Background: In the past few years, new genes involved with familial predisposition to pituitary tumour development have been recognised, including AIP and SDHx. These factors are likely to underestimate the occurrence of familial pituitary tumour predisposition, commonly thought to account for 5% of all pituitary tumours. Furthermore, the clinical management of aggressive pituitary tumours is challenging, particularly when tumours exhibit resistance to standard hormonal agents and temozolomide. While next generation sequencing panels have aided in the stratification of genetic aberrations in those who are afflicted with better studied cancers such as those of the breast, lung and melanoma and aided in defining new therapeutic options, those with poorly studied and/or rare tumours such as those of the pituitary, particularly in children, have yet to benefit from these new technologies.
Objective: We have developed a pan-cancer genetic screening panel with a pituitary bias, with which we aim to demonstrate the clinical utility for stratifying the genomic landscape of disparate cancer types, thereby improving treatment options and prognoses through discovering new or repurposing existing therapeutics.
Method: Our custom next generation sequencing (NGS) panel (Roche/Nimblegen) contains the eight known familial pituitary tumour genes, plus 25 genes implicated in embryonic pituitary development and a further 270+ genes that have been implicated in various cancers and cancer-related pathways (~0.9 Mb target sequence). Subjects recruited for testing include those with a sporadic pituitary tumour, or patients with a family history of pituitary tumours or other endocrine neoplasia. DNA extracted from blood is interrogated using our >300-gene panel (Illumina HiSDefault 2500 sequencing). Raw sequencing data was analysed by a custom bioinformatic pipeline, with mutations being functionally assessed in silico and in vitro. In addition, RNA sequencing was applied to blood and tumour of a patient with a highly aggressive ACTH-secreting pituitary tumour, who had failed all standard treatments including temozolomide.
Results: We detected three patients with germline mutations in AIP (p.F269F, p.A299V, p.R106C), verified by Sanger sequencing. In addition our patient with an aggressive pituitary tumour indicated suitability for trial of Bevacizumab, an inhibitor of VEGF-A.
Conclusion: Our cancer panel is novel in its applicability to poorly studied cancer types and is designed to uncover new, causative genes as well as potentially identify alternative treatment options. Such a panel could greatly benefit children who are afflicted with rare tumour types who have not yet benefited from cutting-edge technology.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology