Project title: Studying field cancerization as a cause for multifocal ileal NETs

Description

Mäkinen will explore whether field cancerization may contribute to multifocal small intestinal NETs. She theorizes that the expansion of groups of abnormal cells in normal small intestines may lead to the development of multiple independent tumors.

What question will the researchers try to answer?

Can simultaneous, multiple small intestinal NETs arise from “fields” of abnormal cells in a histologically normal small intestine that create the substrate for tumors to develop due to carcinogenic alterations?

Why is this important?

At the time of diagnosis, about one in three small intestinal NET patients harbor multifocal tumors. The mechanisms by which these multifocal NETs arise are not yet understood, hampering the development of precision treatments.

What will researchers do?

Mäkinen will use state-of-the-art, high-throughput technologies to uncover the role of field cancerization in the development of multifocal small intestinal NETs.

How might this improve the treatment of NETs?

Uncovering how multifocal tumors arise could inform decisions regarding treatment, surgery, and patient outcome.

What is the next step?

Should Mäkinen’s research reveal genetic or epigenetic causes of multifocal small intestinal NETs, this information would fuel research aimed at finding ways to interrupt NET development.

Outcomes:

Small intestinal neuroendocrine tumors (SI-NETs) are the most common neoplasms of the small bowel. At the time of diagnosis, as much as one-third of the patients harbor simultaneously multiple primary tumors. The mechanisms by which these multifocal SI-NETs arise are not yet understood. Cancer development is considered as a multistep process, which begins when a cell or a small group of cells break free from the normal constraints of cell division and start proliferating uncontrollably. This research project focuses on these early events in cancer development. We hypothesized that multifocal SI-NETs arise from patches of abnormal cells in the normal small bowel, which have formed as a result of genomic and/or epigenomic alteration(s). This biological process is known as field cancerization. Using various high-throughput sequencing technologies on sets of patient-matched synchronous primary tumors, adjacent normal ileum and whole blood specimens, we observed that primary tumors among the SI-NET patients did not have genomic alterations in common, nor did multiple primary tumors examined from individual patients. These results suggest that each SI-NET develops independently.

Furthermore, we discovered that metastases of the multifocal SI-NET patients can originate from one single primary tumor or different primary tumors, which highlights the need to identify all primary tumors by careful palpation of the entire jejunum and ileum at the time of surgery. Subsequently, we analyzed the normal small intestine of the SI-NET patients in more detail. Some of our data analyses are still ongoing. Based on our preliminary results, we did not observe shared genomic alterations among the normal ileum samples or identify alterations that would likely represent early events in the tumorigenesis of SI-NETs, proposing that SI-NETs unlikely arise from normal small bowel as a result of field cancerization. In conclusion, our results suggest that the tumorigenesis of multifocal SI-NETs may not be exclusively driven by genomic alterations and underscore the need of a deeper understanding of the molecular mechanisms that underlie SI-NETs, which is essential for decisions regarding treatment, surgery, and patient outcome.

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