Independent somatic evolution underlies multifocal small intestine neuroendocrine tumors

Abstract 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, yet the typical path of evolution of these lesions remains unclear. Here, we determined the complete genome sequences of 37 tumors from 5 patients with multifocal SI-NET, allowing elucidation of phylogenetic relationships between multiple intestinal tumors and metastases in individual patients. Notably, lack of shared somatic mutational events strongly supported that the intestinal tumors were of independent clonal origin. Furthermore, adjacent lymph node metastases arose from a single, typically centrally located, intestinal tumor. Thus, we propose that multifocal SI-NETs form primarily by independent somatic evolution rather than local metastatic spread, suggesting a contribution from of a cancer-priming local environmental factor. Significance statement In multifocal cancer, several tumors arise in the same tissue area. Typically, this is due local metastatic spread, eventually leading to multiple tumors arising from a unique precursor clone, or due to a common heritable oncogenic genetic variant shared among all cells in an individual. Here, we find tumor development is independently initiated in multiple separate cells in a cancer of the small intestine, leading to a development of a polyclonal group of tumors that are genetically unrelated in terms of somatic evolution. This implies a contribution from a yet unknown non-genetic factor, thus providing an important future research direction for an enigmatic form of cancer in which genetic driver events are generally lacking.