Department of Clinical Genomics

Hitoshi Ichikawa, Fumie Hosoda, Sachiyo Mitani, Shizuka Shinohara, Erika Arakawa, Fumito Yamazaki, Masaya Sekimizu, Ayano Doi

Introduction

The aim of the Department of Clinical Genomics is to contribute to realize precision medicine for cancer patients based on the molecular profiles of their malignancies. To this end, we have developed a next-generation sequencing (NGS)-based genomic testing system using original gene panels. In addition, we are working on the identification of novel biomarkers and therapeutic targets for several types of malignancies by the use of NGS technologies.

Research activities

1.Development of an original NGS-based genomic testing system

We developed an NGS-based in-house genomic testing system, and have been continuously improving this system to become an accurate and clinically useful in vitro diagnostics (IVD) system. In this system, an original cancer gene panel (NCC oncopanel) has been designed and used. With this gene panel, mutations and amplifications of ~100 genes and fusions of ~10 genes can be accurately identified from FFPE tumor tissue samples. In 2016, we renewed our gene panel (NCC oncopanel v4), and supported the TOPICS-2 study, in which our system was used as a clinical test with quality assurance to detect actionable genetic alterations for cancer patients.

2.Identification of novel biomarkers and therapeutic targets

Through the use of NGS, we are searching novel biomarkers and therapeutic targets for sarcoma, gastric cancer, and pediatric cancer. In 2016, we detected a novel candidate of therapeutic targets for well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS). WDLPS and DDLPS are closely related tumors commonly characterized by MDM2/CDK4 gene amplification, and lack clinically effective treatment options when inoperable. We performed NGS analysis of 19 WDLPS and 37 DDLPS tumor samples using NCC oncopanel v3, and found that these sarcomas had very few gene mutations and a high frequency of amplifications of not only MDM2 and CDK4 but also other genes. Potential driver mutations were found in only 11% samples; however, gene amplification events (other than MDM2 and CDK4 amplification) were identified in 54% of the samples. Receptor tyrosine kinase (RTK) genes in particular were amplified in 32% of the samples. In addition, we found that growth of a WDLPS cell line with IGF1R amplification was suppressed by simultaneous inhibition of CDK4 and IGF1R. These results suggest that combination therapy with CDK4 and RTK inhibitors may be an effective therapeutic option for WDLPS/DDLPS patients with RTK gene amplification.

3.Target sequencing services

We provided target sequencing services using our original genomic testing system with NCC oncopanel and commercially available cancer panel systems, upon requests from researchers in the NCC-Research Institute, the NCC-Hospitals, and the NCC-Hospital East. In 2016, more than 500 samples from various types of cancers were analyzed.

List of papers published in 2016

Journal

1.Ezawa I, Sawai Y, Kawase T, Okabe A, Tsutsumi S, Ichikawa H, Kobayashi Y, Tashiro F, Namiki H, Kondo T, Semba K, Aburatani H, Taya Y, Nakagama H, Ohki R. Novel p53 target gene FUCA1 encodes a fucosidase and regulates growth and survival of cancer cells. Cancer Sci, 107:734-745, 2016

2.Shiba N, Ohki K, Kobayashi T, Hara Y, Yamato G, Tanoshima R, Ichikawa H, Tomizawa D, Park M-J, Shimada A, Sotomatsu M, Arakawa H, Horibe K, Adachi S, Taga T, Tawa A, Hayashi Y. High PRDM16 expression identifies a prognostic subgroup of pediatric acute myeloid leukaemia correlated to FLT3-ITD, KMT2A-PTD, and NUP98-NSD1: the results of the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 trial. Br J Haematol, 172:581-591, 2016

3.Asano Y, Kawase T, Okabe A, Tsutsumi S, Ichikawa H, Tatebe S, Kitabayashi I, Tashiro F, Namiki H, Kondo T, Semba K, Aburatani H, Taya Y, Nakagama H, Ohki R. IER5 generates a novel hypo-phosphorylated active form of HSF1 and contributes to tumorigenesis. Sci Rep, 6:19174, 2016

4.Seki Y, Fujiwara Y, Kohno T, Takai E, Sunami K, Goto Y, Horinouchi H, Kanda S, Nokihara H, Watanabe S, Ichikawa H, Yamamoto N, Kuwano K, Ohe Y. Picoliter-Droplet Digital Polymerase Chain Reaction-Based Analysis of Cell-Free Plasma DNA to Assess EGFR Mutations in Lung Adenocarcinoma That Confer Resistance to Tyrosine-Kinase Inhibitors. Oncologist, 21:156-164, 2016

5.Asao T, Fujiwara Y, Sunami K, Kitahara S, Goto Y, Kanda S, Horinouchi H, Nokihara H, Yamamoto N, Ichikawa H, Kohno T, Tsuta K, Watanabe S, Takahashi K, Ohe Y. Medical treatment involving investigational drugs and genetic profile of thymic carcinoma. Lung Cancer, 93:77-81, 2016

6.Tanabe Y, Ichikawa H, Kohno T, Yoshida H, Kubo T, Kato M, Iwasa S, Ochiai A, Yamamoto N, Fujiwara Y, Tamura K. Comprehensive screening of target molecules by next-generation sequencing in patients with malignant solid tumors: guiding entry into phase I clinical trials. Mol Cancer, 15:73, 2016