Division of Genetics

Teruhiko Yoshida, Hiromi Sakamoto, Hitoshi Zenbutsu, Bunsyo Shiotani, Mineko Ushiama, Yoko Odaka, Misuzu Tsukamoto, Marianne Mazevet Hanae, Masumi Shimizu, Sayaka Mito, Tomoko Ikegami, Akiko Sakamoto, Hitomi Gunji, Noriko Abe, Hiroo Takahashi, Naoya Hayashida

Introduction

According to the organization regulations of the National Cancer Center (NCC), the missions of the Division of Genetics are the analyses and other research on the genetic and genomic germline information related to cancer. Needless to say, however, it is often crucial to deploy the germline investigation in close conjunction with somatic information and insight. In fact, historically, the origin of our division stems from the oncogene research in the 1980s.

Our team and what we do

In 2016, the major research themes of our division were 1) molecular understanding of cancer susceptibility, 2) pharmacogenomics research on cancer treatment, and 3) elucidation of the mechanism underlying DNA replication stress response and genomic instability. Drs. Yoshida and Sakamoto were involved in the theme 1), Drs. Zenbutsu and Shiotani led the themes 2) and 3), respectively.

Research activities

1.Molecular understanding of cancer susceptibility

As a long-standing collaboration with the Institute of Physical and Chemical Research (RIKEN) and the BioBank Japan (BBJ), a genome-wide association study (GWAS) for gastric cancer was performed based on the latest SNP array and imputation method. The initial screening step analyzed 8,877 gastric cancer cases in BBJ and 32,452 controls from several genome epidemiological cohorts in Japan followed by multiple replication steps including patients in the NCC. In addition to the two major susceptibility genes for diffuse type gastric cancer, PSCA and MUC1, which were identified before in our division, three novel loci have been identified.

2.Pharmacogenomics research on cancer treatment

A combination of retrospective and prospective observational studies was launched to identify germline genetic and plasma metabolome factors involved in serious adverse events in the cancer chemotherapy by molecular target agents. The study is a collaboration with RIKEN and the National Institute of Health Sciences (NIHS).

3.Elucidation of the mechanism underlying DNA replication stress response and genomic instability:

A functional analysis of ATR kinase that regulates DNA replication stress was performed. A lung adenocarcinoma model has been established by introducing the mutant K-ras gene, which is known as a driver gene in about 15% of Japanese lung adenocarcinoma cases, into normal lung epithelial cells. In the cells with high ATR expression, DNA replication stress was suppressed. ATR upregulation further promoted cell proliferation and acquisition of anchorage independent growth potential. This suggested that ATR kinase has a function different from well-known tumor suppressing ability. The IC50 value of ATR inhibitor against lung adenocarcinoma cells with different genetic background correlated well with the DNA replication stress levels of individual cells. Based on these findings, we are conducting a comprehensive analysis of ATR specific substrates in order to analyze the novel function of ATR kinase which plays an important role in tumor development and the maintenance of cancer cell survival.

Clinical trials

The Division of Gnetics did not host clinical intervention trials.

Education

The Division of Gnetics accepted an undergraduate student from Chiba University and supervised graduation and thesis research.

Future prospects

2016 is the final year of our division as the current team. The theme 1) will focus more on the hereditary cancer syndromes in the context of germline genomic medicine, which will be promoted as a collaboration between the NCC Hospital and genome core facility of the NCC Research Institute. Dr. Zenbutsu, who is the principal investigator of the theme 2), moved to the Japanese Foundation for Cancer Research in 2016 but will continue the project as a collaboration with the NCC. As regards the theme 3), Dr. Shiotani will focus on DNA replication stress as a hallmark of cancer. Based on the functional analysis of ATR kinase essential for DNA replication stress response and the identification of its specific substrate, his team attempts to elucidate the mechanism against replication stress in cancer cells and illuminate carcinogenesis and create a novel molecular targeted drug specifically works on cancer cells.

