Annual Report 2020

Division of Molecular Oncology

Keisuke Kataoka, Junji Koya, Yasunori Kogure, Sumito Shingaki, Marni B. Siegel McClure, Yuki Saito, Mariko Tabata, Kota Yoshifuji, Yuta Ito, Mitsuhiro Yuasa, Kentaro Yamaguchi, Yuji Kumade, Hirokazu Kariyazono, Yoshiya Kikukawa, Yoko Hokama, Yoshiko Ito, Fumie Ueki

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 various cancers, especially hematologic malignancy, using NGS. By combining genomics with molecular and functional approaches, we aim to achieve the following:

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.

The Team and What We Do

 Using the above-mentioned approaches, in recent years, we have revealed the genetic portrait of adult T-cell leukemia/lymphoma (ATL) (K Kataoka et al., Nat Genet. 2015). In addition, by performing pan-cancer analysis based on this study, we identified PD-L1 genetic alterations leading to cancer immune evasion in a wide variety of cancers (K Kataoka et al., Nature. 2016). Furthermore, we performed another pan-cancer analysis and identified a new mechanism whereby multiple mutations in the same oncogene cooperatively drive oncogenesis (Y Saito, et al., Nature. 2020). Recently, we have developed a new analytical technique, enabling the combined analysis of the transcriptome, cell surface markers, and T-cell/B-cell receptor repertoires at a single-cell level.

Research activities

 Through pan-cancer analysis, we have discovered that multiple mutations (MMs) are commonly observed in several oncogenes. These were particularly prominent in the PIK3CA and EGFR genes, in which 10% of the mutated samples carried MMs respectively. Most of these MMs were located on the same side of the chromosome (in cis). Minor (infrequent) mutations were preferentially selected in MMs. Individually, these minor mutations were functionally weak, but synergistically, they exhibited stronger oncogenic potential. Samples with PIK3CA MMs showed enhanced downstream pathway activation and higher dependency on the mutated gene itself. They also showed higher sensitivity to specific inhibitors. The results of this study show that MMs within individual oncogenes serve as a novel genetic mechanism in cancer pathogenesis, and also provide an explanation as to why functionally weak minor mutations accumulate in cancer (Y Saito, et al., Nature. 2020).

 In addition, we have performed a single-cell transcriptome, surface protein, and T/B-cell receptor analysis to phenotypically characterize premalignant cells in human T-cell leukemia virus type-1 (HTLV-1) infection and the multicellular ecosystem in HTLV-1-induced ATL. We distinguished malignant phenotypes caused by HTLV-1 infection and ATL leukemogenesis and dissected clonal evolution of malignant cells with varying clinical behavior. Within HTLV-1-infected cells, a highly suppressive regulatory T-cell phenotype promotes premalignant clonal expansion. We also delineated differences between virus- and tumor-related microenvironmental changes, including tumor-specific myeloid propagation. Our multi-modal single-cell data provides insights into clonal evolution and the immune landscape of multi-step virus carcinogenesis.

Future Prospects

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

List of papers published in 2020

Journal

1. Shimada K, Yoshida K, Suzuki Y, Iriyama C, Inoue Y, Sanada M, Kataoka K, Yuge M, Takagi Y, Kusumoto S, Masaki Y, Ito T, Inagaki Y, Okamoto A, Kuwatsuka Y, Nakatochi M, Shimada S, Miyoshi H, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Shiozawa Y, Nannya Y, Okabe A, Kohno K, Atsuta Y, Ohshima K, Nakamura S, Ogawa S, Tomita A, Kiyoi H. Frequent genetic alterations in immune checkpoint-related genes in intravascular large B-cell lymphoma. Blood, 137:1491-1502, 2021

2. Boons E, Nogueira TC, Dierckx T, Menezes SM, Jacquemyn M, Tamir S, Landesman Y, Farré L, Bittencourt A, Kataoka K, Ogawa S, Snoeck R, Andrei G, Van Weyenbergh J, Daelemans D. XPO1 inhibitors represent a novel therapeutic option in Adult T-cell Leukemia, triggering p53-mediated caspase-dependent apoptosis. Blood Cancer J, 11:27, 2021

3. Saito Y, Koya J, Kataoka K. Multiple mutations within individual oncogenes. Cancer Sci, 112:483-489, 2021

4. Ito J, Nakano Y, Shima H, Miwa T, Kogure Y, Isshiki K, Yamazaki F, Oishi Y, Morimoto Y, Kataoka K, Okita H, Hirato J, Ichimura K, Shimada H. Central nervous system ganglioneuroblastoma harboring MYO5A-NTRK3 fusion. Brain Tumor Pathol, 37:105-110, 2020

5. Kubota Y, Seki M, Kawai T, Isobe T, Yoshida M, Sekiguchi M, Kimura S, Watanabe K, Sato-Otsubo A, Yoshida K, Suzuki H, Kataoka K, Fujii Y, Shiraishi Y, Chiba K, Tanaka H, Hiwatari M, Oka A, Hayashi Y, Miyano S, Ogawa S, Hata K, Tanaka Y, Takita J. Comprehensive genetic analysis of pediatric germ cell tumors identifies potential drug targets. Commun Biol, 3:544, 2020

6. Kataoka K, Koya J. Clinical application of genomic aberrations in adult T-cell leukemia/lymphoma. J Clin Exp Hematop, 60:66-72, 2020

