Prevalence and clinical correlations of SF3B1 variants in lactotroph tumours.

OBJECTIVE: A somatic mutational hotspot in the SF3B1 gene was reported in lactotroph tumours. The aim of our study was to examine the prevalence of driver SF3B1 variants in a multicentre independent cohort of patients with lactotroph tumours and correlate with clinical data. DESIGN AND METHODS: This was a retrospective, multicentre study involving 282 patients with lactotroph tumours (including 6 metastatic lactotroph tumours) from 8 European centres. We screened SF3B1 exon 14 hotspot for somatic variants using Sanger sequencing and correlated with clinicopathological data. RESULTS: We detected SF3B1 variants in seven patients with lactotroph tumours: c.1874G > A (p.Arg625His) (n = 4, 3 of which metastatic) and a previously undescribed in pituitary tumours variant c.1873C > T (p.Arg625Cys) (n = 3 aggressive pituitary tumours). In two metastatic lactotroph tumours with tissue available, the variant was detected in both primary tumour and metastasis. The overall prevalence of likely pathogenic SF3B1 variants in lactotroph tumours was 2.5%, but when we considered only metastatic cases, it reached the 50%. SF3B1 variants correlated with significantly larger tumour size; higher Ki67 proliferation index; multiple treatments, including radiotherapy and chemotherapy; increased disease-specific death; and shorter postoperative survival. CONCLUSIONS: SF3B1 variants are uncommon in lactotroph tumours but may be frequent in metastatic lactotroph tumours. When present, they associate with aggressive tumour behaviour and worse clinical outcome.

Innovative tumour targeting therapeutics in Cushing's disease.

Cushing's disease (CD) is the most frequent form of endogenous hypercortisolism. Management of this devastating condition relies on pituitary surgery, while effective pharmacological treatment mainly focus on periphery targeting pharmaceuticals. Approved tumour-targeting drugs are limited to dopamine agonists and somatostatin analogues with frequently low efficacy and substantial side effects. Discoveries on the genetics and pathophysiology of corticotroph tumorigenesis brought forward new potential pharmacological targets. Compounds such as retinoic acid although promising in preclinical studies, are not as efficient in the clinic. Others, such as, silibinin, gefitinib and roscovitine are effective in preclinical models, but their efficacy and safety still needs to be determined in patients with CD.