List of papers published in 2016

Journal

1.Shiraishi K, Okada Y, Takahashi A, Kamatani Y, Momozawa Y, Ashikawa K, Kunitoh H, Matsumoto S, Takano A, Shimizu K, Goto A, Tsuta K, Watanabe S, Ohe Y, Watanabe Y, Goto Y, Nokihara H, Furuta K, Yoshida A, Goto K, Hishida T, Tsuboi M, Tsuchihara K, Miyagi Y, Nakayama H, Yokose T, Tanaka K, Nagashima T, Ohtaki Y, Maeda D, Imai K, Minamiya Y, Sakamoto H, Saito A, Shimada Y, Sunami K, Saito M, Inazawa J, Nakamura Y, Yoshida T, Yokota J, Matsuda F, Matsuo K, Daigo Y, Kubo M, Kohno T. Association of variations in HLA class II and other loci with susceptibility to EGFR-mutated lung adenocarcinoma. Nat Commun, 7:12451, 2016

2.Sugano K, Nakajima T, Sekine S, Taniguchi H, Saito S, Takahashi M, Ushiama M, Sakamoto H, Yoshida T. Germline PMS2 mutation screened by mismatch repair protein immunohistochemistry of colorectal cancer in Japan. Cancer Sci, 107:1677-1686, 2016

3.Tanaka M, Nakajima T, Sugano K, Yoshida T, Taniguchi H, Kanemitsu Y, Nagino M, Sekine S. Mismatch repair deficiency in Lynch syndrome-associated colorectal adenomas is more prevalent in older patients. Histopathology, 69:322-328, 2016

4.Budhathoki S, Yamaji T, Iwasaki M, Sawada N, Shimazu T, Sasazuki S, Yoshida T, Tsugane S. Vitamin D Receptor Gene Polymorphism and the Risk of Colorectal Cancer: A Nested Case-Control Study. PLoS One, 11:e0164648, 2016

5.Inoki K, Nakajima T, Sekine S, Sugano K, Tsukamoto S, Yamada M, Mutoh M, Sakamoto T, Matsuda T, Sekiguchi M, Ushiama M, Yoshida T, Sakamoto H, Kanemitsu Y, Saito Y. Depressed-type submucosal invasive colorectal cancer in a patient with Lynch syndrome diagnosed using short-interval colonoscopy. Dig Endosc, 28:749-754, 2016

6.Tanakaya K, Yamaguchi T, Ishikawa H, Hinoi T, Furukawa Y, Hirata K, Saida Y, Shimokawa M, Arai M, Matsubara N, Tomita N, Tamura K, Sugano K, Ishioka C, Yoshida T, Ishida H, Watanabe T, Sugihara K. Causes of Cancer Death Among First-Degree Relatives in Japanese Families with Lynch Syndrome. Anticancer Res, 36:1985-1989, 2016

7.Uchino S, Ishikawa H, Miyauchi A, Hirokawa M, Noguchi S, Ushiama M, Yoshida T, Michikura M, Sugano K, Sakai T. Age- and Gender-Specific Risk of Thyroid Cancer in Patients With Familial Adenomatous Polyposis. J Clin Endocrinol Metab, 101:4611-4617, 2016

8.Shimomura A, Shiino S, Kawauchi J, Takizawa S, Sakamoto H, Matsuzaki J, Ono M, Takeshita F, Niida S, Shimizu C, Fujiwara Y, Kinoshita T, Tamura K, Ochiya T. Novel combination of serum microRNA for detecting breast cancer in the early stage. Cancer Sci, 107:326-334, 2016

9.Kanemoto K, Fukuta K, Kawai N, Tozawa K, Ochiai M, Okamoto K, Ohnami S, Sakamoto H, Yoshida T, Kanai Y, Katoh M, Yasui T, Kohri K, Kakizoe T, Nakagama H. Genomic Landscape of Experimental Bladder Cancer in Rodents and Its Application to Human Bladder Cancer: Gene Amplification and Potential Overexpression of Cyp2a5/CYP2A6 Are Associated with the Invasive Phenotype. PLoS One, 11:e0167374, 2016

Book

1.Shintani B, Zou L. Signaling of DNA Replication Stress Through the ATR Checkpoint. In: Hanaoka F, Sugasawa K (eds), DNA Replication, Recombination, and Repair - Molecular Mechanisms and Pathology, pp 405-428, 2016