Open Access Open Badges Research article

Molecular evidence for the bi-clonal origin of neuroendocrine tumor derived metastases

Beate Rinner1, Birgit Gallè1, Slave Trajanoski1, Carina Fischer1, Martina Hatz1, Theresa Maierhofer1, Gabriele Michelitsch1, Farid Moinfar2, Ingeborg Stelzer3, Roswitha Pfragner4 and Christian Guelly1*

Author Affiliations

1 Center for Medical Research, Medical University of Graz, Stiftingtalstraße 24, Graz, 8010, Austria

2 Institute of Pathology; Medical University of Graz, Auenbruggerplatz 26, Graz, 8036, Austria

3 Clinical Institute of Medical and Chemical Laboratory Diagnostics; Medical University of Graz, Auenbruggerplatz 15, Graz, 8036, Austria

4 Institute of Pathophysiology and Immunology; Medical University of Graz, Heinrichstraße 31a, Graz, 8010, Austria

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BMC Genomics 2012, 13:594  doi:10.1186/1471-2164-13-594

Published: 5 November 2012



Reports on common mutations in neuroendocrine tumors (NET) are rare and clonality of NET metastases has not been investigated in this tumor entity yet. We selected one NET and the corresponding lymph node and liver metastases as well as the derivative cell lines to screen for somatic mutations in the primary NET and to track the fate of genetic changes during metastasis and in vitro progression.


Applying microarray based sequence capture resequencing including 4,935 Exons from of 203 cancer-associated genes and high-resolution copy number and genotype analysis identified multiple somatic mutations in the primary NET, affecting BRCA2, CTNNB1, ERCC5, HNF1A, KIT, MLL, RB1, ROS1, SMAD4, and TP53. All mutations were confirmed in the patients’ lymph node and liver metastasis tissue as well as early cell line passages. In contrast to the tumor derived cell line, higher passages of the metastases derived cell lines lacked somatic mutations and chromosomal alterations, while expression of the classical NET marker serotonin was maintained.


Our study reveals that both metastases have evolved from the same pair of genetically differing NET cell clones. In both metastases, the in vivo dominating “mutant” tumor cell clone has undergone negative selection in vitro being replaced by the “non-mutant” tumor cell population. This is the first report of a bi-clonal origin of NET derived metastases, indicating selective advantage of interclonal cooperation during metastasis. In addition, this study underscores the importance to monitor cell line integrity using high-resolution genome analysis tools.

Neuroendocrine tumors; Clonality of metastases; Somatic mutations