Genetic Medicine and Services
Teruhiko Yoshida, Narikazu Boku, Takayuki Kinoshita, Shimizu Chikako, Mitsuya Ishikawa, Takeshi Nakajima, Shigenobu Suzuki, Tadashi Kumamoto, Shigeki Sekine, Taisuke Mori, Nobuyoshi Hiraoka, Kuniko Sunami, Takahisa Matsuda, Hiromi Sakamoto, Hitoshi Zenbutsu, Mineko Ushiama, Takashi Kohno, Mamoru Kato, Hitoshi Ichikawa, Kokichi Sugano
It has been estimated that roughly 5% of all cancer cases are caused by a highly penetrant monogenic mutation. Major causative genes for most hereditary cancer syndromes were identified in the 1990s, and since then, genetic diagnosis has been considered as a part of standard medical care in oncology clinics. The National Cancer Center Hospital (NCCH) launched the Outpatient Genetic Counseling Clinic in 1998 as a part of collaboration with the Research Institute, especially the Fundamental Innovative Oncology Core (FIOC). However, cancer medical genetics still has a number of issues to be addressed as shown in Figure 1, which is again shown this year with some modifications from the previous year, because it has been the basic set of the agenda of the Department of Genetic Medicine and Services (GeMS).
As shown on the National Cancer Center Hospital (NCCH) Web site the aim and mission of the clinical service of the Outpatient Genetic Counseling Clinic, which is the main routine clinical activity of the Department, are:
- to provide consultation and appropriate medical and genetic information (that is, genetic counseling) to anyone who has a worry related to heredity cancer.
- to provide genetic testing when appropriate.
- to support early diagnosis and treatment based on family history and/or genetic test results.
In 2015, 173 patients and their relatives from 121 families visited the Clinic. In total, 1,414 clients from 955 families have visited the Clinic since its inception in 1998.
Although at least one causative gene has been identified for each of the major hereditary cancer syndromes, overall sensitivity of the current genetic tests is far from 100% and may be around 70-80%, even for the cases that meet clinical and/or screening criteria for hereditary cancer syndromes. The false negative cases may include both inadequate technical sensitivity of the current genetic test methods on the established causative genes (allelic heterogeneity) and also yet-identified genes representing locus heterogeneity. There has been great expectation that the introduction of next generation sequencers (NGS) would change the situation. The staff of the Department of GeMS have established a new Common Protocol to perform NGS-based germline clinical sequencing for patients with negative test results by conventional genetic tests, who would represent a part of the Undiagnosed Disease Patients in the oncology field. The Common Protocol has been adopted by other hospitals and institutions in a long-standing multiinstitute collaborative research group based on the National Cancer Center Research and Development Fund and its predecessor. In addition to whole exome sequencing (WES), a multi-gene panel has been developed based on Agilent SureSelect technology.
The Outpatient Genetic Counseling Clinic has participated in a prospective clinical study to optimize BRCA1/2 genetic tests and a clinical trial of a PARP inhibitor for patients with ovarian or breast cancer, and both are directed by the departments of Breast and Medical Oncology and Breast Surgery.
The Department has accepted attendees for outpatient genetic counseling, so that they could be eligible to take the examination for clinical geneticists and certified genetic counselors acknowledged by the Japanese Society of Human Genetics and the Japanese Society of Genetic Counseling. In 2015, eight doctors were registered as trainees for clinical geneticists in the education committee of clinical geneticists.
The Department of GeMS was launched in November 2015. Although this section reports on the routine clinical activity of the Department and clinical research associated directly with the Outpatient Genetic Counseling Clinic, the scope and mission of the Department extends beyond hereditary cancer syndromes and includes support of the genomic biomarker-driven personalized cancer treatments offered by other clinical departments (Figure 2). The core technology of the new discipline, also known as a precision medicine, is next-generation sequencers, which would bring massive amounts of genomic data to cancer diagnosis, treatment and prevention. The crux of this emerging opportunity is how to convert the sequence data to clinically valid and useful knowledge, which could include incidental or secondary findings. The Department of GeMS is expected to support other departments in the era of genomic medicine.
