Keio University School of Medicine
National Cancer Center Japan
Japan Science and Technology Agency (JST)
In a new study published in the journal Nature Genetics, scientists discovered a brand-new route to cancer in the small intestine. This involves a gene that had previously been overlooked as a tumor gene which may also play a role in cancers of other organs, the authors say.
Small intestinal cancers are rare, accounting for less than 3% of all gastrointestinal cancers. Like colon cancer—one of the world’s most common cancers—they often start as benign growths on the gut’s inner lining, known as adenomas, and can progress into malignant tumors. Once they develop, the chance of recovery is lower than that of colon cancer.
Colon adenomas and cancers often have mutations in a gene called APC. While the mutation is also found in most small intestinal adenomas, most small intestinal cancers have normal versions of the gene. “This suggested that there was another unknown route to cancer in the small intestine,” says Associate Professor Masayuki Fujii of the Department of Integrated Medicine and Biochemistry at Keio University, who led the study.
An overlooked gene
The team examined small intestinal adenomas with normal APC and found raised, protruding adenomas with unique folds and grooves, though most adenomas are flat. Sequencing the protein-coding regions of the genome in these adenomas revealed mutations in COPA, a gene never linked to cancer.
COPA codes for a cage-like structure in the cell that delivers cargo back from the Golgi apparatus to the endoplasmic reticulum, which are organelles within the cell that work together to produce, package, and ship proteins and fats.
“Scientists have exhaustively hunted down genes responsible for cancer. This was a shocking new find,” says Fujii. “The gene’s role in cargo transport suggests this is a new category of ways in which tumors become cancerous.”
Fujii says that COPA may have been overlooked because the mutation type involved is challenging to detect. The mutations are in-frame deletions, where chunks of code are deleted without disrupting the rest of the gene. Historically, these were harder to map onto the genome and more likely to be filtered out during computational analyses.
The team also developed small intestine organoids—miniature, 3D models of the organ—from patient cells. Experiments on these revealed that COPA activates the Wnt pathway, a chain of signals that drives many cancers by promoting cell growth. However, this happened without R-spondin and Noggin, key proteins that often work in tandem to enhance the Wnt pathway. “It’s unusual because the lining of the small intestine typically requires many growth factors for cells to proliferate. Surprisingly, COPA bypasses the need for these two crucial proteins,” says Fujii.
A new category
Compared to other cancers, scientists have been slow to identify and categorize different types of small intestinal adenomas, in part because the tumors are so rare. The current discovery could inform catalogs like the WHO classification of digestive system tumors, which doctors widely use to identify tumor types in a patient.
The findings also provide clues for future treatment, says Fujii, as patients with normal APC may respond better to drugs that prevent activation of the Wnt pathway.
To better understand how COPA mutations lead to small intestinal cancers, a critical step is to decipher how transport errors between the Golgi apparatus and endoplasmic reticulum activate signals in the Wnt pathway. “Could COPA mutations alter the mesh-like patterns on the cage and affect the types of proteins that can be carried inside? That’s an intriguing possibility to look into,” says Fujii.
For the full press release (Japanese only), please see below.