Mutations in this cellular cargo transport gene may help tumors grow through a previously unrecognized mechanism.
Small intestinal cancer is a rare and poorly understood disease, partly because the molecular drivers behind it have remained unclear. Now, researchers from Japan have identified mutations in COPA - a gene involved in cellular cargo transport with no prior link to cancer - as an alternative route to small intestine tumorigenesis. Their findings may help explain how these tumors develop and could inform and advance future diagnosis and treatment strategies.
A signaling system known as the Wnt pathway plays a central role in how cells in the intestine grow, divide, and renew themselves. Decades of research have shown that disruption of this pathway is a defining feature of many intestinal cancers. In particular, mutations in the APC gene - which normally acts as a brake disrupting Wnt signaling - are widely recognized as a key initiating event in colorectal tumors.
Although cancer of the small intestine follows a similar developmental sequence, it is a rare disease, accounting for only 3% of all gastrointestinal cancers. Interestingly, while APC mutations are found in about 90% of small intestinal adenomas (benign), they appear in fewer than 30% of small intestinal adenocarcinomas (malignant form). This discrepancy has long raised an important question: What else is driving tumor formation and cancer progression in these cases?
In a recent study, a research team led by Professor Shigeki Sekine and Professor Toshiro Sato from Keio University School of Medicine, Japan, set out to address this knowledge gap. Their paper, co-authored by Associate Professor Masayuki Fujii and Assistant Professor Naoko Abeto from the same institute, will be published in Nature Genetics journal on June 12, 2026. The study identifies recurrent mutations in a gene with no prior known link to cancer as an alternative driver of small intestine tumorigenesis.
The team began by examining a morphologically distinct set of small intestinal adenomas taken from three patients. These adenomas were protruding rather than flat, with branched glands and unusual structural features. By sequencing the protein-coding regions of the genome in these tumors, the researchers found recurrent deletions in a specific part of a gene called COPA. This gene encodes a component of the coatomer complex, which is involved in transporting proteins between the Golgi apparatus and the endoplasmic reticulum.
To validate this finding, the team screened a broader cohort of small intestinal adenoma and adenocarcinoma cases and identified similar COPA mutations in a fraction of them. Notably, none of these cases carried mutations in APC or other known Wnt pathway genes, confirming that COPA mutations represent a genuinely independent route to tumorigenesis. “Scientists have exhaustively hunted down genes responsible for cancer, so this was a shocking new find,” says Dr. Fujii.
To understand the functional consequences of these COPA mutations, the team grew small intestinal organoids (3D miniaturized and simplified version of an organ produced in the laboratory) from patient-derived tumor tissue, and separately used gene editing tools to introduce the same COPA mutations into healthy small intestinal organoids. Both approaches converged at the same result: COPA mutations activate the Wnt pathway in a way that bypasses the normal requirement for R-spondin and Noggin, two key proteins that act as essential amplifiers of Wnt signaling.
This work has important implications for how small intestinal tumors are classified and diagnosed. Compared to colon cancer, the different subtypes of small intestinal adenomas have been difficult to categorize, in part due to their rarity. “The current discovery could inform catalogues like the WHO classification of digestive system tumors, which doctors widely use to identify tumor types in patients,” explains Dr. Fujii.
Moreover, the findings help explain the previously unresolved gap between the high frequency of APC mutations in small intestinal adenomas and their relative scarcity in adenocarcinomas, suggesting that multiple atypical biological paths drive malignancy in these tissues, with COPA - driven tumorigenesis representing one of them. The researchers hope that further research on COPA mutations may help in development of new diagnostic and treatment strategies for intestinal cancers in patients without APC mutations, potentially improving outcomes in this challenging disease.
Title: Towards a deeper understanding of how small intestine cancers develop
Caption: The results of this study point to mutations in the COPA gene as an important driver of cancer progression in small intestinal adenomas.
Credit: Professor Shigeki Sekine and Professor Toshiro Sato from Keio University School of Medicine, Japan
License type: Original content
Usage restrictions: Cannot be reused without permission.
About Associate Professor Masayuki Fujii from Keio University School of Medicine
Dr. Masayuki Fujii currently serves as Associate Professor at the Department of Integrated Medicine and Biochemistry, Keio University School of Medicine, Japan. He is a physician scientist and biologist who focuses on various aspects of life from health to disease using tissue-derived organoids and their integration with cutting-edge technologies. His work covers tumor evolution, genetic mutations, and new approaches to cancer diagnosis and therapy, particularly in digestive system cancers. He has over 30 peer-reviewed publications to his name.
About Assistant Professor Naoko Abeto from Keio University School of Medicine
Dr. Naoko Abeto is an Assistant Professor in the Department of Diagnostic Pathology at Keio University School of Medicine in Japan. She completed her residency at the National Cancer Center Hospital in Tokyo and has served as a surgical pathologist at Keio University Hospital since 2025. Her primary interest is gastrointestinal pathology, and she studies the histological and molecular processes underlying gastrointestinal tumorigenesis.
Funding information
This work was supported by the National Cancer Center Research and Development Fund (2023-J-2, NCC Biobank, and NCC Core Facility), JSPS KAKENHI (Grant No. 22H04995, 23K27677 and 24K21300) and JST ERATO (Grant No. JPMJER2303).
Reference
Journal：Nature Genetics
DOI： 10.1038/s41588-026-02616-9
Article Title：Recurrent COPA mutation drives R-spondin-independent Wnt activation in intestinal tumors
Media contact:
Name: Tetyana Khatayeva
Email: khatayeva@keio.jp
Keio University
Expert contact:
Name: Dr. Masayuki Fujii
Email: m.fujii@keio.jp
Keio University