Abstract

Objective

Dopamine agonists and somatostatin analogs are commonly used in prolactinomas and somatotropinomas. Response to these therapies is heterogeneous. Whether resistance is linked to specific tumor subtypes or to shared mechanisms of resistance is not known. The aim was to explore distinct molecular subtypes of prolactinomas and somatotropinomas and their association with response to treatment.

Methods

The transcriptome of 46 prolactinomas and 58 somatotropinomas was analyzed. Unsupervised classifications were generated and tested for association with histological and clinical data, including response to treatment.

Results

Four subtypes of prolactinomas were identified, with variable sensitivity to dopamine agonists (P < 10−4). Sensitive tumors accumulated in the subgroup with the highest DRD2 expression, while resistant tumors accumulated in the 3 remaining ones, enriched in genes related to cAMP metabolism, to mitochondrial and ribosomal activity, and to immunity, respectively. Sparsely granulated somatotropinomas (N = 16) presented a separated molecular entity, mixing tumors resistant and sensitive to somatostatin analogs. The remaining somatotropinomas were classified into 5 subtypes, with variable sensitivity to somatostatin analogs (P < 10−4). Sensitive tumors accumulated in 3 subgroups, characterized by GNAS somatic mutation, PIT1 and SF1 coexpression, and the stem-cell marker SOX2 expression, respectively. Resistant tumors accumulated in the 2 remaining ones, enriched in genes related to cell cycle and to mesenchymal differentiation, respectively. Somatostatin receptor 2 (SSTR2) expression was associated with response to somatostatin analogs in sparsely granulated somatotropinomas (P = .022), but not in other somatotropinomas (P = .923).

Conclusions

Prolactinomas and somatotropinomas were classified into distinct transcriptomic groups. Resistance to medical therapies was linked to distinct tumor subtypes, suggesting distinct mechanisms of resistance.