Independent somatic evolution underlies clustered neuroendocrine tumors in the human small intestine

Erik Elias,Markus Lindberg,Susanne E Reinsbach,Arman Ardalan,Erik Larsson,Yvonne Arvidsson,Andreas Muth,Ola Nilsson

doi:10.1038/s41467-021-26581-5

Erik Elias, Markus Lindberg + Show 6 more

Open Access

https://doi.org/10.1038/s41467-021-26581-5

Copy DOI

Abstract

Small intestine neuroendocrine tumor (SI-NET), the most common cancer of the small bowel, often displays a curious multifocal phenotype with several tumors clustered together in a limited intestinal segment. SI-NET also shows an unusual absence of 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 determine the complete genome sequences of 61 tumors and metastases from 11 patients with multifocal SI-NET, allowing for elucidation of phylogenetic relationships between tumors within single patients. Intra-individual comparisons revealed a lack of shared somatic single-nucleotide variants among the sampled intestinal lesions, supporting an independent clonal origin. Furthermore, 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 a cancer-priming local factor.

Highlights

Small intestine neuroendocrine tumor (SI-NET), the most common cancer of the small bowel, often displays a curious multifocal phenotype with several tumors clustered together in a limited intestinal segment
Of particular interest are small intestine neuroendocrine tumors (SI-NETs), the most common cancer of the small intestine, where ~50% of cases display a striking multifocal phenotype that often involves 10 or more morphologically identical tumors clustered within a limited intestinal segment, commonly centered around a regional lymph node metastasis[4,5]
While individual metastases showed credible overlaps only with a single primary tumor, in three cases (Patients 6, 7, and 10) we found that two different primary tumors had metastasized, resulting in independent lymph node or liver metastases (Fig. 2g, h, k)

Summary

Introduction

Small intestine neuroendocrine tumor (SI-NET), the most common cancer of the small bowel, often displays a curious multifocal phenotype with several tumors clustered together in a limited intestinal segment. Of particular interest are small intestine neuroendocrine tumors (SI-NETs), the most common cancer of the small intestine, where ~50% of cases display a striking multifocal phenotype that often involves 10 or more morphologically identical tumors clustered within a limited intestinal segment, commonly centered around a regional lymph node metastasis[4,5]. The evolutionary relationships that govern multiple intestinal tumors and metastases in SI-NET can give insight into the underlying biology, but earlier efforts to determine this have yielded conflicting results[10,11]. We perform whole genome sequencing (WGS) on separate intestinal tumors and adjacent metastases from 11 patients, enabling us to conclusively determine the evolutionary trajectory of multifocal SI-NET lesions within single individuals

Objectives

Methods

Results

Conclusion