Background: The NETest is a multi-gene assay comprising 51 circulating neuroendocrine tumor specific transcripts. The quotient of the 51-gene assay is based upon multi-algorithmic data analysis. Eight cancer hallmarks or omes (apoptome, epigenome, growth factor signalome, metabolome, proliferome, plurome, secretome SSTRome) represent 29 genes. The NETest is an accurate diagnostic (>90%) but its prognostic utility has not been assessed. In this study, we describe expansion of the NETest omic cluster components and demonstrate that integration amplifies NETest prognostic accuracy.
Methods: Group 1 (n=222; including stable disease (SD: n=164), progressive disease (PD: n=76) and controls (n=139)). Group 2: NET Registry #NCT02270567 (n=88, prospective samples (SD n=54 and PD n=34) with up to 24 months follow-up. We used PubMed literature review, interactomic analysis, non-parametric testing, Kaplan-Meier survival curves and Chi2 analyses to inform and define the prognostic significance of NET genomic hallmarks.
Results: 2020 Interactomic analysis: Reassessment of 47 NETest genes identified a further 6 omes: fibrosome, inflammasome, metastasome, NECome, neurome and TFome. Group 1 analysis: Twelve omes, excluding the inflammasome and apoptome, were significantly (P<0.05, 2.18.2-fold) elevated compared to controls. In the PD group, 7 omes (proliferome, NECome, epigenome, SSTRome, neurome, metastasome and fibrosome) were elevated (both expression levels and fold-change >2) versus SD. Group 2. All these 7 omes were upregulated. In PD, they were significantly more elevated (P<0.02) than SD. The septet (7) omic expression exhibited a 69% prognostic accuracy. The NETest alone was 70.5% accurate. A low NETest (<40) integrated with epigenome/metastasome levels accurately predicted PD (90%). A high NETest (>40) including the fibrosome/NECome predicted PD development within 3 months (100%). Using decision tree analysis to integrate the 4 omes (epigenome, metastasome, fibrosome and NECome) with the NETest score generated an overall prognostic accuracy of 93%.
Conclusions: Reassessment of NETest omic gene cluster analysis identified 5 additional clinically-relevant cancer hallmarks. Identification of 7 omic clusters (septet) provides a molecular pathological signature of disease progression. The integration of the quartet (epigome, fibrosome, metastasome, NECome) and the NETest score yielded a 93% accuracy in the prediction of future disease status.