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

Abstract

312 Background: Data on intratumoral heterogeneity of small intestine neuroendocrine tumors (SI-NETs) and related liver metastasis is limited. Further investigation might have impact on development of targeted therapy regimens. The aim of the study was to characterize genetic heterogeneity of 5 patients suffering from SI-NETs. Methods: Formalin-fixed, paraffin-embedded tissues samples of primary and metastatic lesion as well as benign liver of five patients with synchronously metastasized, well or moderately 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. Alterations that occurred only in one tumor site were defined as private, whereas mutations present in both metastasis and primary lesion were regarded as common. Results: 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 are large overlap of common methylated CpG sites. Conclusions: SI-NET primary and metastatic lesions show a highly varying degree of intratumoral heterogeneity. Driver events might not be detectable with exome analysis.