Annual Report 2021
Division of Molecular Oncology
Keisuke Kataoka, Junji Koya, Yasunori Kogure, Sumito Shingaki, Yuki Saito, Mariko Tabata, Fumie Ueki, Yoko Hokama, Yoshiko Ito, Koichi Murakami, Yuta Ito, Mitsuhiro Yuasa, Kentaro Yamaguchi, Sara Horie, Tomohiko Tanigawa, Kota Mizuno, Zen Tamura, Yoshiya Kikukawa
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 malignancies using NGS. By combining genomics with molecular and functional approaches, 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.
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). Recently, we have developed a new analytical technique enabling the combined analysis of transcriptome, cell surface markers, and T-cell/B-cell receptor repertoires at a single-cell level and characterization of premalignant cells in human T-cell leukemia virus type-1 (HTLV-1) infection and the multicellular ecosystem in HTLV-1-induced ATL (J Koya et al., Blood Cancer Discov. 2021). In addition, we have performed whole-genome sequencing (WGS) of 150 ATL cases to reveal the overarching landscape of genetic alterations in ATL (Y Kogure et al., Blood. 2020).
Research activities
We have performed single-cell transcriptome, surface protein, and T/B-cell receptor analysis to phenotypically characterize premalignant cells in 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 the clonal evolution of malignant cells with different 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 the clonal evolution and immune landscape of multi-step virus carcinogenesis.
In addition, we performed WGS of 150 ATL cases to reveal the overarching landscape of genetic alterations in ATL. We discovered frequent (33%) loss-of-function alterations preferentially targeting the CIC long isoform. Long but not short isoform-specific inactivation of Cic selectively increased CD4+CD25+Foxp3+ T cells in vivo. We also found recurrent (13%) truncations of REL, which induce transcriptional upregulation and generate gain-of-function proteins. In the non-coding genome, we identified recurrent mutations in regulatory elements, particularly splice sites, of several driver genes. By combining the analyses for coding and noncoding mutations, structural variations, and copy number alterations, we discovered 56 recurrently altered driver genes, including 11 novel ones. Finally, ATL cases were classified into 2 molecular groups with distinct clinical and genetic characteristics based on the driver alteration profile. Our findings will not only help to improve diagnostic and therapeutic strategies in ATL, but also provide insights into T-cell biology and have implications for genome-wide cancer driver discovery.
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 the clinical significance of these alterations, which will help cancer precision medicine.
List of papers published in 2021
Journal
1. Kuno M, Yamasaki S, Fujii N, Ishida Y, Fukuda T, Kataoka K, Uchida N, Katayama Y, Sato M, Onai D, Miyamoto T, Ota S, Yoshioka S, Ara T, Hangaishi A, Hashii Y, Onizuka M, Ichinohe T, Atsuta Y, Inamoto Y. Characterization of myeloid neoplasms following allogeneic hematopoietic cell transplantation. American journal of hematology, 97:185-193, 2022
2. Imahashi N, Terakura S, Kondo E, Kato K, Kim SW, Shinohara A, Watanabe M, Fukuda T, Uchida N, Kobayashi H, Ishikawa J, Kataoka K, Shiratori S, Ikeda T, Matsuoka KI, Yoshida S, Kondo T, Kimura T, Onizuka M, Ichinohe T, Atsuta Y, Kanda J. Impact of donor types on reduced-intensity conditioning allogeneic stem cell transplant for mature lymphoid malignancies. Bone marrow transplantation, 57:243-251, 2022
3. Kogure Y, Kameda T, Koya J, Yoshimitsu M, Nosaka K, Yasunaga JI, Imaizumi Y, Watanabe M, Saito Y, Ito Y, McClure MB, Tabata M, Shingaki S, Yoshifuji K, Chiba K, Okada A, Kakiuchi N, Nannya Y, Kamiunten A, Tahira Y, Akizuki K, Sekine M, Shide K, Hidaka T, Kubuki Y, Kitanaka A, Hidaka M, Nakano N, Utsunomiya A, Sica RA, Acuna-Villaorduna A, Janakiram M, Shah U, Ramos JC, Shibata T, Takeuchi K, Takaori-Kondo A, Miyazaki Y, Matsuoka M, Ishitsuka K, Shiraishi Y, Miyano S, Ogawa S, Ye BH, Shimoda K, Kataoka K. Whole-genome landscape of adult T-cell leukemia/lymphoma. Blood, 139:967-982, 2022
4. Takatori Y, Kato M, Saito Y, Kataoka K, Yahagi N. Genetically proven multiple tumor cell seeding on the wounds of endoscopic resection from an intramucosal rectal cancer. Gastrointestinal endoscopy, 95:393-395, 2022
5. Sagawa R, Sakata S, Gong B, Seto Y, Takemoto A, Takagi S, Ninomiya H, Yanagitani N, Nakao M, Mun M, Uchibori K, Nishio M, Miyazaki Y, Shiraishi Y, Ogawa S, Kataoka K, Fujita N, Takeuchi K, Katayama R. Soluble PD-L1 works as a decoy in lung cancer immunotherapy via alternative polyadenylation. JCI insight, 7:2022
6. Takeuchi Y, Tanegashima T, Sato E, Irie T, Sai A, Itahashi K, Kumagai S, Tada Y, Togashi Y, Koyama S, Akbay EA, Karasaki T, Kataoka K, Funaki S, Shintani Y, Nagatomo I, Kida H, Ishii G, Miyoshi T, Aokage K, Kakimi K, Ogawa S, Okumura M, Eto M, Kumanogoh A, Tsuboi M, Nishikawa H. Highly immunogenic cancer cells require activation of the WNT pathway for immunological escape. Science immunology, 6:eabc6424, 2021
7. Fujii Y, Sato Y, Suzuki H, Kakiuchi N, Yoshizato T, Lenis AT, Maekawa S, Yokoyama A, Takeuchi Y, Inoue Y, Ochi Y, Shiozawa Y, Aoki K, Yoshida K, Kataoka K, Nakagawa MM, Nannya Y, Makishima H, Miyakawa J, Kawai T, Morikawa T, Shiraishi Y, Chiba K, Tanaka H, Nagae G, Sanada M, Sugihara E, Sato TA, Nakagawa T, Fukayama M, Ushiku T, Aburatani H, Miyano S, Coleman JA, Homma Y, Solit DB, Kume H, Ogawa S. Molecular classification and diagnostics of upper urinary tract urothelial carcinoma. Cancer cell, 39:793-809.e8, 2021
8. Okabe M, Morishita T, Yasuda T, Sakaguchi H, Sanada M, Kataoka K, Ogawa S, Shiraishi Y, Ichiki T, Kawaguchi Y, Ohbiki M, Matsumoto R, Osaki M, Goto T, Ozawa Y, Miyamura K. Targeted deep next generation sequencing identifies potential somatic and germline variants for predisposition to familial Burkitt lymphoma. European journal of haematology, 107:166-169, 2021
9. Koya J, Saito Y, Kameda T, Kogure Y, Yuasa M, Nagasaki J, McClure MB, Shingaki S, Tabata M, Tahira Y, Akizuki K, Kamiunten A, Sekine M, Shide K, Kubuki Y, Hidaka T, Kitanaka A, Nakano N, Utsunomiya A, Togashi Y, Ogawa S, Shimoda K, Kataoka K. Single-Cell Analysis of the Multicellular Ecosystem in Viral Carcinogenesis by HTLV-1. Blood cancer discovery, 2:450-467, 2021