PT  - JOURNAL ARTICLE
AU  - Erik Elias
AU  - Arman Ardalan
AU  - Markus Lindberg
AU  - Susanne Reinsbach
AU  - Andreas Muth
AU  - Ola Nilsson
AU  - Yvonne Arvidsson
AU  - Erik Larsson
TI  - Independent somatic evolution underlies clustered neuroendocrine tumors in the human small intestine
AID  - 10.1101/2020.05.06.080499
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2020.05.06.080499
4099  - http://biorxiv.org/content/early/2021/03/25/2020.05.06.080499.short
4100  - http://biorxiv.org/content/early/2021/03/25/2020.05.06.080499.full
AB  - Background Small intestine neuroendocrine tumor (SI-NET), the most common cancer of the small bowel, often displays a curious multifocal phenotype with several intestinal tumors centered around a regional lymph node metastasis. Although SI-NET patients often present with metastatic disease at the time of diagnosis, there is an unusual absence of somatic driver mutations explaining tumor initiation and metastatic spread. The evolutionary trajectories that underlie multifocal SI-NET lesions could provide insight into the underlying tumor biology, but this question remains unresolved. Here, we determined the complete genome sequences of 65 tumor and tissue samples from 11 patients with multifocal SI-NET, allowing for elucidation of phylogenetic relationships between tumors within individual patients. Intra-individual comparisons of whole genome sequences revealed a lack of shared somatic single-nucleotide variants and copy number alterations among the sampled intestinal lesions, supporting that they were of independent clonal origin. Furthermore, each metastasis originated from a single intestinal tumor, and in three of the patients, two independent tumors had metastasized. We conclude that primary multifocal SI-NETs generally arise from clonally independent cells, suggesting a contribution from of a cancer-priming local factor.Competing Interest StatementThe authors have declared no competing interest.