Annual Report 2023
Division of Molecular Pathology
Yasushi Yatabe, Nobuyoshi Hiraoka, Shigeki Sekine, Taisuke Mori, Yoshihisa Kobayashi, Makoto Hirata,
Taiki Hashimoto, Takako Ishiyama, Reiko Ogawa, Chie Naito, Masanori Fuse, Eijitu Ryo, Akane Sei, Melvin Pan,
Chika Takeuchi Richter, Erika, Kawasaki, Rika Murakami, Yukiko Nakamura, Jumpei Kashima, Toshihide Hirai, Yuji Muraoka, Airi Sakyo, Sachiyo Hasegawa, Yui Iwano, Nozomi Handa
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 launched a new study on molecular characteristics using JCOG0802, which compared the treatment outcomes of lobectomy and segmental resection, with pathologists from the Pathology Committee of the World Conference on Lung Cancer. To start molecular analysis, a pilot study was started to select suitable assays for this cohort. We also completed WES and WTS analysis of the 600 tissue arrays we had created. As publication, we released a review of molecular pathology of lung cancer and a review of KRAS in non-small cell lung cancer.
Gastrointestinal cancer: We are analyzing the molecular abnormalities involved in the developmental process of gastrointestinal cancers. In particular, we are focusing on the serrated pathway in colorectal cancer, which is a different carcinogenic pathway from the adenoma-carcinoma sequence.
Head and neck cancer: A large sample comprising approximately 89 cases of oral, esophageal, and colorectal second solid tumors (post bone marrow transplantation cancer) linked to clinicopathological information was collected from multiple centers in Japan. Although some specimens were deficient due to qualitative evaluation, whole exome sequencing (WES) was completed for a total of 174 specimens from 79 cases. The number of cases included 31 oral cancer cases (69 specimens), 30 esophageal cancer cases (70 specimens), and 18 colorectal cancer cases (35 specimens). In addition, 79 age- and sex-matched primary solid tumors (31 oral cancer cases, 29 esophageal cancer cases, and 19 colorectal cancer cases) were collected from our biobank as a control group. A clinical-pathological database was established for these cases following the collection of detailed patient information (medical history, treatment, HLA match, serum data, drugs used, duration, etc.) and pathological analysis (site, multiplicity and spread, histological type, immunohistochemical staining, presence of viral infection, etc.).
Pancreatic cancer: Approximately 300 biliary tract and 200 pancreatic cancers were studied, showing that venous density is a favorable prognostic factor and is closely associated with the formation of tertiary lymphoid structures. Venous and nerve density also correlated significantly with an active immune response. Thus, the vasculature and nervous system have a significant influence on the directionality of the cancer immune microenvironment.
Trans-organ approach: Using EGFR mutant lung cancer cell models, the carcinogenesis mechanism is being investigated from the perspective of drug resistance as a JST-initiated FOREST project. In collaboration with the Division of Genome Analysis Platform Development, we have verified splicing site-creating variants extracted by large-scale data analysis in genome-edited cell models, and demonstrated that antisense oligonucleotides can suppress the carcinogenicity caused by splicing abnormalities.
Genomic profiling and molecular pathogenesis of soft tissue and bone tumors: In 2014, Japan Sarcoma Genome Consortium (JSGC) was established to promote genomic research of bone and soft-tissue tumors. We have been participating in Genome Research in Cancers and Rare Diseases (G-CARD) project under the AMED Program of Practical Research for Innovative Cancer Control Innovative from FY2021, and conducting a whole genome sequencing (WGS) research of bone and soft tissue tumors. To date, WGS has been conducted in 698 cases of tumor and normal paired samples. Currently, we are proceeding with a cross-sectional analysis of tissue types and have also started analysis by tissue type.
Education
We accepted two graduated fellows and trained them in cancer research.
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.