Annual Report 2024
Division of Molecular Pathology
Yasushi Yatabe, Nobuyoshi Hiraoka, Taisuke Mori, Yoshihisa Kobayashi, Makoto Hirata, Takako Ishiyama, Akane Sei, Masanori Fuse, Chie Naito, Eijitu Ryo, Chika Takeuchi Richter, Yukiko Nakamura, Rika Murakami, Sachiko Kurihara, Kentaro So, Aiko Mineki, Nozomi Handa, Jumpei Kashima, Taiki Hashimoto, Toshihide Hirai, Airi Sakyo, Kota Tsurumi
Introduction
Morphological analysis is one of the oldest fields in cancer research; thus this field covers a wide range of knowledge that has been developed for several decades. The Division of Molecular Pathology aims to integrate this knowledge with the rapidly evolving field of molecular biology to study the molecular biological characteristics of tumors from the morphological perspective.
The Team and What We Do
Diagnosis is now made on the basis of various protein expressions and genetic abnormalities that go beyond morphology, and drugs that are highly effective against specific genetic mutations have been developed for some tumors. In the field of molecular pathology, we collaborate closely with the Department of Diagnostic Pathology of the National Cancer Center Hospital, and conduct research on the use of genetic alterations in diagnosis and identification of genetic abnormalities that are useful in diagnosis, based on the questions raised in the diagnostic process. We are also investigating the molecular mechanisms of tumorigenesis and progression based on the results of various biologic research projects and cancer genome medicine.
Research Activities
Lung cancer
We initiated a companion study using JCOG0802 to compare the treatment outcomes of leaf resection and segmental resection, involving pathologists from the Pathology Committee of the World Conference on Lung Cancer. We conducted panel testing on more than 700 FFPE specimens over 10 years old and completed genetic analysis for driver mutations. Furthermore, we completed WES and WTS analysis on 600 tissue arrays previously prepared and are advancing collaborative research.
Head and neck cancer
Since hyalinizing clear cell carcinoma (HCCC) lacks a specific immunohistochemical marker, we explored candidate markers based on its presumed origin from minor salivary gland acini. Immunohistochemical evaluation of 12 cases of HCCC, 12 cases of myoepithelial carcinoma, and 88 cases of salivary gland tumor tissue microarrays demonstrated that NKX3.1 is useful for the differential diagnosis of HCCC. Furthermore, its combined use with SOX10 and CK7 was considered to improve diagnostic accuracy.
We analyzed 98 secondary solid tumors after allogeneic hematopoietic stem cell transplantation using whole-exome sequencing. High tumor mutational burden correlated with prior immunosuppression in colorectal and oral cancers, and a donor-derived esophageal carcinoma was identified. These results provide evidence for guiding immunotherapy eligibility, developing early diagnostic methods such as iodine staining or oral swab tests, and establishing preventive strategies for secondary malignancies.
Pancreatic cancer
We investigated the tertiary lymphoid structures (TLS) in pancreatic cancer tissues, examining their relationship with the tumor microenvironment and their quantitative and qualitative states. We had new insights into specific relationships between cell types constituting TLS and their relationship with the tumor microenvironment, along with new findings regarding their clinical and pathological significance.
Trans-organ approach
The carcinogenic mechanisms from the perspective of drug resistance are investigated as a JST-initiated FOREST project by applying CRISPR technologies to lung cancer cell models. In collaboration with the Division of Genome Analysis Platform Development, we validated splicing-site–creating mutations identified through large-scale data analysis and conducted therapeutic studies using antisense oligonucleotides in vitro. In joint research with the JFCR, we reported on the mechanism of the RNA-sensing system associated with chromosomal segregation abnormalities.
Genomic profiling and molecular pathogenesis of soft tissue and bone tumors
We operate the Japan Sarcoma Genome Consortium (JSGC) and conduct genomic analyses of bone and soft tissue tumors. We are currently participating in the Genome Research in Cancers and Rare Diseases (G-CARD) project under the AMED Program of Practical Research for Innovative Cancer Control from FY2021, as well as conducting a whole genome sequencing (WGS) research of bone and soft tissue tumors. To date, we have collected over 800 tumor and normal tissue samples for whole-genome analysis. Whole-genome sequencing has been performed for approximately 700 cases that passed quality control. Currently, we are prioritizing histological subtype-agnostic analysis, while also progressing with histological subtype-specific analysis. Additionally, we are researching ways to obtain informed consent for whole-genome analysis in new cases and disclose the results upon request.
Education
We accepted two research trainees and are providing research guidance.
Future Prospects
With advances in basic research and the spread of cancer genome medicine, fundamental genetic disorders have been discussed in clinical settings. The aim of our research is to use our morphological approach as a means of assigning biological meaning/significance to individual disease and obtaining background molecular features across the organs.
List of papers published in 2024
Journal
1. Sasaki N, Homme M, Murayama T, Osaki T, Tenma T, An T, Takegami Y, Tani T, Gedeon PC, Kobayashi Y, Cañadas I, Barbie DA, Yao R, Kitajima S. RNA sensing induced by chromosome missegregation augments anti-tumor immunity. Molecular cell, 85:770-786.e7, 2025
2. Iida N, Okada A, Kobayashi Y, Chiba K, Yatabe Y, Shiraishi Y. Systematically developing a registry of splice-site creating variants utilizing massive publicly available transcriptome sequence data. Nature communications, 16:426, 2025