Annual Report 2021
Division of Genomic Medicine
Shinichi Yachida (Chief), Satoshi Shiba (Researcher)
Introduction
In FY2021, we conducted a comprehensive genome analysis, including a whole-genome analysis of refractory and rare cancers. In particular, we collected frozen samples of neuroendocrine carcinomas of the gastrointestinal system, which are extremely difficult to treat and rare, from multiple institutions in the U.S., the Netherlands, and Japan. We performed whole-genome analysis, whole transcriptome analysis, methylation array analysis, and ATAC-seq analysis (Fig. 1) in collaboration with the Division of Cancer Genomics. The results were reported in a paper (Yachida S et al. Cancer Discov. 2022, 12:692) and a press release. We found that pancreatic neuroendocrine carcinomas and non-pancreatic gastrointestinal neuroendocrine carcinomas have similar and different genomic abnormalities.
Furthermore, the genomic abnormalities of pancreatic neuroendocrine carcinomas were subclassified into acinar-type and ductal-type carcinomas with multiple cell types of origin. We found that SOX2, a neuroendocrine transcription factor, is highly expressed in neuroendocrine carcinomas in the gastrointestinal system, and the mechanism depends on methylation rather than demethylation of the promoter region. In addition, we discovered novel fusion genes and other genes characteristic of neuroendocrine carcinomas of the gastrointestinal system.
The evolution of cancer clones was examined in an autopsied case of pancreatic neuroendocrine carcinoma. We found that epigenomic abnormalities, accumulation of gene mutations, and copy number aberrations undergo similar clonal evolution.
In addition to the comprehensive human genome analysis described above, we conducted metagenomic and metabolomic analyses of the intestinal environment, especially gut microbiota, in collaboration with the Division of Endoscopy at the National Cancer Center Hospital. In particular, we compared the intestinal environment before and one year after surgery for colorectal cancer (Shiroma H et al. mSystems. 2022, 7:e0001822). We found that many of the bacteria reported to be associated with advanced colorectal cancer were not detectable after surgery, suggesting that most are a consequence of colorectal cancer rather than its cause.
Education
We educated Osaka University Graduate School of Medicine graduate students using the cross-appointment system with Osaka University Graduate School of Medicine.
Future Prospects
We are currently working on cancer and microbial genomes in humans, and we aim to conduct research that integrates both genomes.
List of papers published in 2021
Journal
1. Yachida S, Totoki Y, Noë M, Nakatani Y, Horie M, Kawasaki K, Nakamura H, Saito-Adachi M, Suzuki M, Takai E, Hama N, Higuchi R, Hirono S, Shiba S, Kato M, Furukawa E, Arai Y, Rokutan H, Hashimoto T, Mitsunaga S, Kanda M, Tanaka H, Takata S, Shimomura A, Oshima M, Hackeng WM, Okumura T, Okano K, Yamamoto M, Yamaue H, Morizane C, Arihiro K, Furukawa T, Sato T, Kiyono T, Brosens LAA, Wood LD, Hruban RH, Shibata T . Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System. Cancer discovery, 12:692-711, 2022
2. Shiroma H, Shiba S, Erawijantari PP, Takamaru H, Yamada M, Sakamoto T, Kanemitsu Y, Mizutani S, Soga T, Saito Y, Shibata T, Fukuda S, Yachida S, Yamada T. Surgical Treatment for Colorectal Cancer Partially Restores Gut Microbiome and Metabolome Traits. mSystems, 7:e0001822, 2022
3. Tanaka H, Suzuki M, Takemoto N, Fukusumi T, Eguchi H, Takai E, Kanai H, Tatsumi M, Horie M, Takenaka Y, Yachida S, Inohara H. Performance of oral HPV DNA, oral HPV mRNA and circulating tumor HPV DNA in the detection of HPV-related oropharyngeal cancer and cancer of unknown primary. International journal of cancer, 150:174-186, 2022
4. Takai E, Omata W, Totoki Y, Nakamura H, Shiba S, Takahashi A, Namikawa K, Mori T, Yamazaki N, Shibata T, Yachida S. Clonal dynamics of circulating tumor DNA during immune checkpoint blockade therapy for melanoma. Cancer science, 112:4748-4757, 2021