Swerdlow SH, Tam CS, Trotman J, Vose JM, Weigert O, Wilson WH, Winter JN, Wu CJ, Zinzani PL, Zucca E, Bagg A, Scott DW. Genomic profiling for clinical decision making in lymphoid neoplasms. Blood, 140:2193-2227, 2022

18. Inamoto Y, Takeda W, Hirakawa T, Sakaguchi H, Nakano N, Uchida N, Doki N, Ikegame K, Katayama Y, Sawa M, Kuriyama T, Hiramoto N, Ota S, Ozawa Y, Kataoka K, Kanda Y, Hino M, Kimura T, Atsuta Y, Fukuda T, Nagafuji K. Adenovirus disease after hematopoietic cell transplantation: A Japanese transplant registry analysis. American journal of hematology, 97:1568-1579, 2022

19. Kameda T, Shide K, Kamiunten A, Kogure Y, Morishita D, Koya J, Tahira Y, Akizuki K, Yokomizo-Nakano T, Kubota S, Marutsuka K, Sekine M, Hidaka T, Kubuki Y, Kitai Y, Matsuda T, Yoda A, Ohshima T, Sugiyama M, Sashida G, Kataoka K, Ogawa S, Shimoda K. CARD11 mutation and HBZ expression induce lymphoproliferative disease and adult T-cell leukemia/lymphoma. Communications biology, 5:1309, 2022

20. Shiroshita K, Kobayashi H, Watanuki S, Karigane D, Sorimachi Y, Fujita S, Tamaki S, Haraguchi M, Itokawa N, Aoyoama K, Koide S, Masamoto Y, Kobayashi K, Nakamura-Ishizu A, Kurokawa M, Iwama A, Okamoto S, Kataoka K, Takubo K. A culture platform to study quiescent hematopoietic stem cells following genome editing. Cell reports methods, 2:100354, 2022