Annual Report 2017

Keisuke Kataoka, Yasunori Kogure, Shizue Ichimura, Miki Sagou, Fumie Ueki

Introduction

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

1) Genetically dissect the molecular pathogenesis of human cancers.

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

3)  Establish clinical relevance of genetic alterations.

Our 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; 47(11):1304-15). 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; 534(7607):402-6).

Research activities

 Recently, we investigated clinical relevance of genetic alterations in ATL, and found that aggressive (acute/lymphoma) subtypes were associated with TP53 and IRF4 mutations, whereas STAT3 mutations were more characteristic of indolent ATL. In addition, several genetic alterations, such as PD-L1 amplifications, were independently associated with worse outcome in aggressive and indolent ATL. Therefore, ATL subtypes are further classified into molecularly distinct subsets with different prognosis. Genetic

profiling might contribute to improved prognostication and management of ATL patients (K

Kataoka et al., Blood. 2018; 131(2):215-25).

Future prospects

 As shown in the ATL project, we aim to delineate the entire picture of genetic aberrations in human cancers using NGS. On the basis of 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 cancer precision medicine.

List of papers published in January 2017 - March 2018

Journal

1. Kogure Y, Kataoka K. Genetic alterations in adult T-cell leukemia/lymphoma. Cancer Sci, 108:1719-1725, 2017

2. Miyauchi M, Koya J, Arai S, Yamazaki S, Honda A, Kataoka K, Yoshimi A, Taoka K, Kumano K, Kurokawa M. ADAM8 Is an Antigen of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia Cells Identified by Patient-Derived Induced Pluripotent Stem Cells. Stem Cell Reports, 10:1115-1130, 2018

3. Vallois D, Dupuy A, Lemonnier F, Allen G, Missiaglia E, Fataccioli V, Ortonne N, Clavert A, Delarue R, Rousselet MC, Fabiani B, Llamas-Gutierrez F, Ogawa S, Thome M, Ko YH, Kataoka K, Gaulard P, de Leval L. RNA fusions involving CD28 are rare in peripheral T-Cell lymphomas and concentrate mainly in those derived from follicular helper T cells. Haematologica, 2018

4. Kataoka K, Iwanaga M, Yasunaga JI, Nagata Y, Kitanaka A, Kameda T, Yoshimitsu M, Shiraishi Y, Sato-Otsubo A, Sanada M, Chiba K, Tanaka H, Ochi Y, Aoki K, Suzuki H, Shiozawa Y, Yoshizato T, Sato Y, Yoshida K, Nosaka K, Hishizawa M, Itonaga H, Imaizumi Y, Munakata W, Shide K, Kubuki Y, Hidaka T, Nakamaki T, Ishiyama K, Miyawaki S, Ishii R, Nureki O, Tobinai K, Miyazaki Y, Takaori-Kondo A, Shibata T, Miyano S, Ishitsuka K, Utsunomiya A, Shimoda K, Matsuoka M, Watanabe T, Ogawa S. Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma. Blood, 131:215-225, 2018

5. Sakai H, Hosono N, Nakazawa H, Przychodzen B, Polprasert C, Carraway HE, Sekeres MA, Radivoyevitch T, Yoshida K, Sanada M, Yoshizato T, Kataoka K, Nakagawa MM, Ueno H, Nannya Y, Kon A, Shiozawa Y, Takeda J, Shiraishi Y, Chiba K, Miyano S, Singh J, Padgett RA, Ogawa S, Maciejewski JP, Makishima H. A novel genetic and morphologic phenotype of ARID2-mediated myelodysplasia. Leukemia, 32:839-843, 2018

6. Kon A, Yamazaki S, Nannya Y, Kataoka K, Ota Y, Nakagawa MM, Yoshida K, Shiozawa Y, Morita M, Yoshizato T, Sanada M, Nakayama M, Koseki H, Nakauchi H, Ogawa S. Physiological Srsf2 P95H expression causes impaired hematopoietic stem cell functions and aberrant RNA splicing in mice. Blood, 131:621-635, 2018

7. Isobe T, Seki M, Yoshida K, Sekiguchi M, Shiozawa Y, Shiraishi Y, Kimura S, Yoshida M, Inoue Y, Yokoyama A, Kakiuchi N, Suzuki H, Kataoka K, Sato Y, Kawai T, Chiba K, Tanaka H, Shimamura T, Kato M, Iguchi A, Hama A, Taguchi T, Akiyama M, Fujimura J, Inoue A, Ito T, Deguchi T, Kiyotani C, Iehara T, Hosoi H, Oka A, Sanada M, Tanaka Y, Hata K, Miyano S, Ogawa S, Takita J. Integrated Molecular Characterization of the Lethal Pediatric Cancer Pancreatoblastoma. Cancer Res, 78:865-876, 2018

8. Aoki K, Nakamura H, Suzuki H, Matsuo K, Kataoka K, Shimamura T, Motomura K, Ohka F, Shiina S, Yamamoto T, Nagata Y, Yoshizato T, Mizoguchi M, Abe T, Momii Y, Muragaki Y, Watanabe R, Ito I, Sanada M, Yajima H, Morita N, Takeuchi I, Miyano S, Wakabayashi T, Ogawa S, Natsume A. Prognostic relevance of genetic alterations in diffuse lower-grade gliomas. Neuro Oncol, 20:66-77, 2018