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Quantitative Determination of sst2 Gene Expression in Neuroblastoma Tumor Predicts Patient Outcome¹

Clinical Biochemistry (C.C.R., M.L.B., M.P., C.O.), Andrology (M.M.), Gastroenterology (D.R., A.C.), and Endocrinology (M.S.) Units, Department of Clinical Physiopathology, and Department of Pediatrics (G.B.), University of Florence; Laboratory of Population Genetics, National Institute for Cancer Research (P.S., G.P.T.); and Department of Hematology-Oncology, Giannina Gaslini (B.D.B.), Genoa, Italy

Address all correspondence and requests for reprints to: Mario Maggi, M.D., Andrology Unit, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy. E-mail m.maggi{at}dfc.unifi.it

Neuroblastoma (NB) is the most common pediatric neuroendocrine tumor, and it is characterized by a quite variable clinical course. We previously found a great variability in the expression of somatostatin receptor type 2 (sst2) in several human NB cell lines and primary tumors. In this report we investigated whether expression of sst2 is somehow related to clinical outcome. We performed a retrospective study on 54 patients with a maximum follow-up of 100 months. The concentration of specific messenger ribonucleic acid (mRNA) for sst2 was measured by competitive RT-PCR and validated, in a small subset of samples, by quantitative imaging of gene (in situ hybridization) and protein (immunohistochemistry) expression. We found that sst2 mRNA was variably expressed in all NB tumors (range, 2.5 x 10⁵ to 8 x 10⁹ molecules/µg RNA) with a relevant reduction in the more advanced stage (P < 0.01). Analysis of Kaplan-Meier curves indicated that sst2 expression is positively related to the overall (P < 0.0001) and event-free (P < 0.0001) survival. Expression of sst2 was negatively related to tumor stage (P < 0.02) and MYCN amplification (P < 0.001), a poor prognostic factor. However, the prognostic information derived from sst2 is apparently independent from MYCN amplification, as assessed by stratifying sst2 values according to MYCN. In addition, the expression of sst2 was the only significant prognostic factor (P < 0.02) when it was included in a multivariate model containing other well known prognostic factors such as age, stage, and MYCN amplification. Hence, we propose that sst2 expression represents a new prognostic marker for NB. The main clinical value of a quantitative measure of sst2 lies in its ability to detect patients at low risk, independently from other prognostic factor, including MYCN amplification.

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