Annual Report 2019

Division of Molecular Oncology

Keisuke Kataoka, Junji Koya, Yasunori Kogure, Sumito Shingaki, Marni B. Siegel McClure, Yuki Saito, Mariko Tabata, Kota Yoshifuji, Yuji Kumade, Hirokazu Kariyazono, Yoko Hokama, Yoshiko Ito, Miki Sagou, Fumie Ueki, Yoko Hokama

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:

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 have recently 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).

Research activities

 It had long been believed that oncogenes gain tumor-promoting functions by acquiring single mutations individually, but we have discovered that multiple mutations (MMs) are commonly observed in several oncogenes. They were particularly prominent in PIK3CA and EGFR genes, in each of which 10% of the mutated samples carried MMs. 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, also providing an explanation for why functionally weak minor mutations are accumulated in cancer. In addition, MMs in oncogenes can be exploited as a biomarker for predicting the benefits of molecular targeted therapies. Therefore, the application of our findings to cancer precision medicine is anticipated (Y Saito, et al., Nature. 2020).

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 can help cancer precision medicine.

List of papers published in 2019

Journal

1. Sugiyama E, Togashi Y, Takeuchi Y, Shinya S, Tada Y, Kataoka K, Tane K, Sato E, Ishii G, Goto K, Shintani Y, Okumura M, Tsuboi M, Nishikawa H. Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR-mutated non-small cell lung cancer. Sci Immunol, 5:eaav3937. doi: 10.1126/sciimmunol.aav3937, 2020

2. Akizuki K, Sekine M, Kogure Y, Kameda T, Shide K, Koya J, Kamiunten A, Kubuki Y, Tahira Y, Hidaka T, Kiwaki T, Tanaka H, Sato Y, Kataoka H, Kataoka K, Shimoda K. TP53 and PTEN mutations were shared in concurrent germ cell tumor and acute megakaryoblastic leukemia. BMC Cancer, 20:5, 2020

3. Kakiuchi N, Yoshida K, Uchino M, Kihara T, Akaki K, Inoue Y, Kawada K, Nagayama S, Yokoyama A, Yamamoto S, Matsuura M, Horimatsu T, Hirano T, Goto N, Takeuchi Y, Ochi Y, Shiozawa Y, Kogure Y, Watatani Y, Fujii Y, Kim SK, Kon A, Kataoka K, Yoshizato T, Nakagawa MM, Yoda A, Nanya Y, Makishima H, Shiraishi Y, Chiba K, Tanaka H, Sanada M, Sugihara E, Sato TA, Maruyama T, Miyoshi H, Taketo MM, Oishi J, Inagaki R, Ueda Y, Okamoto S, Okajima H, Sakai Y, Sakurai T, Haga H, Hirota S, Ikeuchi H, Nakase H, Marusawa H, Chiba T, Takeuchi O, Miyano S, Seno H, Ogawa S. Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis. Nature, 577:260-265, 2020

4. 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 BCR, Plo I. TET2 haploinsufficiency alters reprogramming into induced pluripotent stem cells. Stem Cell Res, 44:101755. doi: 10.1016/j.scr.2020.101755, 2020

5. Kubota Y, Uryu K, Ito T, Seki M, Kawai T, Isobe T, Kumagai T, Toki T, Yoshida K, Suzuki H, Kataoka K, Shiraishi Y, Chiba K, Tanaka H, Ohki K, Kiyokawa N, Kagawa J, Miyano S, Oka A, Hayashi Y, Ogawa S, Terui K, Sato A, Hata K, Ito E, Takita J. Integrated genetic and epigenetic analysis revealed heterogeneity of acute lymphoblastic leukemia in Down syndrome. Cancer Sci, 110:3358-3367, 2019

6. Watatani Y, Sato Y, Miyoshi H, Sakamoto K, Nishida K, Gion Y, Nagata Y, Shiraishi Y, Chiba K, Tanaka H, Zhao L, Ochi Y, Takeuchi Y, Takeda J, Ueno H, Kogure Y, Shiozawa Y, Kakiuchi N, Yoshizato T, Nakagawa MM, Nanya Y, Yoshida K, Makishima H, Sanada M, Sakata-Yanagimoto M, Chiba S, Matsuoka R, Noguchi M, Hiramoto N, Ishikawa T, Kitagawa J, Nakamura N, Tsurumi H, Miyazaki T, Kito Y, Miyano S, Shimoda K, Takeuchi K, Ohshima K, Yoshino T, Ogawa S, Kataoka K. Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling. Leukemia, 33:2867-2883, 2019