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

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 supports 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.

Whole genome sequencing reveals the independent clonal origin of multifocal ileal neuroendocrine tumors

“…Chr18 LOH was present in 57% of primary tumors, representing the most recurrent somatic alteration in multifocal ileal NETs, along with amplifications of chromosomes 4, 7, 14, and 20 in 9-13% of tumors. These results are consistent with previous high-throughput sequencing studies of both uni-and multifocal ileal NETs [7,8,10,19,20]. In addition to the previous literature, we observed copyneutral LOH of chr9 in 8% of tumors.…”

“…Intriguingly, we show that multiple metastases in the same patient can originate from one or several primary tumors. Our results are corroborated by recent findings of Elias et al [20] and have an important clinical implication, supporting the concept that identification of all multifocal primary tumors by careful palpation of the entire jejunum and ileum is essential at the time of surgery [48]. We could not detect common somatic alterations among the metastasized primary tumors in our data.…”

“…Only two significant genes, CDKN1B and TNRC6B, were mutated across the studies. A closer look at previous high-throughput sequencing data of SI-NETs revealed three somatic nonsense mutations and two frameshift deletions in TNRC6B among 195 sequenced sample pairs, as well as ten deletions of chr22 [7,8,16,20]. Together with our data, TNRC6B is affected in approximately 8% of SI-NETs and metastases.…”

“…The molecular mechanisms underlying these multifocal lesions are not yet understood. Recently, two high-throughput sequencing studies of multifocal SI-NETs by us and others have suggested these tumors to develop independently [19,20]. Our high-throughput sequencing-based copy-number profiling of 40 multifocal ileal NETs revealed distinct patterns of chr18 allelic loss in individual tumors from the same patient, suggesting these tumors originate independently and that no specific germline allele on chr18 is targeted by somatic LOH [19].…”

“…Our high-throughput sequencing-based copy-number profiling of 40 multifocal ileal NETs revealed distinct patterns of chr18 allelic loss in individual tumors from the same patient, suggesting these tumors originate independently and that no specific germline allele on chr18 is targeted by somatic LOH [19]. Additionally, Elias et al performed WGS of 61 tumor samples (42 primary tumors and 19 metastases) from 11 patients with multifocal SI-NET to study the evolutionary trajectory of multifocal SI-NETs within single patients [20]. They observed lack of shared somatic variation among the primary tumors within the patients, supporting the independent clonal origin of multifocal SI-NETs.…”