Elucidating the evolutionary history of small intestine neuroendocrine tumors

Small intestine neuroendocrine tumor (SI-NET), the most common cancer of the small bowel, has several unusual properties, including multifocality (multiple clustered tumors), low mutation burden, and a curious lack of known driver mutations that can explain tumor initiation and metastasis. The underlying tumorigenic mechanisms are thus poorly understood and therapeutic options are limited.

Despite this, SI-NET remains understudied using modern genomic tools, and we believe new fundamental insights are within reach.

With the help of whole genome sequencing we recently determined the evolutionary trajectories that underlie multifocal SI-NET, which gave important directions for future research.

In this proposal, which involves two PhD students over five years, we will combine genomic, transcriptomic, epigenetic and proteomic data to gain a better understanding of SI-NET progression.

This includes determining detailed life histories of genetic changes within individual patients and mapping of non-mutational events that may contribute to oncogenesis.

The project has considerable potential to result in new mechanistic knowledge, which may open up new avenues into therapeutic targeting of SI-NET in the future.