Figure 1. Major Questions of Patients and Families with Hereditary Cancer Syndromes
Figure 2. Patients and Families Faced With GeMS
List of papers published in 2015
- Hashimoto T, Ogawa R, Matsubara A, Taniguchi H, Sugano K, Ushiama M, Yoshida T, Kanai Y, Sekine S. Familial adenomatous polyposis-associated and sporadic pyloric gland adenomas of the upper gastrointestinal tract share common genetic features. Histopathology, 67:689-698, 2015
- Tanakaya K, Furukawa Y, Nakamura Y, Hirata K, Tomita N, Tamura K, Sugano K, Ishioka C, Yoshida T, Ishida H, Watanabe T, Sugihara K, HNPCC registry and genetic testing project of the Japanese Society for Cancer of the Colon and Rectum, Yamaguchi T, Ishikawa H, Matsubara N, Arai M, Moriya Y. Relationship between smoking and multiple colorectal cancers in patients with Japanese Lynch syndrome: a cross-sectional study conducted by the Japanese Society for Cancer of the Colon and Rectum. Jpn J Clin Oncol, 45:307-310, 2015
- Yamaguchi T, Furukawa Y, Nakamura Y, Matsubara N, Ishikawa H, Arai M, Tomita N, Tamura K, Sugano K, Ishioka C, Yoshida T, Moriya Y, Ishida H, Watanabe T, Sugihara K, HNPCC Registry and Genetic Testing Project of the Japanese Society for Cancer of the Colon and Rectum. Comparison of clinical features between suspected familial colorectal cancer type X and Lynch syndrome in Japanese patients with colorectal cancer: a cross-sectional study conducted by the Japanese Society for Cancer of the Colon and Rectum. Jpn J Clin Oncol, 45:153-159, 2015
- Kumamoto K, Ishida H, Ohsawa T, Ishibashi K, Ushiama M, Yoshida T, Iwama T. Germline and somatic mutations of the APC gene in papillary thyroid carcinoma associated with familial adenomatous polyposis: Analysis of three cases and a review of the literature. Oncol Lett, 10:2239-2243, 2015
- Saeki N, Ono H, Sakamoto H, Yoshida T. Down-regulation of Immune-related Genes by PSCA in Gallbladder Cancer Cells Implanted into Mice. Anticancer Res, 35:2619-2625, 2015
- Nagashima K, Iwasa S, Yanai T, Hashimoto H, Suzuki K, Ohyanagi F, Shimada Y, Yamamoto N. A double-blind randomized Phase II study of olanzapine 10 mg versus 5 mg for emesis induced by highly emetogenic chemotherapy. Jpn J Clin Oncol, 45:229-231, 2015
- Tanaka Y, Aoyagi K, Minashi K, Komatsuzaki R, Komatsu M, Chiwaki F, Tamaoki M, Nishimura T, Takahashi N, Oda I, Tachimori Y, Arao T, Nishio K, Kitano S, Narumi K, Aoki K, Fujii S, Ochiai A, Yoshida T, Muto M, Yamada Y, Sasaki H. Discovery of a Good Responder Subtype of Esophageal Squamous Cell Carcinoma with Cytotoxic T-Lymphocyte Signatures Activated by Chemoradiotherapy. PLoS One, 10:e0143804, 2015
- Saeki N, Ono H, Yanagihara K, Aoyagi K, Sasaki H, Sakamoto H, Yoshida T. rs2294008T, a risk allele for gastric and gallbladder cancers, suppresses the PSCA promoter by recruiting the transcription factor YY1. Genes Cells, 20:382-391, 2015
- Yamanoi K, Arai E, Tian Y, Takahashi Y, Miyata S, Sasaki H, Chiwaki F, Ichikawa H, Sakamoto H, Kushima R, Katai H, Yoshida T, Sakamoto M, Kanai Y. Epigenetic clustering of gastric carcinomas based on DNA methylation profiles at the precancerous stage: its correlation with tumor aggressiveness and patient outcome. Carcinogenesis, 36:509-520, 2015
- Suzuki M, Chiwaki F, Sawada Y, Ashikawa M, Aoyagi K, Fujita T, Yanagihara K, Komatsu M, Narita M, Suzuki T, Nagase H, Kushima R, Sakamoto H, Fukagawa T, Katai H, Nakagama H, Yoshida T, Uezono Y, Sasaki H. Peripheral opioid antagonist enhances the effect of anti-tumor drug by blocking a cell growth-suppressive pathway in vivo. PLoS One, 10:e0123407, 2015
- Budhathoki S, Iwasaki M, Yamaji T, Sasazuki S, Takachi R, Sakamoto H, Yoshida T, Tsugane S. Dietary heterocyclic amine intake, NAT2 genetic polymorphism, and colorectal adenoma risk: the colorectal adenoma study in Tokyo. Cancer Epidemiol Biomarkers Prev, 24:613-620, 2015
- Fujita T, Chiwaki F, Takahashi RU, Aoyagi K, Yanagihara K, Nishimura T, Tamaoki M, Komatsu M, Komatsuzaki R, Matsusaki K, Ichikawa H, Sakamoto H, Yamada Y, Fukagawa T, Katai H, Konno H, Ochiya T, Yoshida T, Sasaki H. Identification and Characterization of CXCR4-Positive Gastric Cancer Stem Cells. PLoS One, 10:e0130808, 2015
- Iwakawa R, Kohno T, Totoki Y, Shibata T, Tsuchihara K, Mimaki S, Tsuta K, Narita Y, Nishikawa R, Noguchi M, Harris CC, Robles AI, Yamaguchi R, Imoto S, Miyano S, Totsuka H, Yoshida T, Yokota J. Expression and clinical significance of genes frequently mutated in small cell lung cancers defined by whole exome/RNA sequencing. Carcinogenesis, 36:616-621, 2015