Genetic heterogeneity of primary lesion and metastasis in small intestine neuroendocrine tumors.

February 28, 2018

Walter D1,2, Harter PN3,4, Battke F5, Winkelmann R6, Schneider M6, Holzer K7,8, Koch C9,4,10, Bojunga J9,4,10, Zeuzem S9,4,10, Hansmann ML6, Peveling-Oberhag J9,6,11, Waidmann O9,4,10.


Data on intratumoral heterogeneity of small intestine neuroendocrine tumors (SI-NETs) and related liver metastasis are limited. The aim of this study was to characterize genetic heterogeneity of 5 patients with SI-NETs. Therefore, formalin-fixed, paraffin-embedded tissue samples of primary and metastatic lesions as well as benign liver of five patients with synchronously metastasized, well differentiated SI-NETs were analyzed with whole exome sequencing. For one patient, chip based 850k whole DNA methylome analysis was performed of primary and metastatic tumor tissue as well as control tissue. Thereby, 156 single nucleotide variants (SNVs) in 150 genes were identified and amount of mutations per sample ranged from 9-34 (mean 22). The degree of common (0-94%) and private mutations per sample was strongly varying (6-100%). In all patients, copy number variations (CNV) were found and the degree of intratumoral heterogeneity of CNVs corresponded to SNV analysis. DNA methylation analysis of a patient without common SNVs revealed a large overlap of common methylated CpG sites. In conclusion, SI-NET primary and metastatic lesions show a highly varying degree of intratumoral heterogeneity. Driver events might not be detectable with exome analysis only, and further comprehensive studies including whole genome and epigenetic analyses are warranted.