Early initiation of small intestine neuroendocrine tumors

Small intestine neuroendocrine tumor (SI-NET) is normally diagnosed late in life and has several unusual properties, including low proliferation rate, low mutation burden, lack of driver mutations, and frequent multifocality in the form of polyclonal tumor clusters. This sets SI-NET aside from other adult cancers and raises questions about the timeline of initiation and progression. Here, we investigated the evolutionary history of multifocal and unifocal SI-NET using whole genome sequencing data, obtaining timing information on primary tumors, metastases and key genetic events. Despite the late onset, the results indicated that major genetic alterations and the establishment of advanced metastatic tumor cell clones can often be traced back to childhood or adolescence in SINET. This was validated by re-examination of archival CT/MR scans, allowing longitudinal tracking of individual tumors up to 12 years prior. Metastases were detected at a high degree of consistency in the historical imaging data and estimated growth rates suggested several additional decades of tumor expansion. Collectively, our data support that slow growth of advanced lesions over half a century or more may precede SI-NET diagnosis in late adulthood.