Endocrine Abstracts

Background

In about 2/3 of pheochromocytoma patients, no pathogenic germline variant can be identified that might be responsible for the onset of the disease. However, in many patients, we observe the repeated appearance of one or more common polymorphisms in the gene RET. Each of them has been shown to be of no significance for pheochromocytoma and multiple endocrine neoplasm type 2 development, when analysed individually. We decided to test whether the co-appearance of more than one polymorphisms might have any impact on pheochromocytoma.

Materials and methods

51 pheochromocytoma patients with excluded pathogenic variants in the genes RET, VHL, SDHB and SDHD and with no clinical symptoms that would be indicative of neurofibromatosis type 1 were included in the study. The control group consisted of 51 healthy volunteers with no clinical symptoms that would indicate adrenal diseases and with negative family history for familial syndromes caused by pheochromocytoma-predisposing genes. The status of the following polymorphisms in the gene RET was evaluated by Sanger sequencing: rs1799939 (exon 11), rs1800861 (exon 13), rs1800862 (exon 14), rs2472737 (intron 14), rs1800863 (exon 15). Statistical analyses were performed with Statistica v13, with α = 0.05 as statistical significance cutoff value.

Results

As expected, none of the polymorphisms differed between the patient and the control group when analysed independently. The groups did also not differ in the total number of the rarer variants identified nor the number of different polymorphisms present in the patient. Also, no disease-predisposing minimal haplotype has been identified by stepwise regression analysis. The pheochromocytoma group was then divided into three subgroups by unsupervised k-means clustering, based on the five analysed polymorphisms. Those three groups did not differ in means of age of disease onset, sex, localisation of the tumour, or PASS. However, significant differences were found for Ki-67 (P = 0.0294) and the hormonal status (P = 0.0306).

Conclusions

Although it is well established that common variants in RET are not responsible for the development of pheochromocytoma, their analysis might turn out useful in the prediction of a patient’s clinical appearance. In order to draw final conclusions on the possible meaning of RET polymorphisms in the course of pheochromocytoma, a bigger number of patients needs to be analysed. However, our study indicates that this direction of research might be of clinical interest.