Localization of sporadic neuroendocrine tumors by gene expression analysis of their metastases

Abstract

A characteristic of human gastroenteropancreatic neuroendocrine tumors (GEP-NET) is a minute unobtrusive primary tumor which often cannot be detected by common physical examinations. It therefore remains unidentified until the tumor has spread and space-occupying metastases cause clinical symptoms leading to diagnosis. Cases in which the primary cannot be located are referred to as NET with CUP-syndrome (cancer of unknown primary syndrome). With the help of array-CGH (comparative genomic hybridization, Agilent 105K) and gene expression analysis (Agilent 44K), microdissected primaries and their metastases were compared to identify up- and down-regulated genes which can be used as a marker for tumor progression. In a next analysis step, a hierarchical clustering of 41.078 genes revealed three genes [C-type lectin domain family 13 member A (CD302), peptidylprolyl isomerase containing WD40 repeat (PPWD1) and abhydrolase domain containing 14B (ABHD14B)] which expression levels can categorize the metastases into three groups depending on the localization of their primary. Because cancer therapy is dependent on the localization of the primary, the gene expression level of these three genes are promising markers to unravel the CUP syndrome in NET.

Gene expression accurately distinguishes liver metastases of small bowel and pancreas neuroendocrine tumors

“…Other gene expression classifiers have included NETs where the primary sites were not verified by surgery. [26,27] The 92-gene classifier developed by Kerr et al relies on primary site determinations made by a central pathology adjudication committee. [26] Although they applied rigorous methods to define the primary site, inclusion of biopsy specimens without surgical confirmation of the presumed primary site introduces uncertainty into classifier development and validation.…”

“…Posorski et al reported a three-gene expression signature for distinguishing gastrointestinal NETs, but this was based on expression measured in primary and metastatic NETs from only 17 patients, including samples from gastric, colonic, and unknown primaries in addition to PNETs and SBNETs. [27] Due to the low numbers of individual tumor types and lack of additional validation specimens, the value of this gene expression signature remains unproven. The much larger study by Kerr et al determined a 92-gene expression signature to classify cancers of unknown primary based on a database of 2094 tumors of all types and validated on 790 others, including 50 neuroendocrine tumors.…”

“…Gene expression signatures differentiating NETs have been reported, but suffer from small sample sizes, inclusion of specimens from primary tumors and metastases, or lack of sufficient validation, and have yet to find widespread clinical application. [25–27] Our own group has investigated gene expression profiles of SBNETs and PNETs to identify markers that could indicate the primary site of origin. Initial studies of G protein-coupled receptor and exon expression arrays in a limited number of clinical specimens suggested that a formula based on expression of the oxytocin receptor ( OXTR ) and secretin receptor ( SCTR ) in metastases might discriminate between metastases of small bowel versus pancreatic origin.…”

Integration of 3D multimodal imaging data of a head and neck cancer and advanced feature recognition

“…This limitation can be partially overcome by laser-based tissue microdissection as it allows a more precise sample preparation for further molecular analysis [2]. However, tissue microdissection is a time consuming technique and highly sensitive downstream analyses are needed [2][3][4], due to the limited number of samples.…”

Hereditäre Syndrome neuroendokriner Tumore

“…1 zeigt beispielhaft 2 Fälle eines metastasierten Tumors des Ileums mit unterschiedlichen Genexpressionsprofilen. Der Fortschritt in den genetischen Untersuchungen wird jedoch bald neue Erkenntnisse zur Pathogenese der NET und ihrer Metastasen aufweisen, wie kürzlich exemplarisch von Posorski et al gezeigt, die nachwiesen, dass die Detektion von 3 Markergenen ausreicht, um den Ursprung der häufigsten neuroendokrinen, primären Tumorlokalisationen des Ileums und des Pankreas anhand der Genexpression zuverlässig vorherzusagen [16].…”