By Anna Greene, PhD, NETRF Director of Research
What if small intestine neuroendocrine tumors (SI-NETs), often diagnosed in people over age 60, actually begin decades earlier, in childhood? And what if the same tumors aren’t driven by typical genetic “on switches,” but instead evolve quietly over time through subtle disruptions in DNA repair and cell identity?
Two major studies published this spring, one in bioRxiv and the other in Nature Scientific Reports suggest exactly that. Together, they reshape our understanding of SI-NETs, when they begin, and how we might treat them more effectively.
Study #1: SI-NETs May Begin in Childhood
A collaborative study from Gothenburg, Sweden, revealed that the seeds of SI-NETs may be planted far earlier than anyone thought. By analyzing the full genomes of tumors and their metastases from 16 patients, researchers showed:
- Some SI-NETs begin developing in childhood or adolescence.
- Key genetic events, like chromosome 18 loss or whole genome doubling, occur decades before diagnosis.
- Slow, steady tumor growth means some SI-NETs evolve silently for 50+ years.
They even confirmed this timeline using archival CT scans, finding that some tumors were detectable up to 12 years before diagnosis, although they were missed at the time.
Why this matters:
1. Redefining Our Timeline
NETRF’s vision has always been to understand and disrupt the timeline of NET development. This preprint shows that SI-NETs can begin in childhood, even if they don’t manifest clinically until age 60+. NETRF has worked for years to fund crucial studies unraveling NET biology; this discovery accelerates the imperative for earlier detection strategies, a key pillar in our research roadmap.
2. A New Window for Intervention
If SI-NETs evolve over decades, there’s a profound opportunity for screening high-risk individuals, such as family members, patients with minor GI symptoms, or those with incidental imaging findings. Imagine earlier interventions when tumors are small, localized, and more treatable.
Study #2: A Quiet Tumor with a Unique Biology
Meanwhile, a second study by researchers at Charité Universitätsmedizin Berlin dug into 39 Grade 1 or 2 SI-NETs using genomic and transcriptomic (gene expression) analysis. What they found was just as surprising:
- No consistent early “driver” mutations, unlike most cancers.
- Germline DNA repair mutations (such as in Fanconi anemia genes) in 9% of patients.
- Defective homologous recombination, a DNA repair pathway, as a potential therapeutic target.
- Consistently low expression of REST, a gene that maintains non-neuronal cell identity by silencing neuronal genes.
- Strong evidence that SI-NETs originate from enterochromaffin cells, a hormone-producing gut cell type.
These findings confirm that SI-NETs don’t behave like typical cancers; they are biologically distinct, often multifocal (multiple tumors at once), and driven more by “what’s missing” than by what’s mutated.
Why This Changes Our Understanding
For decades, researchers have searched for a “smoking gun”, a genomic mutation that sparks the growth of SI-NETs. This new study confirms what previous work suggested: there’s no common initiating mutation.
Instead, the data suggest that SI-NETs may arise from a field effect, an unknown predisposition in a patch of intestinal cells that later accumulates genetic alterations, such as chromosomal instability and DNA repair defects.
This is especially true in patients with multifocal tumors, where independent tumors form with no shared origin, but often in the same region of the gut.
Dr. Felix Bolduan, first author on the publication, states, “We showed that SI-NETs do not possess any common driver mutations and can arise independently without a shared genetic background, indicating that a larger region of the small intestine is, under certain circumstances, susceptible to tumor formation. It is of crucial importance for further studies to identify these circumstances, as they will help us to understand SI-NET biology and may pave the way for novel therapeutic approaches.”
Why These Discoveries Matter—for Patients, Families, and the Future
These studies mark a shift in our understanding of SI-NETs and, more importantly, in our approach to treat them.
1. Earlier Detection Is Within Reach
The first study reveals that tumors often remain undetected for decades. This means novel early detection methods or screening programs for at-risk individuals (such as those with family history or genetic predisposition) could catch tumors before they spread.
2. Genetic Testing Could Save Lives
The second study highlights the importance of germline genetic testing, particularly for mutations in DNA repair genes. Identifying these early could help guide both surveillance and targeted therapy.
3. Precision Medicine Potential
If a patient’s tumor shows defects in DNA repair, treatments like PARP inhibitors, already used in BRCA-related cancers, could be explored in clinical trials for SI-NETs.
4. New Avenues for Research
The consistent loss of REST and the likely origin in enterochromaffin cells point to new targets for drug development and prevention.
At NETRF, we’re already acting on these insights:
- Funding biomarker discovery for early detection
- Supporting research and trials targeting DNA repair deficiencies.
- Investing in single-cell and transcriptomic research to map tumor evolution in its earliest stages.
These discoveries show us that SI-NETs are not only slow-growing, but also slow-starting. For patients, this means that what was once considered an “older adult” cancer may be a lifelong, hidden journey.
With the right science, early diagnosis, and targeted treatment, we can change that.
Listen to the NETWise by NETRF episode on small bowel NETs.
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