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68Ga-DOTATOC PET/CT and somatostatin receptor (sst1–sst5) expression in normal human tissue: correlation of sst2 mRNA and SUVmax

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Abstract

Purpose

By targeting somatostatin receptors (sst) radiopeptides have been established for both diagnosis and therapy. For physiologically normal human tissues the study provides a normative database of maximum standardized uptake value (SUVmax) and sst mRNA.

Methods

A total of 120 patients were subjected to diagnostic 68Ga-DOTATOC positron emission tomography (PET)/CT (age range 19–83 years). SUVmax values were measured in physiologically normal tissues defined by normal morphology, absence of surgical intervention and absence of metastatic spread during clinical follow-up. Expression of sst subtypes (sst1–sst5) was measured independently in pooled adult normal human tissue by real-time reverse transcriptase polymerase chain reaction (RT-PCR).

Results

SUVmax revealed a region-specific pattern (e.g., mean ± SD, spleen 31.1 ± 10.9, kidney 16.9 ± 5.3, liver 12.8 ± 3.6, stomach 7.0 ± 3.1, head of pancreas 6.2 ± 2.3, small bowel 4.8 ± 1.8, thyroid 4.7 ± 2.2, bone 3.9 ± 1.3, large bowel 2.9 ± 0.8, muscle 2.1 ± 0.5, parotid gland 1.9 ± 0.6, axillary lymph node 0.8 ± 0.3 and lung 0.7 ± 0.3). SUVmax was age independent. Gender differences were evident within the thyroid (female/male: 3.7 ± 1.6/5.5 ± 2.4, p < 0.001; Mann-Whitney U test) and the pancreatic head (5.5 ± 1.9/6.9 ± 2.2, p < 0.001). The sst mRNA was widely expressed and heterogeneous, showing sst1 to be most abundant. SUVmax values exclusively correlated with sst2 expression (r = 0.846, p < 0.001; Spearman rank correlation analysis), whereas there was no correlation of SUVmax with the expression of the other four subtypes.

Conclusion

In normal human tissues 68Ga-DOTATOC imaging has been related to the expression of sst2 at the level of mRNA. The novel normative database may improve diagnostics, monitoring and therapy of sst-expressing tumours or inflammation on a molecular basis.

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Acknowledgements

We appreciate the skilful technical support of Julia Joos, Tylay Kilic, Kathrin Klemm, Dipl. Ing. Harald Lahmer, Janina Markese-Asgari, Sandra Schneider, Dr. Jochen Schmitz, Martha Senkowski, Dipl. Ing. Wilfried Sonnenschein, Dipl. Ing. Isabell Stergar, and cand. med. Can Yüksel.

Conflicts of interest

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Authors and Affiliations

  1. Department of Nuclear Medicine, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45122, Essen, Germany

    Christian Boy, Thorsten D. Poeppel, Walter Jentzen, Wolfgang Brandau & Andreas Bockisch

  2. Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, 45122, Essen, Germany

    Till A. Heusner & Gerald Antoch

  3. Department of Endocrinology and Division of Laboratory Research, University of Duisburg-Essen, 45122, Essen, Germany

    Anja Redmann-Bischofs, Nicole Unger, Klaus Mann & Stephan Petersenn

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  1. Christian Boy
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Correspondence to Christian Boy.

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Table. S1

Sequence and localization of somatostatin receptor (sst) primers as well as annealing temperature (T) used for quantitative reverse transcriptase polymerase chain reaction (RT-PCR) data of regional somatostatin receptor expression and size of PCR products (DOC 52 kb)

Table. S2

Supplementary material: Tissue and RNA samples and quantitative real-time RT-PCR. Primers and probes for all target sequences (Table 1) were designed using Primer Express software (PE Applied Biosystems, Warrington, UK). The probes were labelled with a fluorescent dye (6-carboxyfluorescein) and a quencher dye (6-carboxytetramethylrhodamine) (MWG-Biotech, Ebersberg, Germany). PCR reactions were performed using the ABI 7300 Real Time PCR system (Applied Biosystems) and the One-Step RT-PCR Master Mix Reagents Kit from Applied Biosystems. The reactions contained 100 ng RNA sample or serial dilutions of sst-specific cDNAs, the selective receptor’s subtype probe (100 nM) and specific primers. The following experimental protocol was used: reverse transcription (48°C for 30 min), AmpliTaq Gold Activation (95°C for 10 min), PCR program of two temperature cycles repeated 40 times (95°C for 15 s and 60°C for 1 min). One no-template control was included as negative control in every amplification run. The human housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an endogenous control, quantitated by parallel amplification in samples and control tissues (Control-Kit GAPDH, Applied Biosystems). Quantitation of mRNA samples was carried out by relating the PCR threshold cycles obtained from respective samples to cDNA plasmid-specific standard curves. Standard curves were received by plotting the log (calculated copy number) against the threshold cycle. The relative quantities (N) of unknown samples were calculated from the regression line according to the formula: log N = (CT – b)/m, where CT is the threshold cycle, b the y-intercept, and m the slope of the standard curve line. Sst expression levels are presented as the mRNA copy numbers per microgram of total RNA. Copy numbers were calculated as follows: molecules/ng = (1×10−9 /MW × N0 molecules/mole, where MW is the molecular weight of the specific sst receptor subtype and N0 = Avogadro’s number, 6.023 × 1023). Amplifications of respective samples were carried out in triplicate. A detection limit of 25 copies of specific RNA molecules/μg total RNA for all five sst subtypes was determined using the upper limit of cycles. Expression below that limit was considered as absent. To determine the intra-assay variability, the coefficient of variance (CV) was determined for one sample run 10 times in one experiment. CV values were calculated by standard deviation/mean × 100. The CV analysed was 12.92%. To determine the inter-assay variability, the CV was calculated for duplicate readings of one sample, which were run over seven separate occasions. The CV analysed was 16.09% (DOC 25 kb)

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Boy, C., Heusner, T.A., Poeppel, T.D. et al. 68Ga-DOTATOC PET/CT and somatostatin receptor (sst1–sst5) expression in normal human tissue: correlation of sst2 mRNA and SUVmax. Eur J Nucl Med Mol Imaging 38, 1224–1236 (2011). https://doi.org/10.1007/s00259-011-1760-x

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