Succinate dehydrogenase and MYC-associated factor X mutations in pituitary neuroendocrine tumours
Paul Benjamin Loughrey, Federico Roncaroli, Estelle Healy, Philip Weir, Basetti Madhu, Ruth Casey, Steven Hunter, Márta Korbonits
Abstract
Pituitary neuroendocrine tumours (PitNETs) associated with paragangliomas or phaeochromocytomas are rare. SDHx variants are estimated to be associated with 0.3-1.8% of PitNETs. Only a few case reports have documented the association with MAX variants. Prolactinomas are the most common PitNETs occurring in patients with SDHx variants, followed by somatotrophinomas, clinically non-functioning tumours and corticotrophinomas. One pituitary carcinoma has been described. SDHC, SDHB and SDHA mutations are inherited in an autosomal dominant fashion and tumorigenesis seems to adhere to Knudson's two-hit hypothesis. SDHD and SDHAF2 mutations most commonly have paternal inheritance. Immunohistochemistry for SDHB or MAX and loss of heterozygosity analysis can support the assessment of pathogenicity of the variants. Metabolomics is promising in the diagnosis of SDHx-related disease. Future research should aim to further clarify the role of SDHx and MAX variants or other genes in the molecular pathogenesis of PitNETs, including pseudohypoxic and kinase signalling pathways along with elucidating epigenetic mechanisms to predict tumour behaviour.