7. Ueno H, Yoshida K, Shiozawa Y, Nannya Y, Iijima-Yamashita Y, Kiyokawa N, Shiraishi Y, Chiba K, Tanaka H, Isobe T, Seki M, Kimura S, Makishima H, Nakagawa MM, Kakiuchi N, Kataoka K, Yoshizato T, Nishijima D, Deguchi T, Ohki K, Sato A, Takahashi H, Hashii Y, Tokimasa S, Hara J, Kosaka Y, Kato K, Inukai T, Takita J, Imamura T, Miyano S, Manabe A, Horibe K, Ogawa S, Sanada M. Landscape of driver mutations and their clinical impacts in pediatric B-cell precursor acute lymphoblastic leukemia. Blood Adv, 4:5165-5173, 2020

8. Yamashita D, Shimada K, Kohno K, Kogure Y, Kataoka K, Takahara T, Suzuki Y, Satou A, Sakakibara A, Nakamura S, Asano N, Kato S. PD-L1 expression on tumor or stromal cells of nodal cytotoxic T-cell lymphoma: A clinicopathological study of 50 cases. Pathol Int, 70:513-522, 2020

9. Secardin L, Limia CEG, di Stefano A, Bonamino MH, Saliba J, Kataoka K, Rehen SK, Raslova H, Marty C, Ogawa S, Vainchenker W, Monte-Mor BDCR, Plo I. TET2 haploinsufficiency alters reprogramming into induced pluripotent stem cells. Stem Cell Res, 44:101755, 2020

10. Saito Y, Koya J, Araki M, Kogure Y, Shingaki S, Tabata M, McClure MB, Yoshifuji K, Matsumoto S, Isaka Y, Tanaka H, Kanai T, Miyano S, Shiraishi Y, Okuno Y, Kataoka K. Landscape and function of multiple mutations within individual oncogenes. Nature, 582:95-99, 2020

11. Ochi Y, Kon A, Sakata T, Nakagawa MM, Nakazawa N, Kakuta M, Kataoka K, Koseki H, Nakayama M, Morishita D, Tsuruyama T, Saiki R, Yoda A, Okuda R, Yoshizato T, Yoshida K, Shiozawa Y, Nannya Y, Kotani S, Kogure Y, Kakiuchi N, Nishimura T, Makishima H, Malcovati L, Yokoyama A, Takeuchi K, Sugihara E, Sato TA, Sanada M, Takaori-Kondo A, Cazzola M, Kengaku M, Miyano S, Shirahige K, Suzuki HI, Ogawa S. Combined Cohesin-RUNX1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes. Cancer Discov, 10:836-853, 2020

12. Yasuda T, Sanada M, Nishijima D, Kanamori T, Iijima Y, Hattori H, Saito A, Miyoshi H, Ishikawa Y, Asou N, Usuki K, Hirabayashi S, Kato M, Ri M, Handa H, Ishida T, Shibayama H, Abe M, Iriyama C, Karube K, Nishikori M, Ohshima K, Kataoka K, Yoshida K, Shiraishi Y, Goto H, Adachi S, Kobayashi R, Kiyoi H, Miyazaki Y, Ogawa S, Kurahashi H, Yokoyama H, Manabe A, Iida S, Tomita A, Horibe K. Clinical utility of target capture-based panel sequencing in hematological malignancies: A multicenter feasibility study. Cancer Sci, 111:3367-3378, 2020

13. Fukumoto K, Sakata-Yanagimoto M, Fujisawa M, Sakamoto T, Miyoshi H, Suehara Y, Nguyen TB, Suma S, Yanagimoto S, Shiraishi Y, Chiba K, Bouska A, Kataoka K, Ogawa S, Iqbal J, Ohshima K, Chiba S. VAV1 mutations contribute to development of T-cell neoplasms in mice. Blood, 136:3018-3032, 2020

14. Jo T, Nishikori M, Kogure Y, Arima H, Sasaki K, Sasaki Y, Nakagawa T, Iwai F, Momose S, Shiraishi A, Kiyonari H, Kagaya N, Onuki T, Shin-Ya K, Yoshida M, Kataoka K, Ogawa S, Iwai K, Takaori-Kondo A. LUBAC accelerates B-cell lymphomagenesis by conferring resistance to genotoxic stress on B cells. Blood, 136:684-697, 2020

15. Sekiguchi M, Seki M, Kawai T, Yoshida K, Yoshida M, Isobe T, Hoshino N, Shirai R, Tanaka M, Souzaki R, Watanabe K, Arakawa Y, Nannya Y, Suzuki H, Fujii Y, Kataoka K, Shiraishi Y, Chiba K, Tanaka H, Shimamura T, Sato Y, Sato-Otsubo A, Kimura S, Kubota Y, Hiwatari M, Koh K, Hayashi Y, Kanamori Y, Kasahara M, Kohashi K, Kato M, Yoshioka T, Matsumoto K, Oka A, Taguchi T, Sanada M, Tanaka Y, Miyano S, Hata K, Ogawa S, Takita J. Integrated multiomics analysis of hepatoblastoma unravels its heterogeneity and provides novel druggable targets. NPJ Precis Oncol, 4:20, 2020

16. Matsukawa T, Yamamoto T, Honda A, Toya T, Ishiura H, Mitsui J, Tanaka M, Hao A, Shinohara A, Ogura M, Kataoka K, Seo S, Kumano K, Hosoi M, Narukawa K, Yasunaga M, Maki H, Ichikawa M, Nannya Y, Imai Y, Takahashi T, Takahashi Y, Nagasako Y, Yasaka K, Mano KK, Matsukawa MK, Miyagawa T, Hamada M, Sakuishi K, Hayashi T, Iwata A, Terao Y, Shimizu J, Goto J, Mori H, Kunimatsu A, Aoki S, Hayashi S, Nakamura F, Arai S, Momma K, Ogata K, Yoshida T, Abe O, Inazawa J, Toda T, Kurokawa M,2 Tsuji S. Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy. Brain Commun, 2:fcz048, 2020